Diabetes mellitus is a disorder that develops when the cells of the body do not receive enough insulin. This hormone is produced by the pancreas; it normally enables body cells to take in glucose from the blood to generate energy, and enables the liver and fat cells to take in glucose for storage. A lack of insulin in the cells may occur because the pancreas produces too little, or none at all; alternatively, it may occur because the tissues of the body are resistant to the hormone's effects.
Types, cause and incidence
There are two main types of diabetes mellitus, both of which tend to run in families.
Type 1 (insulin-dependent) diabetes usually develops suddenly in childhood or adolescence. This type of diabetes is an autoimmune disorder in which the immune system destroys insulin-secreting cells in the pancreas and insulin production ceases. Affected people may be genetically predisposed to developing the condition; the disease process may be triggered by viral infection. They must have insulin injections or they may fall into a coma and die.
Type 2 (non-insulin-dependent) diabetes tends to develop gradually, mainly in people over the age of 40. This type is becoming more common in younger people, however, and is probably linked to dieting. Although insulin is still produced, there is not enough to meet the body’s needs because the tissues become relatively resistant to its effects. Obesity and inheritance are possible contributory factors; many people who develop Type 2 diabetes are overweight, and affected people often have close relatives with the condition.
Diabetes mellitus affects more than 347 million people worldwide (WHO 2013). Type 2 diabetes is by far the more common form of the disease. About 1 in 50 people in the UK has type 2 diabetes. It is three to four times more common in black people, and seven times more common in Asians. It also becomes more common with increasing age.
Lack of insulin causes high levels of glucose to remain in the blood. This, in turn, results in a high level of glucose in the urine. This condition, termed glycosuria (glucose present in the urine - not normally the case), causes the passage of large quantities of urine, excessive thirst, and urinary tract infections. Lack of glucose in the cells causes weight loss, hunger, and fatigue, and leads to chemical imbalances.
In Type 1 diabetes, symptoms such as thirst (polydipsia), weight loss, and excessive urination (polyuria) usually develop rapidly over a few weeks. If it is not promptly diagnosed and treated at this stage, it may lead to diabetic ketoacidosis, which is a serious and potentially fatal condition.
Type 2 diabetes may be present for months or even years while causing few noticeable symptoms. It may only be diagnosed when a complication (see below), such as poor vision, is detected during a medical check-up.
Some complications of diabetes mellitus result from damage to capillaries (tiny blood vessels) throughout the body. These conditions include retinopathy (damage to the retina, which is the lightsensitive part of the eye) and diabetic nephropathy (kidney damage). Damage to the blood vessels supplying nerves causes diabetic neuropathy (damage to nerve fibres); this may first appear in the fingers and toes, then spread up the limbs. The loss of sensation, and poor circulation, may result in ulcers on the feet and legs. Other problems include dizziness on standing and, in men, erectile dysfunction (impotence). People with diabetes have a greater risk of developing atherosclerosis (accumulation of fatty deposits on the lining of the arteries), hypertension (high blood pressure), other cardiovascular disorders, and diabetic cataract (opacity in the lens of the eye).
If diabetes mellitus is suspected, a urine sample will be taken and tested for the presence of glucose. The diagnosis is confirmed by a blood test to detect abnormally high levels of glucose in the blood. If the results of this test are unclear, a glucose tolerance test may be done. The person is asked to fast for several hours, and then is given glucose; the blood and the urine are tested 30-minute intervals to show how efficiently the body is utilizing the glucose. Tests may also be carried out to detect and assess damage to organs such as the eyes, kidneys, and heart.
Treatment aims to keep blood glucose levels as normal as possible. Dietary control is an essential element. The ideal diet for a person with diabetes resembles the sort of healthy eating plan recommended for everyone. If the person is over-weight, and particularly if he or she has Type 2 diabetes, weight loss can be achieved by a reduced-calorie diet. Also, regular exercise and treatment with anti-diabetic drugs may be required.
In addition to general treatment, all people with Type 1 diabetes need to have regular injections of insulin. The injections are usually self-administered two, three, or four times a day. The insulin doses need to be matched to activity levels and food intake. If the glucose/insulin balance is not maintained, hyperglycaemia (too much glucose in the blood) or hypoglycaemia (too little glucose in the blood) may develop. Careful monitoring of blood glucose levels is also an essential part of self-treatment. Pancreas transplants have been tried as a possible cure for the condition, but with little success.
Research is being done on a possible treatment involving transplantation of clusters of insulin-producing cells. Treatment of type 2 diabetes usually consists of dietary measures, weight reduction, exercise, and anti-diabetic drugs, often hypoglycaemic drugs such as sulphonylureas. Some people eventually need insulin injections. In general, careful control of blood glucose levels reduces the risk of complications or, if such problems have already developed, slow their progression. People with diabetes should have regular medical check-ups so that any complications can be detected as early as possible. Additional tests, such as measurement of glycosylated haemoglobin (which shows blood glucose levels over the previous three months) and urine tests to detect proteinuria, can improve medical control and aid early detection of problems.
With modern treatment and efficient self-monitoring, people with diabetes mellitus can usually live a normal life; however, the disease is irreversible and life expectancy is reduced.
More on symptoms
As the level of glucose in the blood rises, the volume of urine required to carry it out of the body is increased, causing not only a frequent need to urinate (polyuria) but also constant thirst. The high levels of sugar in the blood and urine impair the body’s ability to fight infection, leading to urinary tract infections (such as cystitis and pyelonephritis), vaginal yeast infections (candidiasis), and recurrent skin infections. Because the body’s cells are starved of glucose, the sufferer feels weak and fatigued.
The body's cells are able to obtain some energy from the breakdown of stored fat, resulting in weight loss. The chemical processes involved in this breakdown of fat are, however, defective, especially in insulin dependent diabetics. They lead to the production of acids and substances known as ketones, which can cause coma and sometimes death. Other possible symptoms of undiagnosed diabetes include blurred vision, boils, increased appetite, and tingling and numbness in the hands and the feet.
Symptoms will develop in every untreated person who has insulin dependent (Type 1) diabetes, but will appear in only one third of those who have the noninsulindependent form (Type 2). There are many people with Type 2 diabetes who are unaware of it. The disease is often diagnosed only after complications of the diabetes have been detected.
- Diabetes mellitus in detail - non-technical
- Diabetes mellitus type 1: diagnosis and management in primary care - technical
- Diabetes in pregnancy - technical
Diabetes mellitus in great detail - technical
- Diagnosis of diabetes
- Metabolic basis of diabetes
- Types and classification of diabetes mellitus
- Monogenic diabetes: maturity-onset diabetes of the young (MODY) and neonatal diabetes
- Management of diabetes Intercurrent events in diabetes and their management
- Acute metabolic complications of diabetes and their treatment
- Chronic complications of diabetes
- Further reading
Diabetes mellitus can be defined as a state of chronic hyperglycaemia sufficient to cause long-term damage to specific tissues, notably the retina, kidney, nerves, and arteries. It is due to inadequate production of insulin and/or ‘resistance’ to the glucose-lowering and other actions of insulin, and is a significant and growing threat to global health, probably affecting 250 million people worldwide.
Definitions—normal fasting blood glucose concentration is in the range 3.5 to 5.5 mmol/litre, and even large carbohydrate loads do not raise the concentration above 8 mmol/litre. Widely accepted diagnostic criteria for diabetes and other hyperglycaemic states are (1) diabetes mellitus—fasting glucose more than 7.0 mmol/litre (126 mg/dl) and/or a value exceeding 11.1 mmol/litre (199 mg/dl), either at 2 h during a 75-g oral glucose tolerance test or in a random sample; (2) impaired glucose tolerance—2-h oral glucose tolerance test value between 7.8 and 11.1 mmol/litre (140–199 mg/dl); (3) impaired fasting glucose—fasting glucose 5.6 to 6.9 mmol/litre (100–125 mg/dl). The role of HbA1C as a diagnostic test is currently under review.
Impaired glucose tolerance is a not a stable state: within 5 years, about 25% of subjects deteriorate into type 2 diabetes, while a further 25% revert to normoglycaemia.
Type 1 diabetes
This condition, previously referred to as ‘juvenile-onset’ or ‘insulin-dependent’ diabetes, most commonly develops in childhood, with highest incidence in northern European countries, and accounts for 5 to 15% of all cases of diabetes.
Aetiology—Type 1 diabetes is caused by an autoimmune, predominantly T-cell-mediated process that selectively destroys the pancreatic β cells. Genetic factors explain 30 to 40% of total susceptibility: at least 10 loci are involved, with the HLA class II locus IDDM2 having by far the greatest effect. Environmental factors that have been implicated include viral infection (particularly coxsackie B), bovine serum albumin from cow’s milk (by immunological cross-reactivity) and other toxins. Notable β-cell selective autoantibodies that are commonly found are those that recognize GAD65 (a heat shock protein), IA-2 (a protein tyrosine phosphatase-like molecule), ZnT8 (a zinc transporter molecule) and insulin itself, but these are clearly not the immediate cause of the disease. Several years of progressive autoimmune damage usually precede the clinical onset of diabetes.
Pathogenesis—in untreated type 1 diabetes, insulin concentrations are generally 10 to 50% of nondiabetic levels in the face of hyperglycaemia which would normally greatly increase insulin secretion. Such severe deficiency cannot sustain the normal anabolic effects of insulin and leads to runaway catabolism in carbohydrate, fat, and protein metabolism. A similar clinical picture of insulin dependence can be caused by other forms of severe pancreatic damage.
Clinical features—classical presentation of untreated or poorly controlled type 1 diabetes is with onset over days or a few weeks of polyuria (caused by osmotic diuresis due to hyperglycaemia), thirst, weight loss, and general tiredness/malaise. Other features can include blurred vision (due to hyperglycaemia-related refractive changes in the lens), infection (particularly genital candidiasis), and diabetic ketoacidosis. Chronic diabetic complications are not seen at presentation.
Type 2 diabetes
Type 2 diabetes (previously referred to as ‘non-insulin-dependent’ or ‘maturity-onset’) is a heterogeneous condition, diagnosed empirically by the absence of features suggesting type 1 diabetes. It is most commonly diagnosed in those >40 years of age, with peak incidence at 60 to 65 years, and it accounts for 85 to 90% of diabetes worldwide, but with striking geographical variation (prevalence <1% in rural China, 50% in Pima Indians of New Mexico).
Aetiology—type 2 diabetes is due to the combination of insulin resistance and β-cell failure. Genetic factors explain 60 to 90% of total susceptibility, with a polygenic pattern reflecting the inheritance of a critical mass of minor diabetogenic polymorphisms in genes that influence insulin secretion, insulin resistance, pancreatic development and obesity. An important specific risk factor for type 2 diabetes, which aggravates insulin resistance, is obesity—particularly if this develops after the early twenties, and especially around the waist. The mechanism of β-cell failure in human type 2 diabetes is not known.
Clinical features—in type 2 diabetes significant hyperglycaemia may have been present for several years at the time of diagnosis, hence cases are often discovered by screening or at routine health checks. Many cases present with classical symptoms of osmotic diuresis, blurred vision and genital candidiasis. The hyperosmolar nonketotic state can present with confusion or coma, but diabetic ketoacidosis is rare. Chronic diabetic complications may be a presenting feature.
Monogenic and other types of diabetes
Maturity-onset diabetes of the young (MODY)—most often caused by mutations in the genes for glucokinase (MODY2) and HNF-1α (MODY3). This diagnosis should be considered if there is a family history of young-onset diabetes in more than one generation, with at least one family member diagnosed under the age of 25; affected members are not markedly obese; there is no evidence of insulin resistance; fasting C-peptide is detectable and within the normal range; islet cell or anti-GAD autoantibodies are absent; other associated features are present.
Other types of diabetes include those related to pancreatic disease (chronic pancreatitis, cystic fibrosis, haemochromatosis) and gestational diabetes.
Management of diabetes
General aspects—management requires tackling cardiovascular risk factors and obesity in addition to hyperglycaemia. Important issues include (1) dietary modification—reducing total energy intake in patients who are overweight (body mas index >28 kg/m2), improving dietary composition (fat <30% total energy intake, with saturated animal fat <10%; carbohydrates—preferably pulses, root/leaf vegetables and fruit—>55% total energy intake; sodium <6 g/day); (2) increasing physical activity; (3) smoking cessation; and in some patients (4) antiobesity drugs and/or bariatric surgery.
Glucose-lowering drugs—these include (1) insulin—soluble (regular, or short-acting) insulin injected subcutaneously begins to lower glucose within 30 min, has a peak effect between 1 and 2 h and lasts 3 to 5 h; long-acting preparations (e.g. isophane and lente insulins) are used to cover basal insulin requirements; (2) insulin analogues—have improved physicochemical characteristics for subcutaneous absorption and can be fast acting, e.g. insulin lispro and insulin aspart, or long acting, e.g. insulin glargine (Lantus) and insulin detemir (Levemir); (3) oral hypoglycaemic agents—(a) sulphonylureas and meglitinides—insulin secretagogues; (b) metformin—a biguanide that acts primarily by inhibiting gluconeogenesis in the liver; (c) thiazolidinediones—act to improve insulin sensitivity; (d) α-glucosidase inhibitors—partly block digestion of complex carbohydrates and so damp post-prandial glycaemic rises, but are of low efficacy and poorly tolerated; (e) incretin mimetics—augment insulin secretion.
Type 1 diabetes—patients must be given insulin immediately and for life. Standard treatment involves giving a short-acting insulin 20 to 30 min before eating or a fast-acting insulin immediately before eating, and a twice (sometimes once) daily dose of a long-acting insulin. Common practice is to commence with low dosages of long-acting insulin, e.g. 8–12 U in the morning and 4–6 U at night, with short/fast-acting insulin then added to cover excessive prandial hyperglycaemia. Premixed insulins (e.g. 30% short-acting with 70% long-acting) can be given twice daily and are more convenient than giving short- and long-acting insulins separately, but they lack flexibility. Administration is usually by conventional syringes or pen injection devices, but pumps can be used to administer continuous subcutaneous infusions of insulin.
Type 2 diabetes—the first-line oral hypoglycaemic agent for so-called ‘dietary failure’ is metformin, with a (usually) sulphonylurea or (sometimes) thiazolidinedione added as second-line treatment. A once-daily dose of a long-acting insulin can be combined effectively with metformin. Insulin therapy can range from once- or twice-daily long-acting insulin in subjects with residual insulin, to the more intensified basal and prandial regimens used in type 1 diabetes (>200 U/day may be required in very obese, insulin-resistant patients).
Treatment targets for blood glucose—these have been selected to reduce the risk of chronic diabetic complications. Avoiding acute episodes of hyper- and hypoglycaemia is also important. Management should aim for fasting blood glucose below 5.5 mmol/litre, postprandial peak glucose below 7.5 mmol/litre, and HbA1c 6.5% or less (‘good’ control defined as below 7%, ‘poor’ control as over 8%).
Multidisciplinary care—diabetes is best managed by the combined efforts of a well-trained primary care team and a team of specialists with complementary and overlapping skills: physician, specialist diabetes nurse, dietitian, and chiropodist. Patients require education about diabetes, with key elements including (1) causes of hyperglycaemia and diabetic symptoms; (2) own treatment—diet and lifestyle; drawing up and injecting insulin; oral agents; recognizing and treating hypoglycaemia ‘hypos’; (3) self-monitoring technique—targets and danger levels; how to respond to poor control; (4) ‘sick-day’ rules—monitoring during intercurrent illness; how to adjust own treatment; when and how to call for help (never stop taking your insulin; check your blood glucose every 4 h; test your urine for ketones; call for help if you start vomiting, have glucose over 15 mmol/litre that does not come down after insulin, get hypos, get ketones in the urine, are worried, and don’t know what to do).
Acute metabolic complications of diabetes
Diabetic ketoacidosis—uncontrolled hyperglycaemia with hyperketonaemia severe enough to cause metabolic acidosis. Precipitating factors include new presentation of type 1 diabetes, omission or underdosing of insulin by patients known to have type 1 diabetes, and intercurrent illness (compounded by failure to monitor blood glucose and take appropriate action). Usual presentation is with classical hyperglycaemic symptoms together with acidotic (Kussmaul) breathing and ketotic foetor, evidence of dehydration and hypovolaemia, and signs of any precipitating condition. Drowsiness and coma are late features. Diagnosis is confirmed with a finger-prick blood glucose measurement and urinalysis for ketones: other investigations should include a biochemical screen, full sepsis screen, arterial blood gas analysis and ECG. Management requires (1) fluid replacement—usually with 0.9% saline (typically 1–2 litres in 2 h, then 1 litre in 4 h, then 4 litres in next 24 h); (2) potassium replacement—typically 20 mmol of KCl to each litre of intravenous fluid if K+ is normal (3.5–5.0 mmol/litre), but adjusted in response to frequent monitoring; (3) intravenous insulin—initially at a rate of 6 U/h, then titrated down according to a sliding scale; (4) treatment, when possible, of any precipitating condition. Intravenous fluids and insulin can be discontinued when the patient can eat and drink, and they can be restarted on their usual insulin regimen (or a typical maintenance regimen can be introduced).
Hyperosmolar non-ketotic state (HONK)—is distinguished from diabetic ketoacidosis by the absence (because circulating insulin levels are high enough to suppress lipolysis and ketogenesis) of marked hyperketonaemia and metabolic acidosis. Presentation is typically with classical hyperglycaemic symptoms; confusion, drowsiness and coma are commoner than in diabetic ketoacidosis. Typical biochemical features include severe hyperglycaemia (>30 mmol/litre) and hypernatraemia (sodium often >155 mmol/litre). Management is largely as for diabetic ketoacidosis, excepting that (1) 0.45% saline is often given if plasma sodium is over 150 mmol/litre or osmolality over 350 mosmol/kg; (2) intravenous insulin infusion at low doses rapidly controls hyperglycaemia in most cases; (3) the risk of thrombotic events is particularly high, hence prophylactic doses of low molecular weight heparin should be given.
Hypoglycaemia—an inevitable side-effect of antidiabetic drugs that raise circulating insulin levels. Typical features include (1) autonomic symptoms—pallor, sweating, tremor, and tachycardia, and (2) symptoms of neuroglycopenia—commonly drowsiness, confusion, incoordination, and dysarthria, but also automatic or disinhibited behaviour and focal neurological deficits. Diagnosis is confirmed with a finger-prick blood glucose measurement below 3.5 mmol/litre in an appropriate clinical context. Treatment is with (1) oral glucose or sucrose or other carbohydrate—if the patient can swallow safely; or (2) intravenous glucose (15–20 g as 10% or 50% solution) or intramuscular glucagon (1 mg)—if the patient is not able to swallow safely.
Chronic complications of diabetes
Long-term tissue damage is the major burden of diabetes, the greatest source of fear for diabetic people, and the most expensive item in the diabetes health care budget. Microvascular complications—retinopathy, neuropathy, and nephropathy—are specific to diabetes and reflect damage inflicted on the microcirculation throughout the body. Macrovascular disease is atherosclerosis, which behaves more aggressively than in nondiabetic people, and causes typical coronary heart disease, stroke and peripheral arterial disease.
Pathogenesis—possible mechanisms for diabetic complications include glycation of proteins and macromolecules, overactivity of the polyol pathway, activation of protein kinase C and abnormal microvascular blood flow.
Diabetic eye disease—is the commonest cause of blindness in people of working age in most Westernized countries. Stages of diabetic retinopathy are (1) background—microaneurysms, hard exudates, haemorrhages (flame, dot, blot), cotton wool spots (<5); (2) preproliferative—rapid increase in microaneurysms, intraretinal microvascular abnormalities, multiple deep haemorrhages, cotton wool spots (>5), venous beading/loops/duplication; (3) proliferative—new vessels on the disc or elsewhere, fibrous proliferation on the disc or elsewhere, preretinal or vitreous haemorrhages; (4) advanced eye disease—retinal detachment, retinal tears, rubeosis iridis, neovascular glaucoma. Disease of the macula (maculopathy), serious enough to affect central vision, can accompany any stage of diabetic retinopathy including background, and may be present in newly diagnosed type 2 patients. Management requires (1) general preventive measures—tight glycaemic control, control of hypertension, stopping smoking, regular (annual) eye screening; and (2) specific treatments—laser photocoagulation can preserve useful vision in many cases of proliferative retinopathy and maculopathy.
Diabetic neuropathies—recognized clinically distinct syndromes include (1) diffuse symmetrical polyneuropathy—classically a distal ‘glove and stocking’ peripheral polyneuropathy that affects all sizes of sensory and motor fibres; (2) autonomic neuropathy—manifest as sexual difficulties (erectile failure, ejaculatory failure), postural hypotension, disturbed gastrointestinal motility, abnormal sweating, neuropathic bladder, abnormal blood flow, sudden unexplained death; (3) acute mononeuropathy; (4) diabetic amyotrophy; (5) cranial and other nerve palsies. Management is difficult: specific treatments have so far been disappointing. Numb feet are at greatly increased risk of ulceration and require sensible shoes and good foot care. Poor glycaemic control should be corrected. Pain may be difficult to treat: simple analgesics are generally ineffective; tricyclic drugs can suppress neurogenic pain; anticonvulsants may help. Autonomic neuropathic symptoms may be treated as follows: (1) erectile failure with oral phosphodiesterase type 5 inhibitors (e.g. sildenafil); (2) postural hypotension with compression stockings, fludrocortisone and/or midodrine; (3) gastroparesis with erythromycin, metoclopramide or domperidone; (4) excessive sweating with oral clonidine or topical glycopyrrolate cream; (5) neuropathic bladder with regular bladder training, but intermittent self-catheterization may be needed.
Diabetic nephropathy is the commonest cause of endstage renal disease in the developed world, causing 44% of incident cases requiring renal replacement therapy in the United States of America and 24% in the United Kingdom in 2008 Most of these have type 2 diabetes, and in some countries the proportion of patients with endstage renal disease who have type 1 diabetes is falling.
Aetiology and pathology—causation is related to glycaemic control (e.g. glycation of proteins, oxidative stress, sorbitol overproduction, alteration in growth factors), hypertension, genetic factors, and dietary and other environmental factors. Pathological hallmarks are thickening of the glomerular basement membrane and mesangial expansion, with or without nodule formation, secondary to an accumulation of extracellular matrix.
Staging and natural history—is classically described in terms of urinary albumin excretion rate (UAER): (1) normoalbuminuria—UAER less than 20 µg/min, albumin/creatinine ratio (ACR) less than 2.5 mg/mmol (men), less than 3.5 mg/mmol (women); (2) microalbuminuria (also called incipient nephropathy)—UAER 20 to 200 µg/min, ACR 2.5 to 30 mg/mmol (men), 3.5 to 30 mg/mmol (women); and (3) clinical proteinuria (sometimes called clinical nephropathy or overt nephropathy)—UAER greater than 200 µg/min, ACR greater than 30 mg/mmol. This staging does not map well onto that for chronic kidney disease based upon estimated glomerular filtration rate (eGFR) (see Chapters 21.4 and 21.6).
Clinical features—most patients (>60%) will have a normal UAER throughout their diabetic life, but 1 to 2% of the remainder develop persistent microalbuminuria each year. Once UAER exceeds 200 µg/min, there tends to be a relentless increase in proteinuria, occasionally into the nephrotic range, and GFR declines progressively at a rate that largely depends on blood pressure control.
Prevention—in both type 1 and type 2 diabetes, tight glycaemic control can prevent microalbuminuria.Whether intensive blood pressure control using angiotensin converting enzyme (ACE) inhibitors can prevent microalbuminuria is controversial. In both type 1 and type 2 diabetes, intensive blood pressure control using ACE inhibitors or angiotensin II receptor blockers (ARBs) slows progression from microalbuminuria to clinical proteinuria and slows the rate of decline in GFR (more so in type 1 than type 2).
Management—aims for: (1) good control of glycaemia (typical recommendations are for HbA1c level <7.5% (58 mmol/mol) (NICE) and <7.0% (53 mmol/mol) (American Diabetes Association) in type 1 and 6.5–7.5% (48 – 58 mmol/mol) in type 2); (2) good control of hypertension (<130/80 mmHg, with even lower targets recommended in those with heavy proteinuria) using an ACE inhibitor and/or an ARB; and (3) other interventions, including some or all of serum lipid lowering, low-dose aspirin, smoking cessation and reduction of dietary protein and salt.
Prognosis—mortality is higher for people with diabetes and increased albuminuria compared to those with normoalbuminuria. In type 2 diabetes, the annual mortality is almost 5% for patients with clinical proteinuria, and almost 20% for those with a serum creatinine greater than 175 µmol/litre or in endstage renal disease. Survival on dialysis remains worse for patients with diabetes compared to those without: 1 year survival was 83% in the UK in 2008 compared to 88% for the non-diabetic population. Cardiovascular disease is the commonest cause of death, and multifactorial cardiovascular risk-factor intervention has been shown to reduce mortality and morbidity in type 2 diabetes, and is mandatory for all patients with diabetic nephropathy.Macrovascular disease—(1) dyslipidaemia—first-line treatment is with statins, aiming for a 30 to 40% reduction in LDL and to achieve an LDL level below 2.6 mmol/litre in all patients and below 1.8 mmol/litre in those with overt cardiovascular disease; (2) hypertension—clinic blood pressure should be reduced to a target of 130/80 mmHg, with angiotension converting enzyme (ACE) inhibitors often recommended as first line; (3) coronary heart disease—there should be a low threshold for referring patients with diabetes presenting with typical or atypical chest pain suggestive of angina for further evaluation; (4) stroke—investigation and management are conventional; (5) peripheral vascular disease—investigation and management are conventional.
Diabetic foot disease—ulceration and severe ischaemia leading to gangrene of the toes or forefoot are the commonest problems. Many problems can be avoided by teaching the patients basic foot care, by regularly checking their feet and shoes, and by providing prophylactic podiatry and special footwear as appropriate. Typical manifestations include (1) neuropathic ulcers—occur at high-pressure sites (heel, metatarsal heads) and appear cleanly punched out of the surrounding callus; (2) ischaemic ulcers—tend to affect the edges of the foot and toes; (3) traumatic damage—e.g. symmetrical damage across the toes and margins of the feet from tight shoes; with (4) all lesions prone to be complicated by infection. Management requires the prevention of further trauma, treatment of infection, and optimization of the circulation. Charcot’s arthropathy most commonly affects the ankle and joints in the mid- and forefoot, which in advanced cases degenerate (usually painlessly) into a ‘bag of bones’: treatment is often unsatisfactory—off-loading pressure with a plaster-cast boot may temporarily halt bone destruction; bisphosphonate infusions may slow the disease process by inhibiting osteoclast activity.
Diabetes mellitus can be defined as a state of chronic hyperglycaemia sufficient to cause long-term damage to specific tissues, notably the retina, kidney, nerves, and arteries, but this functional label gives little insight into the long and colourful history of this disease, its clinical and scientific importance, or its immense personal and socioeconomic impact. Diabetes was recognized in antiquity, and its clinical features (with empirical treatment guidelines) were recorded over 3500 years ago in the Egyptian Ebers papyrus. Our understanding of the disease has advanced greatly, especially during the last two decades, but many aspects of its management remain imperfect. The American Diabetes Association has proposed a generally accepted classification of diabetes mellitus into three types: type 1 is associated with β-cell destruction leading to absolute deficiency of insulin, is immune-mediated and of unknown root cause; type 2 is associated with a relative insulin deficiency and insulin resistance—a range of abnormalities occur, and in some patients a secretory defect predominates; type 3 diabetes is used to encompass diabetes caused by specific defects, other endocrine abnormalities, and drug-induced diabetes, and accounts for about 5% of patients.
The incidence of all types of diabetes is rising, but in developed countries—once patients have been treated for ketoacidosis and with modern regimens for insulin treatment and systems in place for diabetic care—the prognosis is improved for those with type 1 disease and relates to glycaemic control. Extensive studies have shown a strong relationship between glycaemic control, the fraction of glycated haemoglobin (HbA1c), and disease outcomes. Treatment of raised blood pressure and abnormal blood lipids has also contributed to the improved outcomes of nephropathy, retinopathy, myocardial infarction and stroke. In both type 1 and type 2 diabetes, there are compelling data to show that outcomes are improved by intensive therapy: better glycaemic control appears to have no overall effect on the macrovascular complications, but lowering blood pressure has significant benefits on both small vessel (microvascular) and macrovascular disease.
Diabetes is a significant and growing threat to global health. Worldwide, diabetes probably affects 250 million people. This number was eightfold less in 1985 (30 million) and the world prevalence is predicted to reach 380 million by 2025.
Diagnosis of diabetes
Blood glucose concentrations are normally tightly regulated: fasting values lie between 3.5 and 5.5 mmol/litre and even large carbohydrate loads do not raise the concentration more than 8 mmol/litre. It is logical to define diabetes by the blood glucose concentrations which cause the chronic complications of the disease but the choice of the diagnostic glucose levels has been contentious (and has stirred up much passion among epidemiologists). One difficulty is that some diabetic complications show a ‘threshold’ effect with the risk rising above a cut-off level (e.g. fasting plasma glucose of 6 to 7 mmol/litre for retinopathy), whereas macrovascular disease (atheroma) does not (see later). Another problem is that even the current criteria are not self-consistent: e.g. up to 30% of patients with a diagnostic raised fasting glucose will have a 2h value in the glucose tolerance test that is below the diagnostic cut-off.
The current diagnostic criteria for diabetes and other hyperglycaemic states have been approved by the World Health Organization (WHO) and most national diabetes associations. All values refer to venous plasma glucose concentrations:
- ◆ Diabetes mellitus: fasting glucose greater than 7.0 mmol/litre (126 mg/dl) and/or a value exceeding 11.1 mmol/litre, either at 2 h during a 75 g oral glucose tolerance test or in a random sample. The corresponding levels in non-SI units are 126 and 200 mg/dl respectively. The diagnostic fasting glucose level was lowered from the previous value of 7.8 mmol/litre to reflect more accurately the risk of developing diabetic retinopathy
- ◆ Impaired glucose tolerance (WHO): 2 h oral glucose tolerance test value between 7.8 and 11.1 mmol/litre (140–199 mg/dl)
- ◆ Impaired fasting glucose: fasting glucose 5.6 to 6.9 mmol/litre (100–125 mg/dl). The lower value for this range was reduced from 6.0 mmol/litre to 5.6 mmol/litre by the American Diabetes Association in 2003
Impaired glucose tolerance (IGT) and the recently distinguished impaired fasting glucose (IFG) are intermediate categories of hyperglycaemia that carry definite risks and so require follow-up and risk-factor management (see below). They are often transient stages and overlap to some extent: about one-third of subjects with impaired fasting glucose also have impaired glucose tolerance, while one-quarter of those with impaired glucose tolerance also show impaired fasting glucose.
The new criteria put much emphasis on the fasting plasma glucose concentration. However, the time-consuming oral glucose tolerance test is still required in some cases with borderline fasting hyperglycaemia, because the 2-h oral glucose tolerance test value in such patients may be high enough to put them at risk of microvascular complications. Moreover, the oral glucose tolerance test remains the only way to define impaired glucose tolerance.
Practical screening and diagnostic procedures
Certain high-risk groups need to be actively screened for type 2 diabetes, which may be present (and causing complications) for several years before it is noticed. These include subjects predisposed to develop type 2 diabetes through genotype and/or phenotype, those affected by diabetogenic conditions such as pregnancy, endocrine disorders or certain drugs, and those with other cardiovascular risk factors in whom hyperglycaemia must not be missed.
Diabetes is not a trivial diagnosis, and certain practical points must be carefully observed:
- ◆ Glucose should be measured in venous plasma using a quality-controlled laboratory method. Capillary (finger-prick) samples contain higher glucose levels than venous blood, from which glucose has been extracted by the tissue bed; whole-blood glucose levels are lower than in plasma, because red cells actively metabolize glucose and so contain only low concentrations. These differences may reach 0.5 to 1.0 mmol/litre. Portable glucose meters correlate well with laboratory glucose methods, but because of potential technical errors they should not be used to make or refute the diagnosis.
- ◆ An oral glucose tolerance test is indicated for borderline hyperglycaemia. After an overnight fast, the subject drinks 75 g of anhydrous glucose dissolved in 250 ml water (or 419 ml of a glucose drink such as Lucozade Energy Original—73 kcal/100 ml); venous blood is sampled at baseline and 2 h later. Food intake should be normal during the preceding few days: poor nutrition can cause delayed hyperglycaemia with a raised 2 h value (the lag curve).
- ◆ Abnormal values need confirmation. Postchallenge glucose levels in particular can vary considerably. Because of this and possible laboratory error, the diagnosis of diabetes should be verified using a further sample on another day unless there is a clear history of symptoms of hyperglycaemia confirming that this value is not a one-off result.
- ◆ Diabetes is not currently diagnosed from indirect measures of hyperglycaemia such as raised HbA1c or fructosamine levels in blood, or glycosuria. HbA1c and fructosamine reflect average blood glucose concentrations, but the measurements are not sufficiently sensitive or standardized (several different methods are in use) to be used diagnostically although this recommendation is currently under review and is likely to change in the near future. Glycosuria depends on the renal threshold for glucose reabsorption and its presence does not necessarily indicate hyperglycaemia; conversely, glucose may be absent from the urine in diabetic subjects who also have a high renal threshold. However, abnormal results with any of these tests suggest diabetes and indicate the need for formal blood glucose screening.
Impaired glucose tolerance
Impaired glucose tolerance is a not a stable state: within 5 years, about 25% of subjects with impaired glucose tolerance deteriorate into type 2 diabetes, while a further 25% revert to normoglycaemia. The degree of hyperglycaemia in impaired glucose tolerance falls, by definition, below the threshold for microvascular complications but is enough to predispose to cardiovascular disease (see later).
Subjects found to have impaired glucose tolerance must be followed up because of the hazards of both diabetes and macrovascular disease. An oral glucose tolerance test should be repeated at least annually, and dietary and lifestyle advice given to decrease metabolic and cardiovascular risks; increased physical activity, a low-fat diet and weight loss convincingly reduce both the progression to type 2 diabetes (by 58%) and cardiovascular risk. Risk factors such as smoking, hypertension, dyslipidaemia, and obesity should be managed actively. Specific antihyperglycaemic treatments also reduce progression to type 2 diabetes—metformin (24%), rosiglitazone (60% risk reduction, but associated with weight gain)—in addition to pharmacological (orlistat) or physical (bariatric surgery) weight loss interventions. These measures should be used in combination with lifestyle intervention, which is recommended for all subjects with impaired glucose tolerance.
Impaired fasting glucose
As with impaired glucose tolerance, the 5-year risk of progressing to type 2 diabetes appears to be about 25%, and IFG predisposes to cardiovascular disease. Long-term monitoring and management should therefore be as for impaired glucose tolerance.
Metabolic basis of diabetes
Diabetes is due to inadequate production of insulin and/or ‘resistance’ to the glucose-lowering and other actions of insulin. To put this in context, key aspects of normal metabolism will be briefly reviewed.
The islets of Langerhans
There are about 1 million islets of Langerhans in the normal adult: insulin is produced by the β cells, which make up the bulky core of each islet; β cells also synthesize the peptide known as amylin or islet-associated polypeptide. The other islet cell types, mostly surrounding the β-cell core, are the α cells that produce glucagon, the δ cells that produce somatostatin, and the PP cells that synthesize pancreatic polypeptide. All islet cells are derived embryologically from the buds of gut endoderm which also give rise to the exocrine pancreatic tissue.
The various islet cell types communicate with each other through the hormones they secrete into the islet’s rich capillary plexus and probably by paracrine effects on adjacent cells; these interactions presumably regulate hormone secretion. Insulin inhibits release of glucagon, while glucagon powerfully stimulates insulin secretion—an action exploited in the testing of β-cell reserve (see below). Somatostatin suppresses the secretion of insulin and glucagon. Amylin can inhibit insulin and glucagon secretion as well as reduce appetite and gastric emptying. Its physiological role is uncertain but amylin analogues when used as pharmacotherapy have been shown to reduce weight as well as blood glucose levels. Amylin also polymerizes outside the β cell to produce fibrils of amyloid material, which have been implicated in the progressive β-cell damage of type 2 diabetes.
Insulin is a 5800 Da protein made up of an A chain (21 amino acid residues) and a B chain (30 residues), joined covalently by two disulphide bridges. The precursor molecule, proinsulin, consists of the A and B chains linked end-to-end through a connecting (C) peptide which is cleaved off during insulin processing. In the circulation, insulin is monomeric but in crystals and more concentrated solutions (e.g. in the insulin vial and the subcutaneous injection site), six insulin molecules self-associate around a central Zn2+ ion. Self-association influences the pharmacokinetic properties of subcutaneously injected insulin: the rate-limiting dissociation of hexamers into monomers slows the absorption of even fast-acting insulin.
Insulin regulates metabolism in birds, fish, and reptiles as well as mammals, and its structure is remarkably well conserved across the phyla. Three species of insulin are used therapeutically; the human sequence differs from porcine at a single residue (B30) and from bovine at two others. These differences affect the pharmacokinetic and immunogenic characteristics of the insulins (see below). The physicochemical behaviour of insulin has been successfully manipulated in synthetic ‘designer’ insulins that have improved absorption profiles: modification of the C terminus of the B chain, a region crucial for self-association, produces analogues that remain in the monomeric state and are therefore absorbed faster than the native soluble insulin (see below).
Insulin biosynthesis and processing
Insulin is a product of the INS gene, located on the short arm of chromosome 11, whose coding region contains three exons. Translation of INS mRNA in the rough endoplasmic reticulum produces preproinsulin, which is successively cleaved during its passage through the Golgi vesicles and secretory vesicles to yield first proinsulin and finally insulin and C-peptide. Proinsulin is converted into insulin by the proteolytic excision of the C-peptide chain; the two intermediate cleavage products (with either end of the C-peptide remaining attached to insulin) are called split products of proinsulin. Normally, almost all proinsulin is processed through this regulated pathway to yield equimolar amounts of insulin and C-peptide. However, a constitutive pathway may predominate in dysfunctional β cells (e.g. in type 2 diabetes and insulinoma), when processing is not complete and large quantities of proinsulin and split products may be released into the circulation.
C-peptide is generally regarded as an inert byproduct of insulin production. However, its structure is also conserved across species and it may have vasoactive and other properties.
Insulinopathies are point mutations in the INS gene which either produce a mutant insulin (e.g. insulin Chicago: a phenylalanine for leucine substitution at residue B25) or interfere with one of the cleavage sites of proinsulin so that the mutant split product cannot be further processed (e.g. proinsulin Tokyo). These conditions are inherited as autosomal dominant traits; circulating insulin-like or proinsulin-like immunoreactivities may be extremely high but glucose intolerance is often surprisingly mild.
Glucose is the main insulin secretagogue; this action of glucose is modulated by other ingested nutrients, by hormones released by the islets and the gut, and by the autonomic innervation of the islet. The process gives insight into the mode of action of the sulphonylureas and related drugs, and the cause of maturity-onset diabetes of the young (see below).
The amount of insulin released by the normal β cell is tightly coupled to blood glucose levels and begins to increase immediately when blood glucose rises. The ability of the β cell to sense ambient glucose levels accurately and rapidly depends on the glucose transporter isoform GLUT-2 and the glucose metabolizing enzyme glucokinase, while insulin release hinges on depolarization of the β-cell membrane which is controlled by a specific ion channel, the ATP-sensitive K+ channel. The characteristics of GLUT-2 allow glucose at physiological concentrations to freely enter the β cell, where it is immediately converted by glucokinase into glucose 6-phosphate—the point of entry into the glycolytic pathway which ultimately yields ATP; ATP production within the β cell is therefore proportionate to extracellular glucose.
ATP binds to and closes the ATP-dependent K+ channel; when open, this channel allows K+ ions to leave the β cell along their concentration gradient and thus helps to maintain the negative charge inside the β-cell membrane. ATP-induced closure of the channel therefore causes K+ ions to accumulate within the cell and the membrane to depolarize, which triggers the opening of specific (voltage-gated) Ca2+ channels in the membrane. Ca2+ ions then flood into the β cell from the outside and activate the contractile proteins which drag the secretory vesicles containing insulin and C-peptide to the cell surface. Here, the vesicles fuse with the cell membrane and release their contents into the extracellular space (exocytosis), from where insulin and C-peptide enter the islet capillaries.
Sulphonylureas induce insulin secretion by closing the same ATP-sensitive K+ channel as glucose: they bind to a specific sulphonylurea receptor (SUR1) linked to the K+ channel protein (called Kir 6.2). Repaglinide also closes this K+ channel, but binds to a different site from the sulphonylureas. By contrast, diazoxide locks the channel open, hyperpolarizing the β-cell membrane and inhibiting insulin secretion—hence its use in treating insulinoma.
Glucagon and glucagon-like peptide 1 7–36 amide (GLP-1; a gut peptide with insulin secretagogue (incretin) actions) both stimulate insulin secretion by raising cytosolic Ca2+ concentrations; binding to their receptors increases generation of cAMP which blocks removal of Ca2+ into intracellular organelles. Conversely, somatostatin and possibly amylin act to decrease production of cAMP and inhibit insulin secretion. Arginine stimulates insulin secretion, possibly by depolarizing the β-cell membrane as it enters the cell (it is cationic).
The autonomic nervous system is an important modulator of insulin secretion; it is stimulated by the parasympathetic (vagal) outflow and inhibited by the sympathetic. Vagal stimulation is mediated by acetylcholine acting via muscarinic receptors, while the inhibitory sympathetic neurotransmitter is noradrenaline, interacting with α2-adrenoceptors.
Defects in insulin secretion due to mutations affecting glucokinase are responsible for 20% of cases of maturity-onset diabetes of the young (MODY), i.e. glucokinase-dependent MODY (MODY 2). This impairs ATP production from glucose, blunting the insulin response of the β cell to rising glucose and resulting in variable hyperglycaemia (see below). By contrast, familial neonatal hyperinsulinism is caused by inactivating mutations in ABCC8 (SUR1) or KCNJ11 (Kir6.2) that result in closure of the ATP-sensitive K+ channel, leading to sustained insulin secretion and severe hypoglycaemia soon after birth. Activating mutations of KCNJ11 (Kir6.2) cause impaired ATP-sensitive K+ channel closure and have recently been shown to be a cause of persistent neonatal diabetes that can be treated with high dose sulphonylureas.
Insulin concentrations in peripheral blood show basal levels of about 10 mU/litre (1 mU/litre is approximately equivalent to 6.5 pmol/litre) that tend to fall overnight, on which are superimposed prandial peaks reaching 80 to 100 mU/litre, roughly proportionate to the amount eaten. The prandial peaks are elicited by the insulin secretagogue effects of glucose and other nutrients, augmented by incretin gut peptides (such as GLP-1) and the vagal outflow (the early cephalic phase of insulin release).
Very frequent sampling (every minute) shows that ‘basal’ insulin secretion is in fact pulsatile, with clear but low-amplitude peaks every 9 to 13 min. This may help to keep the target tissues sensitive to insulin; loss of this pulsatility is an early sign of β-cell dysfunction in type 2 diabetes. An acute insulin secretagogue challenge (e.g. an intravenous glucose bolus) induces a sharp ‘first-phase’ insulin peak, loss of which is another early abnormality in type 2 diabetes.
The insulin response elicited by eating is larger than when an equivalent nutrient load is given intravenously. This is because glucose entering the gut stimulates neuroendocrine cells in the gut wall to release ‘incretin’ hormones which act on the β cell to enhance insulin secretion (the enteroinsular axis). An important incretin appears to be GLP-1, a product of alternative processing of the preproglucagon gene (glucagon itself is not produced, in contrast to the islet α cell). GLP-1 released from the small intestine augments insulin release in the presence of glucose, slows gastric emptying and acts on the central nervous system to generate a feeling of satiety, effects currently being exploited in the treatment of type 2 diabetes by use of long-acting GLP-1 analogues or inhibitors of GLP-1 breakdown (see below).
Peripheral insulin levels are lower than those in the portal vein, into which the islets drain, because up to 30 % of insulin is removed on its first pass through the liver—one of the main targets for insulin action. The kidney also actively clears and degrades insulin; the circulating half-life is only a few minutes.
C-peptide provides a robust measure of residual β-cell function, because it is cleared more slowly than insulin and its plasma concentrations are therefore more stable. C-peptide is generally measured after intense β-cell stimulation with the powerful insulin secretagogue glucagon; alternatives are a heavy oral load of carbohydrate, mixed meal stimulation including amino acids (such as Boost or Sustacal) or simply the measurement of 24-h secretion of C-peptide in urine (it is cleared largely intact through the kidneys). In normal subjects and most with type 2 diabetes, peak C-peptide concentrations at 6 min after 1 mg of intravenous glucagon are 1 to 4 nmol/litre, whereas type 1 diabetic individuals are typically C-peptide negative, with peak levels less than 0.2 nmol/litre after 5 years. However, at diagnosis of type 1 diabetes there may be overlap with levels in patients with type 2 diabetes and accordingly the test is not used diagnostically.
The insulin receptor and signal transduction
The insulin receptor belongs to the family that also includes the insulin-like growth factor 1 (IGF-1) receptor. Insulin receptors are found in the obvious insulin target tissues (fat, liver, and skeletal muscle) but also in unexpected sites, such as the brain and gonads, in which glucose uptake does not depend on insulin.
The insulin receptor is a 400-kDa heterotetramer composed of two α and two β glycoprotein subunits, interconnected by disulphide bridges. Both α and β subunits are encoded within a complex gene (22 exons) on chromosome 19q. The α subunit (135 kDa) lies entirely extracellularly, while the β subunit (95 kDa) spans the cell membrane and extends into the cytoplasm. Part of the intracytoplasmic tail functions as a tyrosine kinase, attaching phosphate groups from ATP to tyrosine residues elsewhere on the receptor (autophosphorylation) and on other intracellular proteins. This tyrosine kinase activity is essential for insulin signalling and for insulin to exert its many effects on its target tissues. Insulin binds to a site on the extracellular α subunits, and binding triggers a conformational change in the receptor which activates the tyrosine kinase domain of the β subunits.
The activated receptor phosphorylates tyrosine residues on specific intracellular proteins which initiate the signal transduction pathway within the target cell. One group of proteins is the insulin receptor substrate family (IRS 1–4) that vary in their tissue distribution and subcellular localization. Additional substrates include Shc, Cbl, p62dok and Gab-1. All these substrates carry docking sites for proteins possessing specific src homology region SH2 domains. Docking of these proteins by the IRS molecules and other substrates begins a cascade of intracellular reactions that lead ultimately to the effects of insulin on glucose, lipid, and protein metabolism and its many other actions. A key element is the phosphatidylinositol 3-kinase pathway which appears to mediate almost all of insulin’s effects on glucose transport, lipogenesis, and glycogenesis. The mitogen-activated protein kinase pathway, by contrast, is particularly relevant to insulin’s actions on cell growth, with less relevance to its metabolic effects.
Receptors that bind insulin are internalized, i.e. taken up into the target cell by an invagination of the cell membrane that is coated with the protein clathrin. Bound insulin is degraded in the lysosomes, while most of the insulin receptors are carried back to the cell surface and reinserted into the membrane. The density of receptors on the cell surface is therefore a dynamic quantity, regulated partly by new receptor synthesis and partly by receptor recycling, which in turn is determined by insulin binding. Prolonged exposure to high insulin concentrations increases the proportion of internalized receptors and so decreases the density of receptors available on the cell surface. This down-regulation of receptors reduces the sensitivity of the target tissue to insulin.
Many mutations have now been described in the insulin receptor, including point mutations that cause single-residue substitutions or truncation of the α or β subunits. The most severe mutations affect the insulin binding extracellular domain and result in so-called leprechaunism, while less severe mutations affect the tyrosine kinase domain and interfere with insulin signaling (Rabson–Mendenhall syndrome). Both syndromes are associated with severe insulin resistance (type A) as well as serious mental and physical abnormalities, confirming the importance of insulin in fetal development.
Antibodies may develop against the insulin receptor and usually cause insulin resistance with variable hyperglycaemia (the type B insulin resistance syndrome); rarely, hypoglycaemia results from antibodies that activate the receptor (analogous to thyrotoxicosis induced by antibodies to the thyroid-stimulating hormone receptor in Graves’ disease).
Metabolic actions of insulin
Insulin functions as an anabolic hormone, favouring the uptake, utilization, and storage of glucose, the storage of lipids as triglyceride, and preventing the breakdown of protein.
Insulin lowers blood glucose in two main ways. At low basal concentrations (overnight and between meals) it shuts off the production of glucose by the liver, which is the main determinant of fasting glycaemia. Hepatic glucose output is fuelled by both glycogen breakdown (glycogenolysis) and gluconeogenesis (i.e. glucose synthesis from substrates including lactate, glycerol, and alanine and other amino acids); the rate-limiting enzymes for these processes are powerfully inhibited by insulin. Conversely, insulin stimulates glycogen synthesis.
At higher concentrations, such as after meals, insulin also stimulates glucose transport into skeletal muscle (where it is utilized to provide energy via glycolysis or stored as glycogen) and into fat (where it is used to synthesize triglycerides). In both these tissues, insulin enhances glucose uptake through a specific glucose transporter protein, GLUT-4. Insulin causes GLUT-4 units to be translocated rapidly to the cell surface and inserted into the membrane: there, GLUT-4 units act as hydrophilic pores through which glucose can cross the otherwise impermeable membrane into the cell, following its concentration gradient. Insulin also stimulates GLUT-4 synthesis. Overall, insulin acting via GLUT-4 can increase glucose uptake into muscle and fat by up to 40-fold over the basal, non-insulin-mediated, glucose uptake. Non-insulin-mediated glucose uptake occurs through other glucose transporter isoforms that operate in the absence of insulin, notably GLUT-1 in peripheral tissues and erythrocytes and GLUT-3 in brain.
Insulin inhibits triglyceride breakdown (lipolysis), while promoting its synthesis (lipogenesis). Lipolytic enzymes that split triglyceride into glycerol and free fatty acids are powerfully inhibited by insulin, even at low basal insulin concentrations. Profound insulin deficiency, such as in untreated type 1 diabetes, is therefore required before uncontrolled lipolysis occurs and generates enough free fatty acids to cause ketoacidosis (see below).
Insulin inhibits protein catabolism and thus reduces the generation of amino acids which can act as gluconeogenic precursors to enhance glucose production by the liver and kidney. Insulin also promotes protein synthesis and cellular and tissue growth.
These include vasodilatation, mediated by endothelial production of nitric oxide; growth and differentiation of the fetal nervous system; and enhanced tubular reabsorption of Na+ ions by the kidneys.
Measurements of insulin action
Glucose lowering is the most easily tested biological action of insulin, and forms the basis for most measurements of insulin resistance. Several methods are used in the research setting; theoretically, the simplest could be used in clinical diabetes care, to identify patients with marked insulin resistance who might benefit particularly from insulin-sensitizing drugs such as the thiazolidinediones:
- ◆ Homeostatic model assessment (HOMA) is an index derived by mathematical modelling of the relationship between the fasting glucose and insulin concentrations: with decreasing insulin sensitivity, insulin secretion increases in an attempt to maintain euglycaemia, resulting in compensatory hyperinsulinaemia. Homeostatic model assessment yields measures of both insulin resistance and β- cell function; the test can be performed on a single fasting blood sample and the results compare well with the insulin–glucose clamp.
- ◆ Insulin–glucose (hyperinsulinaemic–euglycaemic) clamp. Insulin is infused intravenously to achieve constant high concentrations and a separate infusion of glucose is adjusted to maintain blood glucose ‘clamped’ at a normal value. The more glucose required, the greater is the insulin sensitivity. The clamp is generally regarded as the gold standard method but demands blood glucose measurements every few minutes and takes some hours to perform.
- ◆ Intravenous glucose tolerance test. An intravenous glucose bolus stimulates insulin release, and mathematical modelling of the relationship between the insulin peak and the decay in blood glucose levels can yield indices of both insulin secretion and insulin sensitivity.
Insulin resistance (or insensitivity) is a poorly defined term signifying decreased biological activity of insulin, and which is usually equated with impaired glucose-lowering.
There is no universal normal range for insulin sensitivity, because the ability of insulin to lower glucose varies considerably between and within individuals—it is influenced e.g. by levels of physical activity and fitness. Subjects with ‘insulin-resistant’ conditions such as type 2 diabetes or essential hypertension commonly show reductions of 40 to 60% in glucose disposal (measured by the clamp technique), as compared with matched healthy controls, yet many apparently normal subjects also have comparable decreases in insulin sensitivity. There is no argument about extreme examples of insulin resistance: in some patients with leprechaunism, over 20 000 U/day of insulin have failed to control hyperglycaemia and ketosis. A working definition of clinically relevant insulin resistance in insulin-treated diabetic patients is a daily requirement of more than 1.5 U/kg.
Causes of insulin resistance
Inherited causes include the very rare mutations affecting the insulin receptor or postreceptor signalling pathways which can lead to extreme insulin resistance (type A insulin resistance syndrome); milder polygenic defects contribute to the insulin resistance of type 2 diabetes (see below). Insulin receptor mutations cause clinically distinct syndromes, often with acanthosis nigricans and, in women, features of polycystic ovary disease and masculinization; hyperglycaemia is variable. Specific syndromes include the speculatively named leprechaunism and various inherited lipodystrophies in which fat is lost from subcutaneous and other depots in defined but unexplained anatomical patterns. Recently, mutations affecting the PPARG gene (the target for the thiazolidinedione drugs; see below) have been shown to modify insulin sensitivity. Several mutations in loci that predispose to obesity have recently been reported, but interestingly, only a subset of these also predispose to type 2 diabetes (e.g. LEP, FTO, and TCF7L2) suggesting that genetic influences in addition to obesity are required for the generation of diabetes.
Obesity induces insulin resistance, especially in skeletal muscle, and weight loss can improve insulin sensitivity in the obese. Insulin resistance is particularly associated with truncal (central) obesity, where fat is deposited in and around the abdomen; both the subcutaneous and intra-abdominal (visceral) fat depots have been implicated to various degrees that may reflect ethnic and other differences.
It is still not clear how an increased fat mass can decrease whole-body insulin sensitivity, but circulating fat-derived products are presumed to be responsible. Intra-abdominal fat depots would secrete potentially diabetogenic mediators into the portal circulation—where they would be delivered directly to the liver—and this may explain the association of visceral adiposity with insulin resistance. Possible candidates include free fatty acids and the cytokine tumour necrosis factor-α (TNFα); both are secreted by adipocytes and, under experimental conditions at least, interfere with aspects of insulin action. Levels of free fatty acids are raised in obese subjects, apparently because lipolysis is enhanced, and free fatty acids may cause hyperglycaemia by competing with glucose metabolism in liver and muscle. In liver, free fatty acids enhance gluconeogenesis by stimulating the rate-limiting enzyme pyruvate carboxylase and so increase hepatic glucose production. In muscle, free fatty acids inhibit glycolysis at the level of phosphofructokinase and glucose oxidation via pyruvate dehydrogenase, causing a decrease in glucose utilization and a secondary reduction in glucose uptake (the glucose–fatty acid or Randle cycle). In vitro, TNFα inhibits the tyrosine kinase activity of the insulin receptor that is crucial for insulin signalling. Production of TNFα by adipose tissue is increased in obesity but its role as a mediator of insulin resistance in human obesity is uncertain. Recently, a novel adipocyte product, adiponectin, has been shown to enhance insulin sensitivity in rodents; intriguingly, circulating adiponectin concentrations are decreased in human obesity. Several other recently identified hormones released by adipose tissue (adipokines) also have effects on insulin action (e.g. resistin, visfatin, interleukin-6) but their role in type 2 diabetes is less well defined. Obesity is also accompanied by the ectopic deposition of triglyceride in liver and skeletal muscle, and the accumulation of triglyceride is correlated with impairment of insulin action in these tissues.
Physical inactivity strongly predisposes to obesity and also promotes insulin resistance which can be reversed by regular exercise. The mechanism is unknown but physical training is known to stimulate translocation of GLUT-4 glucose transporters to the surface of muscle cells independently of insulin. In addition, muscle contraction enhances expression of the enzyme AMP kinase which mediates improved glucose transport and fatty acid metabolism. AMP kinase has recently been shown to be a molecular target of two drugs known to reduce insulin resistance (metformin and rosiglitazone).
There are several other acquired causes of insulin resistance. Intrauterine growth retardation may contribute (see the Barker–Hales hypothesis below). Physiological states of insulin resistance, due to the appropriate oversecretion of the counter-regulatory hormones whose metabolic actions oppose those of insulin, are puberty and pregnancy. Endocrine diseases that induce insulin resistance and can cause glucose intolerance and overt diabetes through excessive production of anti-insulin hormones include acromegaly (prevalence of diabetes and impaired glucose tolerance each c.25%), Cushing’s disease (diabetes c.30%), thyrotoxicosis, and the very rare glucagonoma (diabetes in >90% of cases). In these disorders, diabetes is mostly nonketotic, although insulin may be needed to control hyperglycaemia.
Intercurrent illnesses, e.g. myocardial infarction, stroke, or severe infections, induce the secretion of counter-regulatory stress hormones that can cause marked insulin resistance—insulin-treated diabetic patients may need twice their usual insulin dosages during such episodes. Many drugs decrease insulin sensitivity, including glucocorticoids, β2 adrenoceptor agonists (ritodrine, salbutamol), and certain oral contraceptive pills containing high-dose oestrogen or levonorgestrel; glucocorticoid-induced hyperglycaemia commonly requires insulin treatment. Acquired lipodystrophies, most notably that induced by drugs used to treat HIV, especially protease inhibitors (PIs) and nucleoside analogue inhibitors of viral reverse transcriptase (NRTIs), are also associated with insulin resistance and the development of diabetes.
The type B insulin resistance syndrome is due to the development of autoantibodies against the insulin receptor which interfere with insulin binding and/or signalling. Most patients are young women, usually with pre-existing autoimmune diseases such as lupus erythematosus, and masculinization often occurs. ‘Immune insulin resistance’ describes insulin-treated patients with very high insulin requirements (sometimes several thousand U/day) because of high titres of insulin-binding antibodies that bind and inactivate administered insulin. This has become very rare since the introduction of highly purified human-sequence insulin preparations with low immunogenicity (see below).
Metabolic and clinical features of insulin resistance
The metabolic disturbance due to insulin-resistant syndromes ranges from subclinical glucose intolerance to severely symptomatic hyperglycaemia, sometimes with ketosis. A crucial determinant is the capacity of the individual’s β cells to secrete insulin in response to the rises in blood glucose that are due to impaired insulin action. The resulting hyperinsulinaemia is extremely variable, with plasma insulin levels ranging from twice normal in many obese subjects to 500 times normal in patients with defects of insulin receptors. Near normoglycaemia can be maintained as long as hyperinsulinaemia can compensate for the underlying defect in insulin signalling; diabetes occurs when β-cell failure supervenes and insulin secretion falls below a critical level. In the total absence of functional insulin receptors (e.g. in leprechaunism), massive endogenous hyperinsulinaemia or administration of industrial insulin dosages cannot prevent severe diabetes, although very high insulin concentrations may exert some metabolic actions through ‘cross-talk’ with the IGF-1 receptor.
Acanthosis nigricans, a characteristic skin manifestation of severe insulin resistance, may be due to high insulin concentrations activating growth factor receptors (perhaps the IGF1 receptor) that drive the proliferation of keratinocytes and melanocytes. Hyperplasia of these cells leads to a velvety thickening and variable darkening of the skin, especially in the axillae (often with proliferation of skin tags), groin, and nape of the neck. Widespread acanthosis nigricans can also accompany gut tumours, which may also secrete dermal growth factors.
Increased androgen concentrations may lead to hirsutism and occasionally virilization in women with severe insulin resistance; high insulin concentrations may stimulate androgen production by the ovaries, which often show a polycystic appearance. Insulin resistance is a feature of polycystic ovary syndrome, especially in obese patients. Enhancing insulin sensitivity through weight loss or treatment with metformin or the thiazolidinediones can decrease androgen levels and improve hirsutism and menstrual dysfunction.
The metabolic syndrome
The metabolic syndrome (syndrome X) denotes the co-occurrence of insulin resistance and glucose intolerance (ranging from mild to overt type 2 diabetes), with truncal obesity, dyslipidaemia (raised triglycerides and a high low-density lipoprotein:high-density lipoprotein (HDL/LDL) ratio), and hypertension.
These abnormalities are all common in most Westernized populations, and it is still not clear whether or not this constellation of cardiovascular risk factors represents a genuine syndrome with a common underlying cause. Reaven and others have argued that insulin resistance is the central abnormality, and that the key features can be explained either by loss of specific actions of insulin or by the effects of the compensatory hyperinsulinaemia on organs that remain relatively insulin sensitive. For example, raised insulin levels could contribute to hypertension by enhancing retention of Na+ by the kidney; conversely, blood pressure could also be raised through loss of the direct vasodilator action of insulin. The pattern of abnormalities would therefore require insulin resistance to affect certain tissues and specific actions of insulin but not others. Other proatherogenic defects identified in subjects with various features of syndrome X include increased coagulability of the blood (e.g. increased levels of plasminogen activator inhibitor-1) and impaired endothelial-mediated vasodilatation. The relationship of these abnormalities to insulin resistance is uncertain. Obesity, dyslipidaemia, hypertension, and glucose intolerance are all independent cardiovascular risk factors; any possible proatherogenic role of hyperinsulinaemia per se remains controversial.
The aetiology of syndrome X is unresolved; indeed it has been argued that it is not a distinct entity, but simply represents the variable association of several abnormalities that are relatively common in all populations, and especially those that generally overeat and are too sedentary. Adiposity, insulin sensitivity, and blood pressure show variable strengths of familial transmission that differ between populations and generally suggest polygenic inheritance of multiple minor genes. On the other hand, Barker and Hales have suggested that fetal malnutrition programmes insulin resistance, hypertension, and dyslipidaemia in middle to late adult life. The underlying mechanisms remain elusive. Because obesity leads to insulin resistance and glucose intolerance, dyslipidaemia, hypertension, and atheroma, weight gain in middle age may be particularly hazardous in subjects who were underweight at birth.
Clustering of these metabolic and cardiovascular risk factors is important clinically because it predisposes to atheroma formation and substantially increases the risk of dying prematurely from myocardial infarction or stroke. Treatment is currently based on correcting any factors (e.g. type 2 diabetes, hypertension, and dyslipidaemia) present in the individual patient. Lifestyle and dietary modification that achieves weight loss can improve most aspects of the syndrome. Several drugs have been shown to slow progression from impaired glucose tolerance to type 2 diabetes (e.g. metformin, rosiglitazone, and weight-loss drugs such as orlistat), although their role in treatment of the metabolic syndrome remains controversial and rosiglitazone, in particular, fails to decrease cardiovascular risk despite improving insulin sensitivity.
Types and classification of diabetes mellitus
The current WHO classification is based on aetiology. See table below:
|Table 1 Classification of diabetes mellitus according to aetiology|
|Type 1 diabetes||β-Cell destruction, usually leading to absolute insulin deficiency (10–15% of cases in Europe and USA):|
|1B-Idiopathic (e.g. fulminant Type 1 diabetes)|
|Type 2 diabetes||May range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance (80–85% of cases in Europe and USA)|
|Other specific types (Type 3 diabetes)||Other types with specific causes (5% of cases in Europe and USA)|
|A Genetic defects of β-cell function||MODY|
|Others, including mitochondrial DNA defects (MELAS syndrome)|
|Neonatal diabetes: mutations in KCNJ11; imprinting abnormality in ZAC and HYMAI—may be transient|
|B Genetic defects of insulin action||Type A insulin resistance syndrome|
|C Diseases of the exocrine pancreas||Pancreatitis, chronic and acute|
|Carcinoma of the pancreas|
|Cushing’s disease and syndrome|
|E Drug- or chemically-induced||Glucocorticoids|
|Others – phenytoin, pentamidine, nicotinic acid, interferon-α|
|F Infections||Congenital rubella|
|G Uncommon forms of immune-mediated diabetes||Type B insulin resistance (insulin receptor antibodies)|
|‘Stiff man’ syndrome|
|H Other genetic syndromes||Prader–Willi syndrome|
|Wolfram’s syndrome (DIDMOAD)|
|Others, e.g. Laurence–Moon–Biedl syndrome|
|Type 4 diabetes||Gestational diabetes or glucose intolerance|
DIDMOAD, diabetes insipidus, diabetes mellitus, optic atrophy, and deafness; MELAS, myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (associated with type 1 or type 2 diabetes); MODY, maturity-onset diabetes of the young.
(Adapted from American Diabetes Association (2007). Diagnosis and classification of diabetes. Diabetes Care, 30, S42–S47.)
Type 1 and type 2 diabetes together account for 90 to 95% of cases and will be described in detail.
Type 1 diabetes
Type 1 diabetes—previously referred to as juvenile-onset or insulin-dependent diabetes—is due to autoimmune killing of the β cells (the type 1 process). A similar clinical picture of insulin dependence can be caused by other forms of severe pancreatic damage.
Epidemiology and demographic features
Type 1 diabetes is considerably rarer than type 2, accounting for between 5 and 15% of all diabetes and 30 to 50% of insulin-treated cases in various populations. It appears predominantly in childhood, with a peak age at presentation of about 11 years in girls and 14 years in boys—hence the old description of juvenile-onset. However, it can develop at any age; up to 50% of all cases are diagnosed over the age of 18 and about 5% of newly diagnosed white diabetic patients over 65 years are considered to have type 1 diabetes.
The prevalence of type 1 diabetes varies considerably throughout the world. Incidence is highest in northern European countries (about 30 to 35 cases per 100 000 children per year in Finland and Scotland) and declines progressively towards the equator; there are some isolated hot spots such as Sardinia, where the incidence is as high as in Finland. High susceptibility is found in European populations throughout the world, while African and East Asian populations are relatively spared (incidences of less than 1 per 100 000 per year). Superimposed on this geographical variation are time-related changes in incidence that hint at the importance of the environment in causing the disease. Type 1 diabetes presents more frequently during the winter months, particularly in children aged 10 to 14 years. In many countries (e.g. Norway, Poland, Sweden, and the United Kingdom), there have been sharp 30 to 50% increases in incidence over 10 to 20 year periods, although the explanation and significance of these secular trends are not clear. In particular, there has been a shift to diagnosis at a younger age with a particularly marked rise in cases being diagnosed under the age of 5.
Type 1 diabetes is an autoimmune, predominantly T-cell-mediated process that selectively destroys the β cells. Susceptibility is multifactorial, resulting from the impact of environmental agents in a genetically disadvantaged subject. Of these two components, the environment appears more important; genetic factors explain only 30 to 40% of total susceptibility.
Over 20 genetic loci are associated with type 1 diabetes, at least 10 of which have been confirmed by repeated studies and genome-wide analyses with large cohorts. The best characterized are the HLA class II locus (HLA-DQB1, IDDM1) and the insulin gene promoter region (IDDM2), of which the HLA class II locus has by far the greatest effect (odds ratio for diabetes is 7–13:1 for susceptible alleles).
The HLA class II locus lies within the major histocompatibility complex region on chromosome 6, that encodes several proteins intimately involved in immune responses. Of particular importance is HLA-DQB1; this encodes the DQB1 peptide chain, which forms part of the cleft in the surface of the HLA class II molecule that is crucial in presenting peptide fragments of antigen to the T-helper lymphocyte. Changes in the structure of the DQB1 peptide could therefore influence the coupling between the class II molecule–peptide complex and the T-lymphocyte receptor, and thus modulate the immune response against the (auto)antigenic peptide. Specific DQB1 polymorphisms have been shown to predispose to type 1 diabetes (e.g. DQB1*0302), whereas others (e.g. DQB1*0602) are protective—at least in certain racial groups. The relationships of these polymorphisms to the long-recognized influences of the DR3 and DR4 class II antigens (which increase several-fold the risk of type 1 diabetes) and of the protective DR2 are discussed further in Chapter 13.12.2.
The HLA class II locus corresponds to the insulin gene (INS) whose uniqueness as a β-cell product makes it an obvious candidate gene. The insulin coding sequence is unchanged in type 1 diabetes. However, variation is observed in a region upstream of the insulin gene in which there is a variable number of repeats of the consensus sequence, 5′-ACAGGGGTGTGGGG-3′ one after another, known as the variable number of tandem repeats (VNTR) minisatellite. The short class I VNTR alleles (26–63 repeats) predispose to diabetes, while class III alleles (140–210 repeats) have a dominant protective effect (odds ratio for type 1 diabetes with class I vs class III alleles is 2.2:1). This protective effect appears to be mediated by a two- to threefold increased expression of insulin in the thymus. Insulin, like many other self proteins, is normally expressed at low level in the thymus as part of the process which promotes central tolerance to self antigens amongst T cells. The further increased levels associated with class III alleles thereby results in a relative reduction in the risk of autoimmunity.
Additional loci confirmed to predispose to type 1 diabetes show a strong predominance of genes affecting the immune system, including PTPN22 and CTLA4, both negative regulatory molecules of the immune system, IL2RA (CD25), the high-affinity interleukin-2 receptor and IFIH1, a cytoplasmic helicase that mediates induction of interferon in response to viral RNA. Work is in progress to define more precisely how disease predisposition is increased by the high-risk alleles and should ultimately shed light on the pathogenesis of the disease.
Viruses have long been popular candidates as an environmental trigger for diabetes. Some (e.g. mumps, Coxsackie, cytomegalovirus, and rubella) infect the pancreas but normally damage the entire gland, particularly the exocrine tissue, rather than causing selective β-cell injury. Certain viruses target the β cell in animals (e.g. the Kilham rat virus) and can cause insulin-dependent diabetes, either through their direct cytolytic effects or by provoking a type 1-like autoimmune process. Important contenders in humans are coxsackieviruses (especially B4), rubella, and rotaviruses.
Serological studies indicate that recent Coxsackie B infections are relatively common among newly diagnosed patients with type 1 diabetes; these could represent the final insult in the disease’s long natural history, since the autoimmune process can be detected many years prior to this. Coxsackieviruses capable of damaging rodent β cells have also been isolated post-mortem from the islets of some type 1 diabetic subjects. About 20% of children who survive intrauterine rubella infection develop type 1 diabetes, with typical autoimmune markers. Endogenous retroviruses were previously implicated as aetiological agents but this has not been confirmed in further studies. For other viruses, the epidemiological data are conflicting: e.g. the eradication of rubella by vaccination has not reduced the incidence of type 1 diabetes in Finland while the prevalence of Coxsackie infections is lower in Finland than in the adjacent Russian Karelian population which is genetically related but has a substantially lower type 1 diabetes risk.
Viruses could trigger or maintain autoimmune β-cell damage in various ways. Acute or persistent viral infection of β cells could release β-cell antigens that are normally sequestered beyond the reach of the immune cells. Certain viral proteins may elicit an immune response which cross-reacts with specific β-cell antigens that happen to be similar (molecular mimicry): e.g. peptide sequences of the P2-C capsid protein of coxsackie B viruses may cross-react with glutamate decarboxylase-65 (GAD65) in the β-cell membrane.
Other environmental factors are suggested to include bovine serum albumin from cow’s milk and various toxins. Bovine serum albumin contains a peptide sequence that may crossreact with a β-cell surface protein (see below); this was suggested as an explanation for an apparent excess risk of type 1 diabetes among children fed with cow’s milk in the neonatal period, although a protective effect for breastfeeding remains controversial. Various toxins selectively damage β cells, including streptozotocin, a nitrosourea used to induce experimental diabetes in rodents. Related nitrosamine compounds have been blamed for the higher risk of type 1 diabetes in the children of women who eat fermented smoked mutton (a traditional delicacy in Iceland).
To try to resolve the controversies in this complex area, an international consortium—The Environmental Determinants of Diabetes in the Young (TEDDY; http://archives.niddk.nih.gov/patient/Teddy/teddy.aspx)—has been established. This will follow several thousand children with high-risk HLA genotypes from birth until adolescence to identify infectious agents and dietary or other environmental factors that trigger β-cell autoimmunity in genetically susceptible people.
Type 1 diabetes has strong associations with endocrine and other autoimmune diseases, including Schmidt’s syndrome (with hypothyroidism and adrenocortical failure) and the autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy(APECED) syndrome caused by mutations in the AIRE gene which controls self-tolerance by influencing thymic expression of autoantigens. Type 1 diabetes is also a feature of the IPEX syndrome (immunodysregulation, polyendocrinopathy, and enteropathy, X-linked syndrome) caused by mutations in the key T cell regulatory gene, FOXP3.
Most β-cell damage is probably inflicted by T lymphocytes. Insulitis—infiltration of the islets with immune cells, mostly cytotoxic/suppressor (CD8+) T lymphocytes—is a pathognomic feature of the disease, and circulating T-helper lymphocytes can be identified that react against β-cell antigens including proinsulin and GAD65.
Various circulating autoantibodies also occur. Some target antigens are unique to the β cell, while other autoantigens are shared by other islet cell types. Notable β-cell selective autoantibodies are those that recognize GAD65, a heat shock protein (hsp60), and insulin itself. GAD catalyses the conversion of glutamic acid to γ-aminobutyric acid, whose role in the β cell is uncertain. Studies in rodents with type 1 diabetes suggest that the level of GAD65 expression influences the intensity of the autoimmune attack on the β cells. The GAD67 isoform of the enzyme is also expressed in the central nervous system, and autoimmune damage of GABAergic neurons is presumed to explain the association of type 1 diabetes with the rare ‘stiff man’ syndrome. High frequencies of autoantibodies to the protein tyrosine phosphatase-like molecule IA-2 are also seen. Most recently, autoantibodies against the cation efflux transporter, zinc transporter 8 (ZnT8) have been identified.
GAD65 antibodies are present in 70 to 90% of newly diagnosed type 1 patients, insulin antibodies in 40 to 70%, IA-2 autoantibodies in around 50 to 60% and ZnT8 antibodies in around 70%. Islet cell antibodies detected by immunofluorescence on tissue sections are present in 80 to 90% of newly diagnosed patients but are technically difficult to measure. Recent studies suggest that automated combined testing for GAD and IA-2 has equivalent sensitivity and specificity to islet cell antibodies (ICA) testing. This is increasingly replacing ICA assays, although undoubtedly ICA reactivity encompasses more (as yet undetermined) antigens than insulin, GAD 65, IA-2 and ZnT8 alone. These antibodies cannot explain the selective destruction of β cells: although some islet cell surface antibodies are complement-fixing the majority of the islet cell destruction is believe to be caused by T cells.
High titres of each of these classes of antibodies have some value in predicting diabetes in high-risk individuals—the combination of high titres of three autoantibodies (GAD, IA-2, and insulin or ICA) amongst family members of subjects with type 1 diabetes is 90% predictive of disease, although hyperglycaemia may not develop for 20 years or more. However, they are clearly not the immediate cause of the disease: single autoantibody-positive individuals rarely progress to disease, suggesting that these autoantibodies are general markers of autoimmunity against the β cell, rather than evidence of β-cell destruction, which is primarily cell mediated. Titres of all these antibodies tend to be high at presentation and (according to prospective studies of high-risk subjects) during the months leading up to this. Thereafter, antibody levels decline progressively and may even become undetectable, possibly through dwindling of the antigen load that perpetuates autoimmunity as any remaining β cells disappear.
Natural history of type 1 diabetes
The damage to β cells might be initiated by direct viral attack, environmental toxins, and/or a primary immune attack against specific β-cell antigens such as GAD65, perhaps via molecular mimicry. T-helper lymphocytes (CD4+) are activated by β-cell antigens presented together with diabetogenic class II antigens by antigen-presenting cells (dendritic cells). Activated T-helper cells produce cytokines that attract T and B lymphocytes and encourage them to proliferate in the islet, leading to insulitis. B lymphocytes might then damage β cells by producing antibodies against released β-cell antigens, while cytotoxic (CD8+) T lymphocytes directly attack β cells carrying the target autoantigens. Insulitis is a patchy and unpredictable process that might flare up after encounters with new environmental triggers such as viral infections, but which can also fade and abort for unknown reasons.
Several years of progressive autoimmune damage usually precede the clinical onset of diabetes. This long prediabetic phase is asymptomatic, although careful testing (e.g. with the intravenous glucose tolerance test) reveals loss of the first phase, then increasingly obvious disturbances of insulin and C-peptide secretion, and eventually glucose intolerance. Finally, when the β-cell mass has been eroded to a critical level (probably 5 to 10% of normal), falling insulin secretion can no longer restrain hyperglycaemia and clinical diabetes develops.
Residual β-cell mass is variable at presentation of type 1 diabetes: some newly diagnosed type 1 patients are C-peptide positive, and β-cell secretion may improve temporarily during the ‘honeymoon period’ that can follow the lowering of blood glucose when insulin treatment is started (see below). As a result, it is not possible to absolutely distinguish type 1 and type 2 diabetes by measurement of C-peptide at diagnosis although levels tend to be very much lower in type 1 diabetes. With continuing β-cell destruction, endogenous insulin production declines progressively, and more than 90% of type 1 patients become permanently C-peptide negative within 5 years of presentation. The loss of C-peptide is more rapid in individuals diagnosed in childhood than in new onset disease in adults. Ultimately, insulitis burns itself out and the immune cells retreat, leaving islet remnants that are devoid of β cells but which still contain intact α, δ, and PP cells. Interestingly, there is a concomitant 50% reduction in the size of the exocrine pancreas in patients with long-standing type 1 diabetes: this appears not to result in clinically significant malabsorption and the mechanism by which it occurs is unknown.
The protracted prediabetic phase provides an opportunity to prevent subjects with active insulitis from developing clinical disease. A combination of autoantibody titres and genetic markers (HLA haplotypes) can be used to predict the chances of the disease developing in high-risk subjects, such as the siblings of children with type 1 diabetes; various immunosuppressive and immunomodulatory treatments are currently undergoing clinical trials as forms of early intervention or prevention.
Metabolic disturbances of type 1 diabetes
In untreated type 1 diabetes, insulin concentrations are generally 10 to 50% of nondiabetic levels in the face of hyperglycaemia which would normally greatly increase insulin secretion. Such severe deficiency cannot sustain the normal anabolic effects of insulin and leads to runaway catabolism in carbohydrate, fat, and protein metabolism. Each of these processes accelerates hyperglycaemia, while the oxidation of excess free fatty acids generated by triglyceride breakdown can result in diabetic ketoacidosis.
Basal hyperglycaemia is due mainly to unrestrained production of glucose by the liver and is accentuated after eating by the failure of glucose to be cleared peripherally. Hepatic glucose output is boosted, especially by increased gluconeogenesis: the normal inhibition of the process by insulin is lost, while the supply of gluconeogenic precursors (glycerol from lipolysis, amino acids such as alanine from protein breakdown) is increased. Enhanced gluconeogenesis in the kidney may also contribute. Postprandial glucose uptake into muscle and fat, mediated by insulin and GLUT-4, is greatly decreased; this is partly offset by increased non-insulin-dependent glucose uptake into peripheral tissues, via glucose transporters that do not require insulin. The overall result is hyperglycaemia, commonly in the range of 15 to 25 mmol/litre and higher after meals. Glucose concentrations of over 40 mmol/litre are not uncommon during intercurrent illness and especially when insulin treatment is omitted or not increased sufficiently.
Lipolysis is stimulated by severe insulin deficiency, generating glycerol (a gluconeogenic precursor) and free fatty acids, the substrate for ketone formation. Ketogenesis is particularly enhanced by concomitant glucagon excess (see below). Mobilization of body fat contributes to the marked weight loss in untreated type 1 diabetes.
Loss of the net anabolic effect of insulin encourages catabolism of proteins (primarily through the proteasome-mediated pathway), thus generating amino acids including gluconeogenic precursors such as alanine and glutamine. Muscle wasting may be prominent.
The effects of hypoinsulinaemia are compounded by the counter-regulatory hormones which are secreted in excess in response to stress (e.g. infections, myocardial infarction, trauma, surgery) and when circulating volume falls (e.g. in hyperglycaemic dehydrated patients). Insulin deficiency also leads to increased glucagon secretion, because insulin normally inhibits the α cells.
Glucagon increases hepatic glucose production, both by driving glycogen breakdown and by increasing uptake of glucogenic amino acids by the liver and enhancing gluconeogenesis. It also stimulates ketogenesis by increasing entry of free fatty acids (as their fatty acyl-CoA derivatives) into liver mitochondria. Glucagon excess is an important factor that promotes diabetic ketoacidosis, acting synergistically with insulin deficiency (see below).
Cortisol and catecholamines enhance gluconeogenesis. Cortisol, catecholamines, and growth hormone oppose the lipogenic action of insulin and favour lipolysis, in the presence of hypoinsulinaemia. Cortisol is a powerful inducer of proteolysis, whereas growth hormone cooperates with insulin to stimulate protein synthesis.
Clinical features of type 1 diabetes
The classical presentation of untreated or poorly controlled type 1 diabetes reflects the consequences of catabolism and hyperglycaemia (see table below. These features usually develop progressively and quite rapidly over a period of a few days to a few weeks.
|Table 2 Typical features of type 1 and type 2 diabetes, with some distinguishing characteristics|
|Type 1 diabetes||Type 2 diabetes|
|Osmotic and glycosuric symptoms: polyuria, nocturia, enuresis; thirst, polydipsia; blurred vision; genital candidiasis (pruritus vulvae, balanitis)||+ → ++||± → ++|
|Systemic symptoms: malaise, tiredness, lack of energy||+ → ++||0 → ++|
|Catabolic features: recent weight loss; muscle wasting and weakness||+ → ++||0 → +|
|Ketoacidosis||Spontaneous||Rare; mostly precipitated by intercurrent illness|
|Diabetic microvascular complications at presentation||–||±|
|Age at presentation||Young > old||Old > young|
|Obesity||Unusual||++ (almost invariable in white people)|
|Clinical insulin dependence (weight loss and hyperglycaemia without insulin replacement)||+||–|
|C peptide||low especially 5 years after diagnosis||normal or raised|
|HLA DR3 or DR4||++||–|
|Islet cell antibodies: ICA, GAD, IA-2||++||–|
GAD, glutamic acid decarboxylase; HLA, human leukocyte antigen; ICA, islet cell antibodies; IA-2, insulinoma associated antigen-2.
Diuresis is due mainly to the osmotic effect of glucose remaining in the renal tubule, when its concentration exceeds the reabsorption threshold for glucose (corresponding generally to plasma glucose levels of about 10 mmol/litre). The osmotic loads of urinary ketones and of electrolytes that are obligatorily lost with glucose also contribute. Urine output may reach several litres per day, causing polyuria, nocturia, and in children, enuresis.
Thirst generally parallels urine output and can be very intense; it is characteristically made worse by sugar-rich drinks. Taking water to bed at night is a useful sign of pathological thirst. A high fluid intake is an important homeostatic response to diuresis, and patients unable to drink (e.g. through nausea in ketoacidosis) can rapidly become dehydrated and hypovolaemic.
Weight loss, due to loss of fat and muscle and later to dehydration, can be dramatic and reach several kilograms over a few weeks. The energy deficit caused by catabolism and urinary losses of glucose can amount to several hundred calories per day. Appetite is often increased; the mechanism in humans is not known; falls in circulating leptin and insulin, both of which act on the central nervous system to inhibit feeding, are probably responsible for hyperphagia in diabetic rodents.
Systemic symptoms include tiredness, malaise, lack of energy, and muscular weakness.
Blurred vision is commonly due to changes in the shape of the lens due to osmotic shifts, typically causing long-sightedness. Rarely, acute ‘snowflake’ cataracts develop because of reversible refractile changes, rather than the permanent denaturation of lens proteins in senile cataract.
Infections are often present because hyperglycaemia predisposes to infections and also because infections stimulate the secretion of stress hormones. Genital candida infections, causing recurrent pruritus vulvae in women and balanitis in men, are frequent and should always prompt testing for diabetes. Pyogenic skin infections and urinary tract infections, sometimes complicated by severe renal damage, are also common, and certain rare infections have a particular predilection for diabetic people (see below).
Diabetic ketoacidosis presents with hyperglycaemic symptoms, which are usually severe, together with nausea and vomiting, acidotic (Kussmaul) breathing, the smell of acetone on the breath, and, especially in children, altered mood and clouding of consciousness that may progress to coma. Diabetic ketoacidosis is described in detail later.
Unlike type 2 diabetes, which is often present for several years before diagnosis, hyperglycaemia in newly presenting type 1 patients develops too acutely for chronic diabetic complications to appear. Because obvious symptoms appear quickly, very few cases are picked up fortuitously, although doctors who have forgotten to think of diabetes in their differential diagnosis of weight loss or hyperventilation may be surprised when hyperglycaemia is detected by routine screening. With the rising incidence and awareness of diabetes in the general population (due to rising rates of type 2 diabetes), an increasing number of cases of type 1 diabetes are detected before ketosis develops—giving rise, especially in adults, to confusion over whether the diagnosis is type 1 or type 2 diabetes.
Prognosis of type 1 diabetes
Before the introduction of insulin during the early 1920s, type 1 diabetes was invariably fatal, usually within months. With various semistarvation diets, hyperglycaemic symptoms could be improved somewhat and life extended by a few miserable months.
With modern insulin treatment, type 1 diabetic patients can be rescued from diabetic ketoacidosis, although one-third of deaths in diabetic children and young adults are still due to metabolic emergencies, notably ketoacidosis. The main threat to survival with type 1 diabetes is now chronic tissue damage, particularly renal failure from nephropathy, and vascular disease, notably myocardial infarction and stroke. Throughout adult life, the overall risk of dying within 10 years is about fourfold higher for patients with type 1 diabetes than for their nondiabetic peers.
There is encouraging evidence from Europe and the United States of America that the outlook for type 1 diabetes has improved over the last 10 to 20 years, with definite declines in the incidence of microvascular complications and extended survival—at least in countries able to afford effective diabetes care. This is partly attributable to tighter control of hyperglycaemia, which can reduce by 30 to 40% the risks of nephropathy and retinopathy developing or progressing to a clinically significant degree (see below). Other measures have undoubtedly contributed, including better treatment of raised blood pressure and blood lipids.
Tragically, however, in many parts of the world patients with type 1 diabetes still die today as they did a century ago, simply because insulin is not available.
Type 2 diabetes
Type 2 diabetes is a heterogeneous condition, diagnosed empirically by the absence of features suggesting type 1 diabetes and of the many other conditions that cause hyperglycaemia. Diagnostic accuracy may depend on the thoroughness of investigation: e.g. up to 10% of subjects with late-onset diabetes show evidence of autoimmune β-cell damage and thus probably have slowly evolving type 1 diabetes (so-called latent autoimmune diabetes in adults, LADA).
The term ‘type 2’ replaces ‘non-insulin-dependent’ and ‘maturity-onset’ which were both clumsy and misleading: many type 2 patients require insulin to control hyperglycaemia and increasingly type 2 diabetes is being diagnosed in (overweight) children.
Epidemiology and demographic features
Type 2 diabetes accounts for 85 to 90% of diabetes worldwide. It is very common, affecting at least 3 to 4% of the white populations in most countries, with rates rising to between 8 and 11% in eastern Europe and North America. The prevalence rises with age to well over 10% of those over 70 years. It is substantially more common in certain immigrant populations living in more affluent countries, e.g. 10 to 15% of adults in some Asian or Afro-Caribbean groups in the United Kingdom are affected, compared with a prevalence of 4% in the white population.
Type 2 diabetes is most commonly diagnosed in those over 40 years of age and the incidence rises to a peak at 60 to 65 years. However, much younger people are now presenting with type 2 diabetes, following the rapid rise in childhood obesity. Up to one-third of North Americans diagnosed as diabetic under 20 years of age have type 2 diabetes, with Afro-Caribbean and Hispanic populations being at particular risk. Maturity-onset diabetes of the young (MODY) due to single-gene defects, commonly presents before 25 years of age in more than one generation, and is now classified separately (see below for more details); clinically MODY is becoming increasingly difficult to distinguish from common (polygenic) type 2 diabetes.
The prevalence of type 2 diabetes shows striking geographical variation—entirely different from that of type 1—and ranges from less than 1% in rural China to 50% in the Pima Indians of New Mexico. Prevalence is also rising rapidly, especially in developing countries and, worldwide, will increase by at least 50% within 10 to 15 years. This pandemic can be largely explained by Westernization, and is following in the wake of the obesity that is spreading throughout the world. The Pima Indians illustrate this process especially vividly; most developed and developing countries are now showing the same phenomenon, albeit more slowly. Diabetes was rare while the Pima tribes led a frugal existence in desert conditions and were lean and physically active. Following urban resettlement and exposure to overnutrition and inactivity, there were rapid increases in the prevalence of obesity (currently 80% of adult Pima Indians have a body mass index (BMI) of over 30 kg/m2) and later of type 2 diabetes. The Pima Indians’ spectacular susceptibility to obesity and diabetes may be explained by the selection of thrifty genes, i.e. those encouraging the storage of excess energy as fat, which would favour survival in their original harsh environment. In a setting of readily available food, cars, and television, the same thrifty genes would lead to obesity and ultimately diabetes (see below).
There is a 3:2 male preponderance among subjects with type 2 diabetes in Western countries although worldwide there is a 10% excess of females.
Type 2 diabetes is due to the combination of insulin resistance and β-cell failure, the latter preventing sufficient insulin secretion to overcome insulin resistance. These two components vary in importance between different individuals, who may be clinically quite similar, and each has numerous possible causes. Susceptibility is determined by the interactions between genes and environment. The steeply rising prevalence of type 2 diabetes suggests that diabetogenic genes are common and are now enjoying an unparalleled opportunity to express themselves through the global spread of Westernized lifestyle and obesity.
Overall genetic susceptibility to type 2 diabetes is probably 60 to 90%, rather less than was previously deduced from twin studies. Generally, transmission does not follow simple mendelian rules, and this polygenic pattern reflects the inheritance of a critical mass of minor diabetogenic polymorphisms which interfere with insulin action and/or insulin secretion. Having a first-order relative with the disease increases an individual’s chances of developing it fivefold, representing a lifetime risk in white people of about 40%.
Much progress has been made recently in identifying the gene loci predisposing to type 2 diabetes by using genome-wide scanning in large population databases. Importantly, these findings have been verified by repeat analyses in other data sets to exclude spurious statistical findings arising from the very large number of statistical comparisons performed. At least 9 loci have been confirmed, with predicted effects on insulin resistance (PPARG) and obesity (FTO), but interestingly, a greater number of confirmed loci seem to relate to pancreas development and/or insulin secretion (TCF7L2, KCNJ11, HHEX–IDE, CDKAL1, CDKN2, IGF2BP2, and SLC30A8). Although confirmed, the influence of each locus is relatively weak: the strongest association is with TCF7L2 (odds ratio for diabetes of high risk polymorphism is 1.5) with the remaining loci conferring odds ratios of 1.1 to 1.25. Taken together, the known loci still only explain a small proportion of the inheritance of type 2 diabetes, indicating that there are many more minor loci to be identified. Interestingly, none of the defined loci for common polygenic type 2 diabetes are the same as those identified to cause the much rarer monogenic diabetes syndromes of maturity-onset diabetes of the young (MODY, see below)
These clearly play a critical part, because obesity and type 2 diabetes are spreading too rapidly to be explicable by changes in the genome; environmental factors are also important in practice because they may be modified to treat and prevent the disease. Known environmental diabetogenic factors mostly induce insulin resistance (e.g. obesity, pregnancy, intercurrent illness, certain drugs). Hyperglycaemia per se can both impair insulin sensitivity and inhibit insulin secretion (glucotoxicity).
Obesity, itself determined by both genes and environment, is one of the most important risk factors, apparently due to aggravation of insulin resistance (see above). The diabetogenic properties of excess fat depend not only on its bulk but also on its anatomical distribution and the time of life at which it is laid down. The risks of developing type 2 diabetes begin to increase steeply once the BMI exceeds 28 kg/m2; some studies estimate the risk at a BMI over 35 kg/m2 to be 80-fold higher than for individuals with a BMI of less than 22 kg/m2—a lifetime risk of about 50%. Fat in the truncal (central) distribution is more diabetogenic than that deposited around the hips and thighs, and the visceral (intra-abdominal) depot is strongly associated with insulin resistance. Increasing adiposity after the early twenties, especially around the waist, aggravates the risk of a high BMI.
Physical inactivity, especially from the twenties onwards, is an independent predictor of diabetes in middle age, the risk increasing by about threefold for sedentary people as compared with regular athletes. This is due to worsening insulin resistance, which can be improved by physical training and may in part be due to changes in activity of the enzyme AMP kinase in skeletal muscle.
The Barker–Hales hypothesis suggests that poor fetal growth can programme enduring metabolic and vascular abnormalities that are manifested in adult life, especially in people who were underweight at birth but then become obese. These abnormalities include key features of the metabolic syndrome (hyperglycaemia, hypertension, dyslipidaemia), resulting in atheroma formation, myocardial infarction, and stroke (see above). Evidence, mainly from animals, suggests that maternal and therefore fetal malnutrition during a critical early phase of fetal development can reduce β-cell mass and permanently impair insulin secretory reserve; deficiencies of sulphur-containing amino acids may be responsible in experimental animals but the relevance to humans is unknown. Other studies suggest that insulin sensitivity may also be reduced into adult life.
β-Cell failure is an obligatory defect in the pathogenesis of type 2 diabetes: near normoglycaemia can be maintained even in severe insulin resistance (e.g. due to mutations in the insulin receptor), as long as the β cell can respond to the challenge and secrete enough insulin to overcome the resistance.
Subtle abnormalities of insulin secretion, including loss of the physiological pulses and of the first-phase response to intravenous glucose injection, are seen in normoglycaemic subjects who later develop the disease. These defects presumably indicate that the β cell is already stressed in trying to produce enough insulin to overcome insulin resistance. Normoglycaemic first-order relatives of type 2 diabetic subjects also show loss of pulsatility of insulin secretion which might indicate an inherited tendency to β-cell failure. The key role of β-cell failure in predisposing to type 2 diabetes has recently been underlined by the finding that most of the confirmed genetic susceptibility loci for type 2 diabetes relate to islet cell function or development rather than insulin resistance (see above).
The mechanism of β-cell failure in human type 2 diabetes is not known. Histologically, the islets in type 2 diabetes show no features of type 1 autoimmune insulitis, and β-cell mass is not so dramatically reduced. Animal models of the disease suggest various causes, including synchronized β-cell apoptosis (possibly mediated by nitric oxide) in the Zucker diabetic fatty rat, and the deposition of amyloid fibrils (see above) in the rhesus monkey. Amyloid deposits are also prominent in the islets of some type 2 diabetic patients but may merely be due to dysfunctional β-cell hypersecretion rather than the cause of β-cell damage. Once hyperglycaemia is established, glucotoxicity per se may further worsen both insulin secretion and insulin resistance. Elevated free fatty acid levels resulting from insulin resistance have also been proposed to impair β-cell function—so-called lipotoxicity—but this remains controversial.
In established type 2 diabetes, insulin secretion is unequivocally subnormal and tends to decline progressively with time, as illustrated by the long-term follow-up data from the United Kingdom Prospective Diabetes Study. Initially, plasma insulin levels may be higher than in nondiabetic subjects but are still inappropriately low, as the normal pancreas would produce much higher insulin concentrations in response to diabetic levels of blood glucose. Conventional radioimmunoassays may overestimate insulin levels in type 2 diabetic patients because of cross-reaction with incompletely processed insulin precursors (proinsulin and its split products) released by the constitutive pathway which operates in the malfunctioning β cell (see above). Many type 2 patients ultimately need insulin replacement; this indicates relatively severe insulin deficiency, although still not as profound as in type 1 diabetes. Some type 2 patients who require insulin early have autoimmune markers characteristic of type 1 diabetes, suggesting that they in fact have an indolent variant of type 1 diabetes. Although patients with type 1 diabetes have significantly lower insulin C-peptide levels at diagnosis than in type 2 diabetes, there remains overlap in the ranges such that C-peptide alone only has a sensitivity of 83% in diagnosing type 2 diabetes even in children.
Longitudinal and cross-sectional studies indicate that insulin resistance develops first and that compensatory increases in insulin secretion can initially maintain near normoglycaemia. Worsening insulin resistance is thought to drive the β cells towards maximal insulin output, a metastable stage that probably corresponds to impaired glucose tolerance (see above). Rescue is still possible if insulin resistance is decreased, e.g. through weight loss or insulin-sensitizing drugs: about 25% of subjects with impaired glucose tolerance return to normoglycaemia within 5 years. However, if insulin resistance persists or worsens, the β cells fail and insulin production falls. At this point, the brake limiting hyperglycaemia is released and blood glucose rises into the diabetic range. The bell-shaped response of insulin secretion, initially increasing to compensate but ultimately failing, has been termed the ‘Starling curve’ of the β cells because it recalls the classical plot of cardiac output against preload in heart failure.
In common type 2 diabetes, these events usually take many years, and significant hyperglycaemia may have been present for several years at the time of diagnosis. The whole process can be greatly accelerated by acute increases in insulin resistance as those induced by steroid treatment or pregnancy, to give just two examples.
Metabolic disturbances in type 2 diabetes
Hyperglycaemia is the most obvious abnormality, the extreme case being the hyperosmolar nonketotic state. Lipid metabolism is also disturbed but true ketoacidosis occurs only exceptionally and is usually provoked by intercurrent events such as infections or myocardial infarction.
Blood glucose concentrations are raised both in the basal (fasting) state and after eating. This reflects the impairment of insulin action in both liver and skeletal muscle, where insulin respectively shuts off hepatic glucose production and stimulates glucose uptake after meals. Hepatic glucose output is increased, due mainly to unsuppressed gluconeogenesis, and this is largely responsible for hyperglycaemia overnight and before meals. In muscle, GLUT-4 activity and glycogen synthesis are especially decreased; this reduces insulin-stimulated glucose uptake into muscle after meals, although basal glucose uptake (noninsulin mediated glucose uptake; see above) is higher than in normal subjects because of the mass action effect of hyperglycaemia. The degree of hyperglycaemia varies widely: many patients have fasting plasma glucose levels of 8 to 13 mmol/litre with postprandial peaks of up to 20 mmol/litre, while values exceeding 60 mmol/litre are not uncommon in the hyperosmolar nonketotic state.
Insulin deficiency is less profound than in type 1 diabetes, so mobilization of triglyceride (loss of body fat, ketoacidosis) and catabolism of protein (muscle breakdown) are not usually pronounced. Diabetic ketoacidosis may develop in patients with apparently typical type 2 diabetes who can subsequently be controlled by oral hypoglycaemic agents rather than insulin (see ‘Flatbush diabetes’ below). Diabetic ketoacidosis is usually precipitated by severe intercurrent illness (e.g. myocardial infarction, stroke, or pneumonia) in which excessive secretion of counter-regulatory stress hormones exacerbates the metabolic disturbance caused by relative insulin deficiency.
Many cases present with classical symptoms of osmotic diuresis, blurred vision due to hyperglycaemia-related refractive changes in the lens, and genital candidiasis (see Table 2).
Weight loss may occur but is generally less dramatic than with newly presenting type 1 diabetes, and may not be obvious because many type 2 patients—over two-thirds in the United Kingdom—are obese. Rapid or severe weight loss in patients who otherwise appear to have type 2 diabetes should be regarded with suspicion as it may point to an early need for insulin replacement (and possibly type 1 diabetes itself) or to coexisting illness: a well-recognized but unexplained association with recent onset type 2 diabetes is carcinoma of the pancreas.
The hyperosmolar nonketotic state can present with confusion or coma (see below); as mentioned above, diabetic ketoacidosis is rare.
Chronic diabetic complications may be a presenting feature, because hyperglycaemia severe enough to cause tissue damage may already have been present for several years. Extrapolating the numbers of microaneurysms (which only develop at diabetic glucose concentrations) in type 2 patients at various intervals after diagnosis suggests that significant hyperglycaemia is present for an average of 5 to 7 years before diagnosis. Common problems are arterial disease (myocardial infarction, stroke, and peripheral vascular disease), cataracts—which are especially common in the older population—and retinopathy, especially maculopathy, which can damage central vision, and foot ulceration.
Increasing numbers of people with diabetes are detected by screening, either in high-risk groups such as the obese and those with cardiovascular disease, or at routine health checks. Many of these are nominally asymptomatic but will admit to symptoms such as nocturia or perineal irritation if asked directly.
Prognosis of type 2 diabetes
A long-held and prevalent misconception is that type 2 diabetes is mild. Some patients do have relatively unexciting or asymptomatic hyperglycaemia but this can still be enough to cause complications which wreck the patient’s life just as much as in type 1 diabetes. Moreover, hyperglycaemia can be as hard to control (even with insulin) as in type 1 patients.
Overall, life expectancy is shortened by up to a quarter in patients with type 2 diabetes presenting in their forties, with vascular disease (myocardial infarction and stroke) being the main cause of premature death. Renal failure from diabetic nephropathy is becoming more common in type 2 patients as their survival from vascular complications improves, and the disease is now the most frequent pathology among people waiting for renal replacement therapy in the United States of America and some European countries.
Type 2 diabetes is therefore an important threat to the patient’s health and survival, and must be taken seriously by patients and their medical attendants, even if the blood glucose concentrations are not dramatically raised. Accordingly, treatment guidelines for the disease are rigorous. See table below:
|Table 3 Treatment targets for patients with diabetes|
|Low risk||Arterial risk||Microvascular risk|
|Fasting blood glucose (mmol/litre)||< 5.5||> 6.5||> 6.0|
|Postprandial peak glucose (mmol/litre)||< 7.5||≥ 7.5||> 9.0|
|HbA1c (DCCT aligned)||≤ 6.5||> 6.5||> 7.5|
|Serum lipids (mmol/litre)|
|Low risk||Arterial risk||High arterial risk|
|Total cholesterol||< 4.8||4.8–6.0||> 6.0|
|HDL cholesterol||> 1.2||1.0–1.2||< 1.0|
|LDL cholesterol||< 2.0||2.0–3.0||> 3.0|
|Fasting triglycerides||< 1.7||1.7–2.2||> 2.2|
|Blood pressure (mmHg)|
|General||< 130/80||> 140/90|
|Patients with microalbuminuria||< 125/75|
|Body-mass index (kg/m2)|
|Low risk||Acceptable||Increased risk|
|Men||< 25||25–27||> 27|
|Women||< 24||24–26||> 26|
DCCT, Diabetes Control and Complications Trial; HDL, high-density lipoprotein; LDL, low-density lipoprotein.
‘Ideal’ treatment targets (‘low-risk’ values) may not be appropriate for some patients. Risks are stratified for arterial disease and/or microvascular complications.
Collated from various sources including: European Diabetes Policy Group (1999). A desktop guide to Type 2 diabetes mellitus. Diabet Med, 16, 716–30; American Diabetes Association (2007). Standards of medical care in diabetes—2007. Diabetes Care, 30, Suppl 1 S4–S41; Ramsay LE, et al. (1999). British Hypertension Society guidelines for hypertension management 1999: summary. BMJ, 319, 630–5.
Monogenic diabetes: maturity-onset diabetes of the young (MODY) and neonatal diabetes
Maturity-onset diabetes of the young (MODY)
While the vast majority of diabetes is polygenic in origin, there is now an expanding list of single-gene loci that are associated with diabetes either in the neonatal period, in childhood, or in early adulthood. In 1974, Tattersall described a rare familial form of non-insulin-dependent diabetes that he distinguished from the generality of cases by its early age of onset, autosomal dominant inheritance, and an apparently low risk of microvascular complications. The term ‘maturity-onset diabetes of the young’ (MODY) came to be applied to individuals in which (1) a diagnosis of type 2 diabetes had been made under the age of 25; (2) there is evidence of autosomal dominant inheritance (diagnosis under the age of 25 in more than one generation); and (3) subjects can be managed without insulin.
In 1992, the first conclusive evidence for the existence of monogenic diabetes was provided when a subset of MODY (now known as MODY 2) was linked to the glucokinase gene locus. There are now seven forms of MODY, accounting for around 1% of all cases of diabetes, in which the gene has been identified.
Two forms predominate and have a distinctive clinical picture. MODY 2 (glucokinase mutations) is similar to the initial cases described by Tattersall with mild, nonprogressive fasting hyperglycaemia and a very low risk of long-term complications even without treatment. By contrast, MODY 3 (HNF1A mutations) is associated with progressive decline in glycaemic control. In addition, the renal threshold for glucose is low and there is a high risk of long-term complications. Of particular importance, MODY 3 is exquisitely sensitive to sulphonylureas and most patients wrongly diagnosed as having type 1 diabetes have been successfully transferred from insulin to sulphonylureas with improvement in glycaemic control. Doses required may be as low as one-quarter of the normal adult starting dose.
A diagnosis of MODY should be considered if:
- ◆ There is a family history of young-onset diabetes in more than one generation with at least one family member diagnosed under the age of 25.
- ◆ Affected members are not markedly obese or of normal weight.
- ◆ There is no evidence of insulin resistance—no acanthosis nigricans, low insulin doses if insulin treated, high-density lipoprotein greater than 1.2 mol/litre.
- ◆ Fasting C-peptide is detectable and within the normal range (not elevated).
- ◆ Islet cell or anti-GAD autoantibodies are absent.
- ◆ Other associated features are present. See table below:
|Table 4 Maturity-onset diabetes of the young (MODY)|
|Type||Genetic defect||OMIM||Frequency (% of MODY)||Clinical features||Sensitive to sulphonylureas|
|MODY 1||HNF-4α||125850||1%||Rare. Similar to MODY 3 but renal threshold normal. Consider if MODY 3 screen negative||May be sensitive|
|MODY 2||Glucokinase||125851||20%||Mild, nonprogressive fasting hyperglycaemia (5.5–8.5 mmol/litre, HbA1c < 6%). Glucose increment < 3.5 mmol/litre on OGTT. Complications rarely develop. Frequently do not response well to drug treatment and do not require it||No|
|MODY 3||HNF-1α||600496||60%||Young-onset diabetes. Not particularly overweight and not insulin requiring (no ketosis) or surprisingly good control for several years on little insulin. Detectable C-peptide beyond 3 years post-diagnosis. Low renal threshold. Large glucose increment (> 5 mol/litre) on OGTT. Progressive deterioration in glycaemic control and high risk of complications||Extremely sensitive|
|MODY 4||IPF-1||606392||1%||Rare. Possibly later-onset disease. Some affected family members may not be diabetic||Not determined|
|MODY 5||HNF-1β(TCF2)||137920||1%||Renal cysts and diabetes. Renal, uterine and/or genital developmental abnormalities are typical initial presentation especially renal cysts. Gout, abnormal LFTs. Subclinical pancreatic exocrine insufficiency||No|
|MODY 6||NEUROD1||606394||<1%||Rare||Not determined|
|MODY 7||CEL||610508||<1%||Rare||Not determined|
|MODY X||Unknown||15%||Not defined||Not determined|
HNF, hepatocyte nuclear factor; IPF-1, insulin promoter factor 1; LFT, liver function test; NEUROD1, neurogenic differentiation 1 transcription factor; OGTT, oral glucose tolerance test.
None of these criteria are absolute and where doubt exists, advice from an expert centre should be sought before requesting genetic screening. Detection of MODY 3 is of particular importance because of the excellent response to treatment with sulphonylureas.
Diabetes diagnosed under the age of 6 months is very unlikely to be type 1 (autoimmune) diabetes and alternative causes should be sought. Neonatal diabetes is insulin-requiring diabetes, usually diagnosed with the first 3 months of life, and two subgroups have now been identified. Transient neonatal diabetes mellitus (TNDM) resolves around 3 months after birth although it can return in later life in up to 50% of cases. The most common cause is an imprinting abnormality in the ZACN (ZAC) and HYMAI genes on chromosome 6 at the 6q24 locus. Macroglossia occurs in 23% of cases and is the only nonpancreatic feature. Presenting blood glucose levels are high (from 12 to >50 mmol/litre) and insulin is required: if relapse occurs, this is normally not insulin requiring, at least in the initial stages. MODY 5 and KCNJ11 (Kir6.2) mutations (see below) occasionally also present as TNDM.
Permanent neonatal diabetes mellitus (PNDM) requires continual insulin treatment from diagnosis. The most common cause is a mutation in the KCNJ11 gene, encoding the Kir6.2 subunit of the β-cell KATP channel. Ninety per cent of cases are due to spontaneous (new) mutations so there is no family history. Affected individuals may have a range of neurological abnormalities that in the most severe form are referred to as DEND syndrome (developmental delay, epilepsy, and neonatal diabetes). Patients with Kir6.2 mutations behave as insulin-deficient, with a 30% risk of ketoacidosis and low or undetectable C-peptide levels. However, the majority of patients respond well to high doses of sulphonylureas, given at up to 4 times the normal adult therapeutic dosage (e.g. glibenclamide 0.5–1 mg/kg per day), with the restoration of insulin secretion. Occasionally, MODY 2 and 4 may also present as PNDM as can other rare genetic syndromes (see below).
Other types of diabetes:
Diabetes in pancreatic disease
Chronic pancreatitis, most commonly due to alcohol abuse, causes diabetes that needs insulin in about one-third of cases. Widespread flecks of fine to medium calcification are often scattered through the pancreas, outlining it on a plain abdominal radiograph. Concomitant destruction of the islet α cells means that glucagon secretion is lost as well as insulin; diabetic ketoacidosis is therefore rare, while hypoglycaemia can be profound and prolonged—a particular hazard in those who continue to drink alcohol. Acute pancreatitis causes acute hyperglycaemia in 50% of cases but few develop permanent diabetes.
Carcinoma of the pancreas is associated with newly presenting type 2 diabetes, and should be suspected in older patients with weight loss (especially when accompanied by abdominal or back pain and jaundice). The mechanism is unknown but appears to be due to tumour products that cause insulin resistance rather than to β-cell loss.
Genetic diseases that cause diabetes through pancreatic damage include haemochromatosis and cystic fibrosis. In one-half of cases of haemochromatosis, heavy deposition of haemosiderin in the islets causes diabetes, usually requiring insulin; associated features are slate-grey skin pigmentation due to deposition of iron in the dermis (‘bronze diabetes’), cirrhosis, secondary gonadal failure, and pyrophosphate arthropathy. MRI shows abnormal signals in the liver and pancreas, while serum ferritin concentrations are greatly elevated; diagnosis is usually possible by means of molecular analysis of the HFE gene but Perls’ stain for iron deposition in a liver biopsy may be necessary. Diabetes due to excessive iron deposition in the pancreas is also seen in children surviving thalassaemia major. Cystic fibrosis causes pancreatic exocrine failure, with an increasing risk of diabetes (often requiring insulin) that approaches 25% in subjects who survive beyond 20 years of age.
This includes all degrees of hyperglycaemia (impaired glucose tolerance as well as overt diabetes) diagnosed during pregnancy in previously normoglycaemic women.
This controversial diagnostic category was omitted from the most recent WHO classification. It included ‘fibrocalculous pancreatic diabetes’ and ‘protein-deficient diabetes mellitus’. Fibrocalculous pancreatic diabetes was identified by dense pancreatic fibrosis, the formation of discrete and often spectacularly large stones in the dilated pancreatic ducts, and recurrent abdominal pain; protein-deficient diabetes mellitus was a vaguer entity that lacked the pancreatic stones. Patients conforming to these ‘syndromes’ were rare even in the tropical zones where they were described (<5% of all diabetes), and the current consensus is that they represent type 2 diabetes or chronic pancreatitis superimposed on malnutrition.
This term has been used to refer to diabetes in young Afro-Caribbeans who present with profound diabetic ketoacidosis but later prove to be non-insulin-dependent. It appears that at diagnosis they have both marked insulin resistance and impaired insulin secretion but the latter later recovers, sometimes sufficiently for them to go into prolonged remission. In at least one report there was an excess of HLA DR3 and DR4 alleles, but anti-GAD autoantibodies are negative.
Fulminant type 1 diabetes
This form of diabetes was first described in 2000 in Japan and refers to presentation with severe diabetic ketoacidosis but low HbA1c (<8.5%) relative to their initial marked hyperglycaemia, thus indicating an abrupt onset. Additional typical features include a short history of symptoms (2–10 days), raised pancreatic enzyme levels, and negative anti-GAD (and other) autoantibodies. Prevalence in Japanese and Korean populations may approach 20–30% of cases of rapid onset diabetes with ketosis, especially where the presentation is in adulthood and/or in pregnancy. It is rare in other races including white populations. Pancreatic biopsy reveals T-cell infiltrates in the exocrine pancreas, but without insulitis or features of acute pancreatitis.
Maternal transmission of mutations in mitochondrial DNA (mtDNA), especially the A3243G substitution in the leucine tRNA gene, can result in maternal inheritance of diabetes. Typical clinical presentation includes a presentation age of 20 to 50 with associated sensorineural deafness and short stature as in MIDD syndrome (maternally inherited diabetes and deafness). There is progressive nonautoimmune β-cell failure which may progress rapidly to insulin dependence (40% are insulin-dependent within 4 years) The same mutation occurs in MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) and both MIDD and MELAS can occur in the same family. The ratio of mutant to wild-type mtDNA in the blood (i.e. the degree of heteroplasmy) at diagnosis does not correlate with disease phenotype or severity, presumably because it does not reflect the degree of heteroplasmy in other tissues such as the pancreas.
Management of diabetes
The treatment of diabetes has traditionally concentrated on correcting hyperglycaemia, the most obvious and easily monitored biochemical abnormality and the cause of troublesome symptoms, as well as specific chronic diabetic complications. This approach has not been entirely successful, partly because it is difficult to normalize blood glucose but also because macrovascular disease—the principal cause of morbidity and premature death—is heavily dependent on other factors, notably hypertension and dyslipidaemia. The current treatment targets for both type 1 and type 2 diabetes (see Table 3) are therefore more holistic, tackling cardiovascular risk factors and obesity in addition to hyperglycaemia.
This section describes the roles of lifestyle modification and antidiabetic drugs, followed by specific treatment strategies for type 1 and type 2 diabetes.
Diet and lifestyle modification and management of obesity
About 80% of patients with type 2 diabetes are obese, as are at least 30% of those with type 1 disease. Obesity is arguably one of the greatest obstacles to successful management of diabetes: it worsens insulin resistance, dyslipidaemia, and hypertension and is now recognized in its own right as a risk factor for coronary heart disease. Proven benefits of 10% weight loss in type 2 patients with a BMI of 30 to 40 kg/m2 include falls in fasting glucose of 2 to 4 mmol/litre and a 1% decrease in HbA1c—comparable with sulphonylureas or metformin—and reduced dosages of antidiabetic drugs, including insulin. There may also be variable improvements in blood pressure and dyslipidaemia (decreased triglycerides and low-density lipoprotein cholesterol, increased high-density lipoprotein). The traditional focus on obesity has been on type 2 diabetes, but there is no reason to assume that the cardiovascular hazards of obesity do not also apply to type 1 diabetes.
Weight reduction is regarded as the cornerstone for treating obese type 2 diabetics but is often undermined by a lack of determination. Accordingly, doctors have little confidence in its efficacy and tend to assume that most obese patients will be ‘dietary failures’. However, with clear advice, better understanding of the causes of obesity, and the use of realistic targets, the currently poor track record of diet and lifestyle therapy can be greatly improved. All members of the diabetes team must understand the principles (but not necessarily the detail) of lifestyle management so that a strong and unified message can be given to the patient.
The notion of the ‘diabetic diet’ must now finally be laid to rest. Traditionally, carbohydrate intake was restricted because of the simplistic assumptions that sugar alone raised blood glucose and might even be diabetogenic; this strategy favoured a high fat intake that undoubtedly helped to sustain obesity and probably predisposed to atheroma. Current advice is close to the healthy eating recommendations for the whole population and can therefore be suggested for the patient’s entire family, which will greatly increase the chances of compliance.
The following diet and activity recommendations apply to both type 1 and type 2 diabetes. The aims are to:
- ◆ correct obesity, which worsens insulin resistance, reduces the efficacy of glucose-lowering, antihypertensive, and lipid-modifying drugs, and is an independent risk factor for macrovascular disease.
- ◆ reduce cardiovascular risk, by limiting fat, cholesterol, sodium, and alcohol intakes
- ◆ avoid hypoglycaemia in patients receiving insulin or sulphonylureas by optimizing the timing and content of meals.
Reducing total energy intake
This should be reduced by 500 to 600 kcal/day (2100–2520 kJ/day) in patients who are overweight (BMI >28 kg/m2). This energy deficit mobilizes fat preferentially, whereas protein, glycogen, and water are also lost with more aggressive energy restriction; initially, the rate of weight loss will be 0.5 to 1.0 kg/week (adipose tissue contains c.7000 cal/kg or 29 400 J/kg).
The desired energy intake should be calculated from standard formulae that employ the subject’s age, sex, weight, and level of physical activity to estimate energy expenditure, which must equal energy intake under steady state conditions. The standard dietary history is not useful for trying to assess energy intake, because overweight subjects consistently under-report how much they eat. Specific advice about how to cut energy intake is best left to the dietitian, but hinges on reducing fat intake—a simple message that can be reinforced by the entire diabetes care team. Fat-rich foods not only have the highest energy density (9 cal/g or 38 J/g, compared with 4 cal/g (17 J/g) for carbohydrate and protein), but also have poor satiating effects and so tend to encourage overeating.
The initial target should be a 10% loss of starting weight, not the ‘ideal’ body weight or BMI, which is only rarely attained by obese diabetic patients. When energy intake is cut acutely, type 2 patients often show an immediate fall in blood glucose, due to a drop in hepatic glucose output, even before weight loss begins.
Weight loss during an energy deficit of 500 to 600 cal/day (2100–2520 J/day) is a slow process: for a 100 kg patient, a 10% weight loss may take several months. Frequent contact and encouragement are the best predictors of success, and the patient should be reassured that weight loss by a small but tolerable change in lifestyle is much more likely to be maintained than weight lost by a crash diet. As weight falls, resting energy expenditure also declines: it is proportional to lean body mass, which also decreases, although at a slower rate than fat. This means that greater reductions in energy intake (>600 cal/day or 2520 J/day) will be needed to maintain the same rate of weight loss. If the 10% target is met, further loss towards an ‘ideal’ BMI of around 23 kg/m2 may be feasible.
Weight loss is harder to achieve in diabetic patients than in their nondiabetic counterparts; possible reasons include fears about sugar rather than fat, and the adipogenic effects of insulin, sulphonylureas, and thiazolidinediones. In practice, weight loss of even 10% is not commonly achieved by diet and lifestyle modification alone; only 15 to 30% of newly diagnosed type 2 diabetic patients can normalize glycaemia initially by this means, and fewer than 10% can sustain this for 5 years or more. The progressive β-cell dysfunction in type 2 diabetes (see above) makes it inevitable that the proportion of ‘dietary failures’ will increase steadily.
Improving dietary composition
Intakes of fat, salt, and refined sugar are generally too high in westernized populations. Current recommendations for healthy eating are based on evidence of beneficial effects on body weight, glycaemic control, lipids, and blood pressure. Fat should provide less than 30% of total energy intake (in most industrialized countries, it accounts for 40%). Polyunsaturated or monounsaturated fats (e.g. sunflower or olive oils respectively) are preferred to saturated animal fats, which should comprise less than 10% of total energy intake. Patients may need to be reminded that ‘good’ unsaturated fats still contain 9 cal/g (38 J/g) and therefore sustain obesity just as effectively as the others. Cholesterol should be limited to less than 250 mg/day (less if dyslipidaemia is present).
Carbohydrates should account for more than 55% of total energy intake, preferably in the form of foods rich in soluble fibre (e.g. pulses, root and leaf vegetables, and fruit); the current WHO recommendation for the general population is for the consumption of at least five portions of fruit or vegetables per day. Sugary drinks (especially fizzy glucose solutions that are supposed to give energy) should be avoided, except to treat hypoglycaemia. The present recommendation, which seems reasonable but is not based on evidence, is to limit added sucrose to less than 25 g/day and total sucrose intake to less than 50 g/day.
Protein should contribute 10 to 15% of total energy—close to current levels in the general population. Sodium intake should be less than 6 g/day, and less in patients with hypertension.
Alcohol contains 7 cal/g (29 J/g), and beers and wines in particular can be fattening. Intake should not exceed three units (30 g) per day in men and two units (20 g) per day in women, and should be further limited or avoided in those with hypertension or obesity. Alcohol can delay recovery from hypoglycaemia (see below); ‘diabetic’ beers (low in sugar, but strong in alcohol) and spirits with sugar-free mixers are especially likely to provoke hypoglycaemia.
Moderate amounts of sucrose are acceptable (see above), and noncaloric sweeteners (such as aspartame) have no adverse metabolic effects. Diabetic sweets and foods contain sorbitol or fructose instead of glucose, and are an expensive way to get diarrhoea; they should be avoided by patients, and withdrawn by the manufacturers.
Optimizing meal patterns
Judging the size and content of meals so as to limit glycaemic excursions remains an art rather than a science, and a skill which some patients develop with experience. Dosages of glucose-lowering drugs that act acutely to cover meals (short-acting insulin and sulphonylureas) can be tailored reasonably accurately to meals of similar composition but may not be matched to other meals, even when the total weights of carbohydrate, fat, and protein are similar.
There has been much interest in the ability of various foods to raise blood glucose, usually measured as the ‘glycaemic index’, i.e. the area under the curve of the rise in plasma glucose after eating a standardized load (50 g) of the food, expressed as a percentage of the area under the glucose curve after ingesting 50 g of glucose. Foods with a low glycaemic index include pulses and cereals, probably because of their high fibre and complex carbohydrate contents, while bread has a surprisingly high index. The glycaemic index of many foods such as potatoes and pasta varies widely according to the method of cooking (and even the shape of the pasta), and mixing different foods in a real-life meal has unpredictable effects on the overall postprandial glucose rise. It may be sensible to base meals around components with a low glycaemic index but it is clearly not feasible to use the index to adjust dosages of antidiabetic medication.
Appropriate portion size in meals is also important in limiting overall calorie intake. Portion size has crept up inexorably in restaurants in many countries and probably contributes to the observed association between excessive weight gain and eating outside the family home.
Increasing physical activity
Short-term exercise and improved physical fitness both increase insulin sensitivity, partly through increased translocation of GLUT-4 units to the surface of skeletal muscle cells resulting in increased glucose uptake; this effect is independent of insulin, and can enhance glucose uptake (under clamp conditions) better than metformin or the thiazolidinediones. Physical training also improves muscle blood flow. Several studies, notably the Finnish and American Diabetes prevention trials, have demonstrated that regular physical exercise reduces by over 50% the risk of impaired glucose tolerance progressing to type 2 diabetes. There is also evidence that it significantly decreases cardiovascular events. Exercise must therefore be encouraged in all diabetic patients, but the advice must be realistic, achievable, and safe. Brisk walking for 30 to 40 min every day is better physiologically than a hectic workout in the gym once or twice a week, and is within almost everyone’s reach.
Potential hazards of exercise include hypoglycaemia in patients on sulphonylureas or insulin, which may be delayed by several hours (see below), and cardiac disease. Patients at risk should have an ECG, with consideration for an exercise tolerance test and echocardiography, and appropriate treatment for ischaemic heart disease or heart failure. Exercise remains beneficial and important in these cases but should be built up gradually.
Antiobesity drugs and bariatric surgery in diabetes
Antiobesity drugs may be indicated in selected obese diabetic patients with a BMI over 28 kg/m2 and who have demonstrated, by losing weight beforehand through diet and exercise alone, that they are prepared to make long-term changes in their lifestyle. Without this commitment, clinically useful weight loss is unlikely to be achieved or maintained beyond the period of drug prescription; the medical and pharmacoeconomic benefits of modest weight loss for a couple of years in the obese patient’s middle age are not known but are probably not dramatic.
Drugs currently available in many countries are orlistat, a gastrointestinal lipase inhibitor, and sibutramine, a combined serotonin/noradrenaline reuptake inhibitor. With each of these, up to 30% of obese type 2 patients lose 10% or more of body weight within 6 to 12 months, HbA1c can fall by 1% or more, and dosages of glucose-lowering drugs, including insulin, may be decreased. More recently, the selective type 1 cannabinoid (CB1) receptor antagonist rimonabant was introduced; this reduces insulin resistance and may have the additional benefit of promoting smoking cessation. However, the exacerbation of pre-existing depression or anxiety has resulted in the drug being withdrawn by the manufacturer.
Surgical treatment with gastric banding or gastric bypass operations is indicated in selected patients with a BMI over 40 kg/m2. These operations are generally safe when performed by an experienced team and can achieve dramatic weight loss (up to 70% of excess fat, maintained for several years), often with an impressive reversal of glucose intolerance. Although randomized prospective studies have not been performed, reduction in medication and reversal of the diabetes state has been reported in 50 to 85% of subjects with type 2 diabetes undergoing bariatric surgery. Particularly dramatic results are seen with modern non-malabsorptive gastric by-pass procedures, perhaps because they increase GLP-1 secretion and reduced glucagon levels in addition to causing weight reduction. The cost-effectiveness and optimal indications for the use of weight-loss drugs or surgery in managing type 2 diabetes remain to be established.
Smoking is at least as common among diabetic patients as in the general population. Smoking greatly amplifies macrovascular risk in diabetic subjects: 10-year mortality (mainly from myocardial infarction) is about 50% higher than in diabetic nonsmokers and twice as high as in nondiabetic nonsmokers. Smoking may also accelerate the progression of nephropathy and possibly retinopathy.
Many diabetic people, especially young women, continue to smoke as a means of keeping thin, and because they fear gaining weight if they stop. Nicotine reduces fondness for sweet, energy-dense, foods and may also be mildly thermogenic. Weight gain after stopping smoking averages 3 kg but about 20% of cases gain more than 6 kg; much of this weight is often lost within the following 1 to 2 years, and it can be limited or prevented by careful dietetic support beforehand and in the months after cessation. Moreover, the risks of continuing to smoke are much greater than this degree of weight gain, especially in diabetic people. Pharmacological support to overcome nicotine dependence including the use of nicotine replacement, antidepressants (e.g. bupropion, nortriptyline) and the nicotine receptor partial agonist varenicline each increases the chance of quitting by around two- to threefold.
Insulin is the rational treatment for type 1 diabetes and the only drug that can normalize blood glucose in many type 2 diabetic patients. Unfortunately, subcutaneously injected insulin cannot match the physiological profile of normal insulin secretion and is a poor substitute for the finely tuned β cell with its nearly instantaneous capacity for ‘in-flight’ adjustment. Moreover, insulin given subcutaneously is absorbed into the systemic circulation rather than secreted into the portal system where an immediate effect on the liver, and first pass clearance by that organ, are important in regulating the metabolic actions of insulin.
Insulin was traditionally extracted from pork and beef pancreases in acid ethanol and purified by precipitation and recrystallization. Soluble (or ‘crystalline’) insulin prepared in this way was contaminated with other islet proteins, including glucagon and pancreatic polypeptide, which had an adjuvant-like effect and enhanced the immunogenicity of the injected insulin; immune reactions were relatively common with the ‘dirty’ animal insulins in use until the 1970s (see below). More sophisticated purification techniques including gel filtration yield ‘highly purified’ or ‘monocomponent’ insulins which only rarely provoke immune reactions.
Biosynthetic human-sequence insulin, produced by recombinant DNA technology, entered clinical practice in the early 1980s and was the first genetically engineered protein to be used therapeutically. The current approach is to introduce a synthetic gene for recombinant proinsulin or a novel insulin precursor into yeast; the secreted product is then cleaved enzymatically to yield insulin and C-peptide.
There are some clinically relevant differences between the three species used therapeutically, although the shortcomings of insulin therapy relate mainly to the general pharmacokinetic misbehaviour of injected insulin. Human insulin is more lipophilic than porcine and bovine insulins and is slightly more rapidly absorbed: human soluble insulin especially may lower glucose faster and patients being transferred from other species should be warned of this and prandial doses reduced initially by one-third. Human ultralente has a shorter and steeper action profile than its animal counterparts, particularly the bovine preparation; in real life, human ultralente behaves similarly to lente or isophane insulins and does not provide adequate basal levels for a full 24 h. Human insulin has been suggested to interfere with awareness of hypoglycaemia but the balance of evidence does not support this view (see below). Early beef insulins were especially prone to cause immune reactions (see below), although highly purified preparations do not appear to be particularly immunogenic.
Most insulin manufacturers are now turning to biosynthetic production of human-sequence insulin. Some patients prefer to continue using animal insulins—for reasons that may or may not appear scientifically sound—and these wishes should be respected by both clinicians and the pharmaceutical industry.
Absorption of insulin injected subcutaneously is slow and unpredictable. Individual day-to-day variability in the amount absorbed within a few hours can exceed 50%. This means that small changes (<10%) in insulin dosage are unlikely to influence glycaemic control, and that insulin treatment should generally not be adjusted on a daily basis.
Insulin absorption is influenced by the physical state of the insulin (soluble or delayed action), its speed of dissociation into monomers, the lipophilicity of the insulin species, and by blood flow and other characteristics of the injection site. Absorption is accelerated, and may lead to noticeably faster falls in blood glucose, by stimulating general or local blood flow through exercise, hot climate, saunas, and/or massaging the injection site. Conversely, absorption is slowed when subcutaneous blood flow is reduced, e.g. in cold conditions or hypovolaemic states. Lipohypertrophy, which may develop at frequently used injection sites, can significantly delay absorption—another reason for avoiding such areas.
The anatomical site of injection also influences the rate of subcutaneous absorption. It is fastest in the abdomen (also a good site to limit any effects of exercise) and arm, and slower in the leg. These differences are often eclipsed by the overall variability in absorption. Absorption from muscle is faster, presumably because of its higher blood flow, and this route is preferred for the emergency treatment of hyperglycaemia or ketoacidos if the best option, controlled intravenous infusion, is not practicable.
Soluble (regular or short-acting) insulin injected subcutaneously begins to lower glucose within 30 min, has a peak effect between 1 and 2 h and lasts 3 to 5 h. This action profile is suitable for covering meals or hyperglycaemic emergencies and for use in insulin pumps or infusions. However, it would have to be injected several times per day to control hyperglycaemia around the clock, at the cost of frequent hypoglycaemia. Long-acting preparations are therefore used to cover basal insulin requirements.
Various approaches have been used to slow and prolong insulin absorption, especially the chemical combination of insulin into complexes that release it slowly. More recently, synthetic analogues have been designed whose structure promotes precipitation when injected subcutaneously.
Isophane insulins are also known as NPH (neutral protamine Hagedorn, from the director of the Danish laboratory where they were developed). They consist of a microcrystalline complex of insulin and the highly basic protein protamine (intriguingly isolated from fish sperm), together with trace amounts of Zn2+. Isophanes were derived from protamine–zinc insulin which has a longer but highly unpredictable action profile. Isophanes produce peak plasma insulin levels at variable intervals between 4 and 8 h after injection, and their glucose-lowering action wears off rapidly after 10 to 12 h.
Insulin–zinc suspensions (lente insulins) employ higher Zn2+ concentrations which encourage insulin to form crystalline lattices. Varying the reaction pH can produce either larger crystals which are particularly slow to dissolve (ultralente) or the amorphous semilente which releases insulin faster; the familiar lente is a 70:30 mixture of ultralente and semilente. Ultralente made with bovine insulin has a long, relatively flat action profile that can last 24 h or more, while human ultralente and the lente insulins of all three species have glucose-lowering profiles similar to that of isophane. These long-acting insulins have a cloudy appearance and need to be shaken before use to bring the insulin into suspension; visibly large particles or discoloration indicates that the insulin has become denatured and will have lost activity. Both lente and isophane insulins can be injected alone or mixed with soluble insulin.
Premixed insulins contain a short-acting soluble component together with a longer-acting lente or isophane. The aim is to provide prandial cover and then basal levels for several hours thereafter. Many preparations are available, with the proportion of short-acting insulin varying from 10 to 50%. Mixtures with a 30:70 ratio are popular.
All these insulin types have been produced with porcine-, bovine- and human-sequence insulins, and are available in catridges for pen injection devices.
The pharmacokinetic properties of native insulins of any species are poorly suited to subcutaneous injection: soluble insulins (despite their high-speed trade names) are too slow and prolonged in duration, while long-acting insulins do not provide reliable enough 24-h basal levels to be given once daily. Various synthetic insulin analogues, designed by molecular modelling, have improved physicochemical characteristics.
Fast-acting analogues are modified at the C-terminal end of the B chain, an area crucial in the self-association of insulin molecules, so as to resist dimerization and hexamerization. Insulin hexamers formed in the subcutaneous injection site, dissociate slowly into absorbable monomers, and this is a rate-limiting step in insulin absorption. Faster-acting analogues include insulin lispro (interchanging the B28 lysine and B29 proline residues of the normal human sequence) and insulin aspart, which carries aspartic acid at position B28 instead of the usual proline. They have an appreciably faster and shorter action profile, and day-to-day variability in absorption and glycaemic responses may also be decreased. They can therefore reduce both prandial hyperglycaemia and the risk of postprandial hypoglycaemia. Despite these theoretical advantages, meta-analyses show only very modest reductions in HbA1c (c.0.1%) and reductions in hypoglycaemic episodes when a fast-acting analogue is substituted for soluble insulin, but there are significant improvements in quality of life generally attributable to the convenience of injecting immediately before or after meals rather than 30 min beforehand.
Long-acting insulin analogues have also been developed. These are designed to give a smoother 24-h profile than isophane (‘peakless’ insulin). At present two forms are available. Insulin glargine (A21glycine, with two extra arginine residues extending the C-terminal of the B chain) has an altered isoelectric point such that it is soluble in the vial or cartridge at pH 4 but precipitates under the skin at pH 7. Insulin detemir has a delayed action due to the addition of a fatty acyl chain that binds to plasma proteins such as albumin. It has a slightly shorter half-life than glargine and can be given once or twice daily. Both analogues are clear in the vial or cartridge—potentially a source of confusion with rapidly acting insulin. Claims have been made for improved HbA1c levels and less daytime hypoglycemia, as well as weight loss or neutrality for detemir in type 2 diabetes, but the most robust finding appears to be a reduction in nocturnal hypoglycaemia.
Hypoglycaemia is the most common complication of insulin treatment and can be unpleasant, debilitating, and occasionally life-threatening.
Mild hypoglycaemia is common—many insulin-treated patients have at least one episode most weeks—but serious attacks causing unconsciousness or requiring the assistance of others are rare, about once every 3 patient years. Predictably, the frequency of both mild and severe attacks rises progressively when mean blood glucose levels are lowered by intensive insulin therapy; hypoglycaemia was three times more frequent in the tightly controlled group of the Diabetes Control and Complications Trial than in conventionally treated patients (see below).
The manifestations and treatment of hypoglycaemia are covered in detail later. As discussed there, there is no convincing evidence that the use of human as opposed to animal insulins specifically interferes with awareness of hypoglycaemic symptoms.
Weight gain is due to the anabolic effects of insulin, compounded by energy saved from glycosuria and sometimes by overeating after hypoglycaemia. Fear of weight gain discourages some patients, especially young women, from taking their full insulin dosages; surprisingly often, deliberate omission or underdosing of insulin may be used by patients wishing to stay thin.
Lipohypertrophy is the local thickening of subcutaneous tissue at frequently used injection sites, and is probably due to the lipogenic effects of high local insulin concentrations. Lipohypertrophy can be unsightly and can significantly delay insulin absorption. It can be prevented by rotating injections around several sites, and large lesions can be removed by liposuction.
Insulin allergy, now very rare with highly purified (especially human) insulins, can include local IgE-mediated erythematous reactions or even anaphylaxis. The commonest manifestation is repeated pain at the site of injection. Lipoatrophy (localized pitting of the skin due to loss of subcutaneous fat) is apparently related to a chronic immune response generated around insulin crystals. Immune insulin resistance was seen with impure animal and especially bovine insulins; high titres of insulin-binding antibodies mop up free insulin from the circulation, resulting in very high insulin requirements (occasionally more than 10 000 U/day), sometimes with unpredictable hypoglycaemia following the release of antibody-bound insulin.
Insulin oedema is rare, and is usually seen in patients recovering from ketoacidosis who have been deprived of insulin for long periods. Fluid retention is probably due to the sodium-conserving effects of insulin on the renal tubule, and may cause ankle or generalized oedema. It usually resolves within a few days, although treatment with diuretics or ephedrine may be required. Insulin neuritis refers to severe, persistent neuropathy following the use of insulin in individuals with very poor control glycaemic control; however, this is a consequence of the sudden improvement in metabolic state rather than a side effect of the insulin itself.
Different individuals may need quite different insulin regimens, depending on their residual insulin reserve and severity of insulin resistance, as well as the desired tightness of control and the inconvenience that the patient will accept. Specific insulin schedules used in type 1 and type 2 diabetes are described later.
The healthy pancreas secretes about 40 to 60 U of insulin daily. Therapeutic insulin requirements range from less than this in thin type 1 patients (notably during the ‘honeymoon period’) to more than 200 U/day in very obese, insulin-resistant type 2 patients. High insulin requirements are often due to insulin resistance (see above), whereas low or falling dosages may be caused by weight loss (including anorexia nervosa), coeliac disease, or loss of counter-regulatory hormones in Addison’s disease or hypothyroidism—all these conditions being associated with type 1 diabetes. Changing dosages, especially in previously stable subjects, should prompt investigation of these possibilities. Some patients with ‘brittle’ diabetes or psychological maladaptation to life with diabetes may pretend to take very high or very low dosages (see later). Interestingly, insulin requirements via continuous subcutaneous infusion are typically 30% less than by intermittent injections.
Formularies contain a bewildering assortment of insulins, many distinguished by imaginative claims about their action profile. Practically, prescribers should become familiar with regimens based on one or two preparations from the following broad classes:
- ◆ Fast-acting insulin: either a soluble (regular) insulin such as Humulin S or Actrapid, injected 20 to 30 min before eating, or a faster-acting analogue (e.g. lispro or aspart) which can be given immediately before or even shortly after eating
- ◆ Long-acting insulin: either a lente insulin (e.g.Humulin Zn or Insulatard) or an isophane (e.g.Humulin I or Monotard). With either, circulating insulin falls to below useful levels after 10 to 14 h; they therefore need to be given twice daily in C-peptide negative patients, although those with residual insulin secretion (or who are given three premeal injections of soluble insulin) may be able to maintain good glycaemic control with a single bedtime injection. Bovine (but not human) ultralente can last a full 24 h, but its absorption is erratic and it is rarely used. The long-acting analogues currently available (such as insulin glargine and detemir) have flat, steady action profiles that can provide basal insulin levels with a single daily injection. The timing of long-acting insulin injections does not have to be yoked to mealtimes as tightly as for soluble insulin. It is convenient to inject the dose at bedtime rather than together with the before-supper soluble dose. This is because the action profile of long-acting insulin clashes with the physiological changes in insulin sensitivity that occur overnight. Growth hormone is normally secreted in large spikes on entering deep sleep, typically between 24.00 and 02.00 h; this induces delayed insulin resistance which raises blood glucose during the hours leading up to breakfast. This ‘dawn phenomenon’ is accentuated if insulin levels are falling simultaneously—as happens if long-acting insulin is injected in the early evening. Another hazard with this timing is potentially dangerous nocturnal hypoglycaemia when insulin levels peak during the early morning (typically 02.00–04.00). Both problems can be reduced by delaying the long-acting injection until bedtime (22.00–23.00), when the risk of nocturnal hypoglycaemia is lower, and insulin levels generally persist long enough to counteract the insulin resistance of the dawn phenomenon. If a second injection is required, this can be given with the before-breakfast soluble insulin. Note that the long-acting analogue insulins (glargine and detemir) should not be mixed in the same syringe as short-acting insulin.
- ◆ Premixed insulins (e.g. 30% short-acting with 70% long-acting) are obviously more convenient than giving short- and long-acting insulins separately, but they lack flexibility. Premixed insulin injected 30 to 40 min before breakfast can achieve good glycaemic control through the morning and afternoon, but timing the evening dose is problematic: giving it before supper will tend to cause both early morning hypoglycaemia and fasting hyperglycaemia because of the time course of the long-acting component, and simply increasing the evening dosage often makes nocturnal hypoglycaemia worse while failing to lower the before-breakfast glucose. Premixed preparations including rapidly acting analogues such as insulin aspart or lispro and isophane are also available and may be of some advantage.
Most insulin formulations are now available for both conventional syringes or pen injection devices. Pen injectors are compact, convenient, and easy to use: the required dose is ‘dialled up’ and injected by pressing the plunger; the ratchet mechanism of most pens gives an audible click that can help blind patients to count dosages.
Syringes and pens carry very fine (28–31 G) needles that allow insulin to be injected almost painlessly. The needle should be pushed in vertically and the insulin injected over a few seconds. Injecting into a pinched up fold of skin to avoid intramuscular injection is advisable in places where there is limited subcutaneous tissue. Backtracking of insulin to the skin surface, which can occasionally cause loss of several units of insulin, may be reduced by leaving the needle in place for a short while. A spot of bleeding may occur; very rarely, sudden hypoglycaemia may be due to direct injection of insulin into a subcutaneous vein.
Injections can be given into any site that is accessible and well padded with adipose tissue, especially the abdomen, thighs, buttocks, and upper arms. The abdomen has the advantage (theoretically at least) of relatively faster absorption that is less influenced by exercise, as compared with the limbs. Rotating injection sites, e.g. between the abdomen and leg, or around the quadrants of the abdomen, helps to avoid local reactions, especially lipohypertrophy which can make insulin absorption slow and erratic.
Jet injectors fire a metered dose of insulin as a high-pressure aerosol that penetrates the skin. These have obvious appeal to patients with needle phobia, although there may be bruising and delayed discomfort at the injection site. Jet injectors are bulky and expensive and do not offer any pharmacokinetic advantages over conventional injections.
Several companies have developed an aerosol formulation of insulin that can be inhaled into the lower airways (insulin is not absorbed from the nasal passages). Inhaled insulin has almost identical pharmokinetic characteristics to subcutaneously injected soluble insulin and so its use might be considered to be predominantly a matter of convenience to avoid injections, especially in those with injection site problems or needle phobia. Sophisticated pharmaceutical preparation and delivery devices are required to ensure accurate dosing. It cannot be used by current smokers (as absorption is variably enhanced to an unpredictable degree) or subjects with chronic airways disease including asthma and chronic obstructive pulmonary disease. Transient cough may occur. Regular lung function testing is advised, as there is a progressive fall in lung function although in most people this is no more rapid than the reduction with age. An increase in insulin autoantibodies has been noted although the significance is uncertain. Inhaled insulin can be used in both type 1 and type 2 diabetes although in type 1 diabetes a subcutaneous injection of intermediate acting insulin is still required. The long-term risks of inhaling insulin over many years are not known and there is a theoretical concern of an increased risk of lung neoplasia. Currently no preparations of inhaled insulin are available. The marketed preparation was withdrawn due to poor sales as it was considerably more expensive than subcutaneous insulin.
Portable insulin pumps that administer continuous subcutaneous insulin infusion were developed by Pickup and colleagues in the late 1970s. Modern pumps are compact and light and worn in a belt or holster. Soluble insulin in a special cartridge is delivered through a fine-bore butterfly-type cannula, which is inserted subcutaneously in the anterior abdominal wall or other suitable site and generally left in place for 2 to 4 days; the pump can be safely removed for up to 60 min for bathing or other activities. Different basal rates can be preprogrammed, and mealtime boluses are selected and given by pressing a button. Typical basal rates are 0.5 to 1.5 U/h during the day and 0.5 to 1 U/h overnight, with mealtime boluses (given immediately before meals or snacks) amounting to about 50% of the total daily dose. Most centres use rapid acting analogues in pumps and there is trial evidence to support this.
CSII can achieve relatively steady insulin levels under laboratory conditions and can partly overcome the variability of subcutaneous insulin absorption seen with intermittent injections of larger doses. When used carefully by highly motivated patients who are supported by an experienced diabetes care team, continuous subcutaneous insulin infusion can achieve glycaemic control which is at least as good as that achieved with multiple injections; the two were used side by side in the Diabetes Control and Complications Trial. Insulin pumps are expensive (£2600–£3500 or US$5000–US$6000) as are consumables (another £1800 per year); medical backup can also be costly to provide. Continuous subcutaneous insulin infusion is indicated for well-informed patients with type 1 diabetes who are prepared to monitor their blood glucose frequently, learn carbohydrate counting, and take responsibility for adjusting the pump. It provides more flexibility for varied lifestyles than multiple daily doses. Randomized trials suggest modest reductions in HbA1c and reduced hypoglycaemia. Although not all randomized trials confirm this, with careful patient selection, these benefits are frequently seen in clinical practice and many patients refuse to return to conventionally delivered insulin. CSII appears to be most beneficial in patients striving hard to improve glycaemic control who are limited by recurrent hypoglycaemia. It is widely used in the United States of America and many European countries.
Infections at the infusion site with pyogenic skin commensals or unusual organisms (e.g. atypical mycobacteria) are uncommon but can be troublesome and cause rapid deterioration in glycaemic control. An increased rate of diabetic ketoacidosis was reported with earlier and less reliable pumps. With CSII, the subcutaneous insulin depot is only a few units, and any interruption of insulin delivery (e.g. with pump failure or cannula blockage) can lead to rapid rises in blood glucose and especially ketone levels. However, modern pumps carry no excess risk of diabetic ketoacidosis as compared with intensified injection therapy. Similarly, the risk of hypoglycaemia due to the pump overrunning is now very low.
With the advent of continuous glucose sensing technology, attempts have been made to develop a closed-loop system for CSII. However, to date, these have had limited success as the pump cannot respond rapidly enough to large meals or sudden exercise to avoid major swings of blood sugar. Wireless technology is now available to display glucose levels on the pump, thus allowing the operator to adjust the insulin delivery rate, but continuous sensing is currently twice as expensive as CSII itself because of the cost of the probes.
The peritoneum is a good route for insulin administration: absorption is very rapid across its large surface area and insulin enters the portal circulation. Continuous intraperitoneal insulin infusion has been used in some cases, mostly employing a pump and reservoir implanted subcutaneously in the abdomen and delivering insulin through a flexible cannula sewn into the peritoneal cavity. The reservoir is filled with soluble insulin through an injection port lying just beneath the skin and is emptied by a liquid/gas compression system at a rate that can be varied by an external electromagnetic control. Continuous intraperitoneal insulin infusion can provide basal insulin; meals need to be covered by additional insulin, either injected subcutaneously or triggered by an external control device.
Intraperitoneal pumps are expensive, and convincing indications for their use are rare. They have been successful in some patients with apparently very high subcutaneous insulin dosages but surprisingly normal intravenous requirements. It is now clear that this situation is not due to a mysterious syndrome of ‘subcutaneous insulin resistance’, and that most of, if not all, these patients are interfering with their own treatment (see below). In this setting, continuous intraperitoneal insulin infusion is probably effective because these pumps are difficult to sabotage.
Oral hypoglycaemic agents
The sulphonylureas were the first orally active glucose-lowering drugs to be used and were discovered in the 1930s when early sulphonamide antibiotics were found to cause hypoglycaemia. The first generation (chlorpropamide, tolbutamide) have since been superseded by the second generation (e.g. gliclazide and glibenclamide) and by newer agents such as glimepiride. Repaglinide acts in a similar way to the sulphonylureas.
Mode of action
Sulphonylureas are insulin secretagogues but insulin synthesis is not stimulated. Insulin levels peak within 1 to 2 h and decline within 4 to 6 h for the short-acting drugs (such as gliclazide) but may remain elevated for much longer with chlorpropamide and glibenclamide, which therefore carry a greater risk of hypoglycaemia. An extrapancreatic action has also been attributed to sulphonylureas, i.e. improving insulin sensitivity. This effect is small and is probably explained by the nonspecific decrease in insulin resistance (glucotoxicity) when hyperglycaemia is corrected by any means.
Repaglinide acts in a similar way to the sulphonylureas but is structurally different. It is derived from the nonsulphonylurea part of the glibenclamide molecule (called meglitinide), which was found fortuitously to have glucose-lowering activity of its own. Nateglinide behaves in a similar fashion and both of these drugs are particularly effective at increasing insulin levels after meals, although the marketing title of postprandial glucose regulators is overstated.
Efficacy and potency
The ability of these agents to lower glycaemia depends on how much insulin is available for release from the β cells (which are already stimulated by hyperglycaemia) and by the severity of insulin resistance. In practice, all sulphonylureas lower basal and postprandial glucose levels by no more than 2 to 4 mmol/litre and HbA1c by 1 to 2%; mild hyperglycaemia may therefore be corrected but patients with fasting glucose in excess of 13 mmol/litre are very unlikely to achieve normoglycaemia (primary failure). Moreover, as β-cell function declines progressively in type 2 diabetes, many patients who initially respond well to sulphonylureas will subsequently need additional glucose-lowering drugs; this secondary failure overtakes 5 to 10% of patients per year, in a cumulative fashion. These limitations apply to all sulphonylureas and repaglinide: the more potent drugs have lower therapeutic dosages than the earlier agents but cannot lower glycaemia any further.
Most are taken twice daily with meals; glimepiride is taken once daily and repaglinide with each meal. Chlorpropamide has a very long action profile, while glibenclamide shows variable and sometimes prolonged hypoglycaemic activity. Sulphonylureas and repaglinide bind to circulating proteins and may be displaced by other strongly protein-bound drugs, causing hypoglycaemia (see below). All these drugs are cleared through the kidneys and can accumulate in renal failure, causing frequent hypoglycaemia and other side effects. Gliquidone and tolbutamide are metabolized mainly in the liver and may be slightly less hazardous in patients with renal impairment, although insulin is usually indicated in these cases.
Weight gain is due to the anabolic effects of hyperinsulinaemia, compounded by reduced losses of energy through glycosuria. Weight gain is typically 2 to 3 kg greater than with diet alone or metformin.
Hypoglycaemia is rarer than with insulin, but the risk is greater with longer-acting sulphonylureas (glibenclamide, chlorpropamide), in renal failure, and especially in older people.
Sulphonylureas can cause allergic reactions including skin rashes (notably Stevens–Johnson syndrome) and marrow dyscrasias, and can precipitate acute intermittent porphyria. Side effects exclusive to chlorpropamide include the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and acetaldehyde-mediated facial flushing on drinking alcohol.
The cardiovascular safety of sulphonylureas has remained under a cloud since tolbutamide was associated with an excess of cardiovascular deaths during an essentially uninterpretable study (the University Group Diabetes Program or UGDP) conducted in the 1970s; the presence of the ABCC9 (SUR2) receptor on cardiomyocytes has recently reinforced suspicions that these drugs may trigger ischaemia and arrhythmias (by preventing preconditioning). However, the long-term United Kingdom Prospective Diabetes Study found no evidence that patients treated with sulphonylureas suffered cardiovascular events more often than those treated with insulin. Glimepiride is highly selective for ABCC8 (SUR1).
Indications and contraindications
These drugs can be used as first-line therapy for nonobese subjects with type 2 diabetes in whom lifestyle and dietetic measures have failed to control hyperglycaemia. However, because of their tendency to increase weight, in the overweight majority of type 2 diabetes patients, sulphonylureas are used as second-line agents, typically combined with metformin, which may partly offset the weight gain.
Insulin secretagogues are inappropriate for severely insulin-deficient patients or during intercurrent illness, when insulin is needed, and are unlikely to be effective if fasting glucose exceeds 13 mmol/litre. Sulphonylureas are contraindicated in renal failure: all should be stopped and insulin started if serum creatinine exceeds 250 µmol/litre. Pregnancy has been viewed as a contraindication, because sulphonylureas cross the placenta and could cause fetal hyperinsulinaemia and perhaps teratogenesis; however, a recent study with glibenclamide which has less transplacental passage, did not substantiate these concerns. Sulphonylureas are the therapy of first choice in patients with HNF1α MODY, since these subjects are exquisitely sensitive to these agents, and in patients with the Kir6.2 mutation, who may require very high doses (see above).
Many drugs interact with sulphonylureas, the most common outcome being hypoglycaemia due to displacement and/or decreased clearance of protein-bound sulphonylureas (e.g. by sulphonamides, fibrates, salicylates, and probenecid). Potential interactions must always be checked for any drug being contemplated in patients receiving sulphonylureas.
Choice of drug
There is little to choose between the newer agents; chlorpropamide is now obsolete. Glibenclamide should be avoided in older people because of its unpredictable tendency to cause hypoglycaemia.
Metformin and phenformin are biguanides, the class of compounds responsible for the mild hypoglycaemic action of goat’s rue Galega officinalis (an otherwise undistinguished weed). Phenformin is no longer available in many countries because it carries a 10-fold greater risk of lactic acidosis, and metformin has only fairly recently entered clinical use in the United States of America.
Mode of action
Metformin acts primarily by inhibiting gluconeogenesis in the liver, thus reducing the raised hepatic glucose output which underpins basal and overnight hyperglycaemia; this effectively enhances the action of insulin on the liver. AMP kinase, a key enzyme that balances anabolic and catabolic processes in the liver and other tissues, is an important target for metformin action. Peripheral glucose uptake may also be increased, while gastrointestinal side effects may help to reduce fondness for food. Metformin does not stimulate insulin secretion.
Overall, metformin lowers blood glucose (especially postprandial) by 2 to 4 mmol/litre and HbA1c by 1 to 2%, which is comparable to the effect of sulphonylureas. On its own, metformin does not cause hypoglycaemia, although this can obviously occur when it is combined with either a sulphonylurea or insulin. Weight does not usually increase with metformin, and may fall.
Metformin may have beneficial cardiovascular effects, as the United Kingdom Prospective Diabetes Study found a reduction in vascular events in the metformin-treated group only (see below). It is not clear whether this is related to the specific metabolic effects of metformin (improved insulin sensitivity), to its mild antiobesity properties, or to other actions such as reported reductions in blood pressure and coagulability.
Metformin is given twice or three times daily with meals. It is cleared mainly through the kidneys, and the increase in plasma levels in renal failure is a major risk factor for lactic acidosis. Recently, a slow-release preparation has been marketed which is taken once daily and appears to produce fewer gastrointestinal side effects.
Gastrointestinal symptoms (30% of cases) include altered taste, loss of appetite, heartburn, abdominal discomfort and bloating, and diarrhoea (metformin is the most common cause of this in the diabetic clinic). These problems are mostly mild, but may discourage the patient from taking the drug; they can be reduced by starting with a low dosage and increasing it slowly.
Lactic acidosis is very rare with metformin (about 3 cases per 100 000 patient-years) if it is carefully prescribed. This stems from the mode of action of metformin, namely the inhibition of hepatic gluconeogenesis—a process that constantly consumes the lactate produced by glycolysis. Blood lactate levels are modestly raised in patients receiving biguanides, and can escalate rapidly and cause life-threatening acidosis if lactate is overproduced (e.g. in respiratory or cardiac failure), or is not cleared by the liver (hepatic failure), or if metformin accumulates in renal failure. The risk is also increased in the presence of excessive amounts of alcohol. Lactic acidosis is described in detail later. Megaloblastic anaemia can occur due to impaired absorption of vitamin B12 and 5-yearly vitamin B12 estimations have been recommended.
Indications and contraindications
Metformin is now considered the first-line treatment for type 2 diabetes in type 2 patients whose hyperglycaemia does not respond adequately to modification of diet and lifestyle; as it does not tend to cause weight gain, and may even reduce weight, it is especially valuable in obese patients. Recent American Diabetes Association guidelines propose starting metformin concurrently with lifestyle interventions, but this is not universally accepted. The addition of metformin can also be helpful in obese patients who are poorly controlled by sulphonylureas or insulin. Metformin has also proved beneficial in other insulin-resistant conditions such as polycystic ovary syndrome (resulting in improved fertility, reduced hirsutism and oligomenorrhoea) and impaired glucose tolerance where it reduces progression to diabetes by around 25%.
Contraindications include all the major organ failures—renal, hepatic, cardiac, and respiratory. It should not be used when serum creatinine concentration exceeds 150 µmol/litre or the estimated GFR is less than 30 ml/min. It must also be discontinued 2 days before giving radiographic contrast media, to reduce the risk of renal impairment.
Thiazolidinediones are a novel class of glucose-lowering drugs which improve insulin sensitivity. There are distinct differences between individual thiazolidinediones which influence their therapeutic spectrum and safety. Rosiglitazone and pioglitazone are currently available in many countries; troglitazone has been withdrawn because it caused rare but life-threatening hepatic damage.
Mode of action and pharmacokinetics
Thiazolidinediones bind to specific receptors in the nucleus which have the cumbersome title of peroxisome proliferator activating receptor-γ (PPAR-γ). PPAR-γ and the related PPAR-α (the target for the fibrate class of lipid-lowering drugs) are ligand-activated transcription factors whose natural li gands appear to be fatty acid derivatives. PPAR-γ that has bound a thiazolidinedione forms a heterodimeric complex with another nuclear receptor, retinoid X receptor, bound to its own endogenous ligand, retinoic acid. The heterodimer then binds to specific recognition motifs found in the promoter sequences upstream of many genes, notably those involved in adipocyte and lipid metabolism.
The affinity of individual thiazolidinediones at PPAR-γ parallels their glucose-lowering ability in animal models of type 2 diabetes, but their precise mode of action remains uncertain. Thiazolidinediones exert concerted effects that encourage the storage of triglyceride in mature adipocytes, including the differentiation of preadipocytes into adipocytes and enhanced expression of lipogenic enzymes; overall, circulating levels of free fatty acids fall and this may reduce hepatic glucose production and increase glucose uptake into muscle as described earlier. The net effect is to enhance the action of insulin—hence their description as insulin sensitizers. Thiazolidinediones have negligible glucose-lowering action unless insulin resistance and hyperglycaemia are present. As with metformin, they do not cause hypoglycaemia when used alone, but can exaggerate the hypoglycaemic effects of insulin or sulphonylureas.
Efficacy and potency
Alone, all thiazolidinediones lower glucose by 2 to 3 mmol/litre and HbA1c by 1%, somewhat less than the sulphonylureas. However, in some individuals they can result in marked falls in HbA1c, up to 4%. For unknown reasons, blood glucose declines slowly during thiazolidinedione treatment, and a maximal effect may not be reached for up to 6 months. In terms of dosage, rosiglitazone is the most potent thiazolidinedione but, as with the more potent sulphonylureas, cannot lower blood glucose further than the other thiazolidinediones.
All are metabolized in the liver and cleared chiefly through the kidney. They are highly protein bound.
Weight gain, averaging 1 to 4 kg, is due mainly to subcutaneous fat deposition. This appears to spare the visceral depot associated with insulin resistance and does not negate the glucose-lowering action.
Fluid retention of unknown aetiology may cause a mild dilutional anaemia (haemoglobin typically falls by 1–2 g/dl) and ankle oedema (in 5–10% of cases); heart failure may also be precipitated in patients with pre-existing myocardial dysfunction, especially if they are also treated with insulin. Recent meta-analyses have suggested that rosiglitazone is associated with an increased risk of myocardial ischaemic events, but this has not been confirmed by prospective in a study.
Hepatic damage, ranging from subclinical elevations of hepatic enzymes to fulminant and fatal hepatic necrosis (about one case per 1000 patient-years), has been reported with troglitazone but does not appear to be a risk with rosiglitazone or pioglitazone. Indeed, early indications suggest that thiazolidinediones may be helpful in reducing and possibly reversing steatosis (fat deposition) in the liver that is associated with obesity and insulin resistance and can progress to cirrhosis.
An unexpected class side effect of the thiazolidinediones in clinical trials is an increase in fractures in the limbs rather than the axial skeleton. This is especially a concern in post-menopausal women. Mechanisms appear to include increased bone resorption and suppression of osteoblast formation from mesenchymal progenitors.
Indications and contraindications
Thiazolidinediones are generally regarded as second- or third-line drugs for treating type 2 diabetes when sulphonylureas or metformin (or the combination of the two) are ineffective or unsuitable. They can be combined with either a sulphonylurea or metformin, when HbA1c may fall by more than 1%; if HbA1c has not fallen by more than 1% within 6 months of adding a thiazolidinedione, it should be discontinued especially in view of the recent concerns over heart failure and fractures. When used alone, they have a lower rate of failure than metformin or sulphonylureas alone, but cost and potential side-effect concerns argue against using them as monotherapy. When pioglitazone is used with insulin, insulin dosage can be reduced but weight gain may be problematic; rarely, heart failure may be precipitated (the combination of rosiglitazone with insulin is currently contraindicated). Subjects with impaired glucose tolerance treated with a thiazolidinedione have a lower risk of progressing to overt type 2 diabetes, and the drugs can improve hirsutism and menstrual dysfunction (sometimes inducing ovulation) in women with polycystic ovary syndrome.
Contraindications include congestive heart failure. Although there is no evidence of hepatotoxicity with thiazolidinediones other than troglitazone, it seems prudent to monitor liver enzymes periodically and to stop the drug if transaminases rise to more than 1.5 times the upper limit of normal, or if any other signs of hepatic dysfunction appear.
Acarbose (and the related miglitol and voglibose) are inhibitors of α-glucosidase, an enzyme of the brush border of the small intestine essential for the breakdown of dietary starch to disaccharides, which are then hydrolysed to the absorbable monosaccharides. They partly block digestion of complex carbohydrates and so damp postprandial glycaemic rises but the therapeutic effect is small: postprandial glucose may fall by 1 to 2 mmol/litre, with predictably little impact on overnight glucose, and HbA1c by 0.5% or less. Side effects due to carbohydrate malabsorption (flatus, abdominal bloating, gassy diarrhoea) are common and probably damage compliance. Despite its poor efficacy and low tolerability, acarbose is still widely prescribed and in some countries is regarded as a first-line drug.
These drugs mimic or enhance the action of the incretin hormones that augment insulin secretion. GLP-1 is an incretin that stimulates insulin secretion and may also induce satiety, particularly by delaying gastric emptying. Blood glucose can be lowered comparably to sulphonylureas with GLP-1 infused intravenously. Exenatide (exendin-4) is an analogue of GLP-1, first identified in the saliva and concentrated in the tail of the American venomous lizard, the Gila monster, which by an interesting coincidence lives alongside the diabetes-prone Pima Indians of Arizona. Exenatide shares 50% homology with GLP-1 but has a considerably longer half-life in vivo and is now available as a twice daily subcutaneous injection at a dose of 5 or 10 μg and can be used in combination with metformin or a sulphonylurea—only in the latter case is it associated with an increased risk of hypoglycaemia. Mean falls in HbA1c of 0.8 to 1% are seen with the higher dose and direct comparison suggested that these were similar to the results of addition of insulin with less associated hypoglycaemia. In contrast to the weight gain seen with insulin, exenatide is associated with a modest weight loss of around 4 kg, due in part to direct inhibition of appetite. The main side effect is nausea, which occurs in more than 50% of patients, and precludes continuing therapy in around 10% of patients. Pancreatitis has been reported rarely and the use of these drugs is contraindicated in people who have had a previous of pancreatitis. Animal studies show that exenatide is trophic for β cells; confirmation of this very valuable effect in humans is awaited. An additional once daily GLP-1 analogue, liraglutide is currently available and appears to produce less nausea and equal if not greater glucose lowering. Additional analogues, including once weekly versions are in preparation.
The gliptin class of drugs (including sitagliptin, vildagliptin and saxagliptin) are oral selective inhibitors of dipeptidyl peptidase IV (DPP IV), the enzyme that causes the breakdown of circulating GLP-1. They therefore prolong the survival and enhance the action of endogenous GLP-1. These drugs are better tolerated than exenatide and lisaglutide but do not result in weight loss and have less impact on HbA1c levels. An unexpected side effect is an increase in infections, notably sinusitis which is linked to the expression of DPPIV on the surface of lymphocytes (CD26). The optimal place of the incretin mimetics in treatment of type 2 diabetes remains to be determined but currently they are attractive though expensive options to initiating insulin after failure of metformin and sulphonylureas.
Practical management of hyperglycaemia
Most newly diagnosed diabetic patients are easily allocated to either type 1 or type 2 on clinical criteria (see Table 2) and treatment is started accordingly. However, initial impressions may be misleading: a thin young patient may not need insulin because he has MODY, whereas a classical maturity-onset subject may lose weight rapidly and develop ketoacidosis because he has type 1 diabetes. Continuing monitoring and vigilance are therefore essential. The diagnostic pitfalls of Flatbush and fulminant type 1 diabetes have been mentioned above.
Type 1 diabetes
These patients must be given insulin immediately and for life. The insulin regimen will depend particularly on any remaining endogenous insulin, the patient’s body weight, lifestyle, and motivation. Patients with residual insulin secretion, especially newly presenting and particularly during the ‘honeymoon period’ (see below), can often fill in gaps in insulin replacement and enjoy good glycaemic control with few injections and low insulin dosages. However, C-peptide negative patients will require exogenous insulin to cover both basal and prandial needs to achieve good control. Regimens include:
- ◆ Twice daily long-acting insulin with preprandial short-acting insulin: lente or isophane is injected before breakfast (and can be mixed with prebreakfast short-acting insulin) and at bedtime (see above). Soluble insulin is injected 30 min before breakfast and the evening meal, or a fast-acting analogue (such as lispro or aspart) given with food. Midday meals, unless large, are usually covered satisfactorily by the morning’s long-acting dose and do not need separate short-acting insulin.
- ◆ Once daily long-acting insulin with preprandial short-acting insulin (basal–bolus regimen) is currently unsatisfactory because both lente and isophane run out too quickly, but longer-lasting analogues such as glargine or detemir may be effective when injected once daily at bedtime or breakfast. Short-acting insulin is given separately to cover meals, as above.
- ◆ Premixed insulins injected before breakfast and before the evening meal suit some patients and many doctors, but often fail to control overnight and/or fasting glucose levels (see above).
Insulin dosages should be titrated according to blood glucose and HbA1c monitoring. Highly motivated patients may be suitable for continuous subcutaneous insulin infusion treatment as discussed above.
Patients at risk of ketoacidosis may need hospital admission, but most patients are clinically well and can start insulin as an outpatient, supervised by a specialist diabetes nurse. Good control can often be achieved with long-acting insulin injected at breakfast and bedtime, starting with low dosages (e.g. 8–12 U in the morning and 4–6 U at night) to avoid potentially demoralizing hypoglycaemia. Short-acting insulin can then be added to cover excessive prandial hyperglycaemia. Wherever practicable, patients should be encouraged to give their own injections as soon as possible.
Newly diagnosed patients starting insulin need to be warned about a possible ‘honeymoon period’ of good glycaemic control, when the fall in glucose levels allows partial though temporary recovery of the remaining β cells. Blood glucose can often be easily controlled with low insulin dosages (and exceptionally, without exogenous insulin) but the honeymoon ultimately ends usually within a few months: blood sugar levels and insulin requirements then escalate, because of the progressive loss of remaining β cells over the next 1–5 years.
In real life, relatively few type 1 patients approach the high-quality glycaemic control aspired to in the above table. This largely reflects the pharmacokinetic shortcomings of current insulin preparations and the unpredictable nature of subcutaneous absorption. The patient’s compliance is a crucial determinant of overall diabetic control; teenagers are notoriously resistant to advice about diabetes, as with other matters, and many have markedly elevated HbA1c concentrations. This clearly increases the risk of future diabetic complications.
A few patients have such poor metabolic control that they cannot live a normal life. Most have chronically high blood glucose and suffer recurrent hospital admissions with ketoacidosis; some suffer frequent hypoglycaemia, while others have an unstable or ‘brittle’ blood glucose profile that can swing rapidly between hyper- and hypoglycaemia. Occasionally, endocrine or intercurrent illnesses are found to be responsible , but most cases remain idiopathic after even intensive investigation. See table below:
|Table 5 Causes of poor glycaemic control in type 1 diabetic patients|
|High insulin requirements, chronic hyperglycaemia ± recurrent ketoacidosis||Obesity|
|Endocrine diseases: Cushing’s syndrome, thyrotoxicosis|
|Drugs: especially glucocorticoids|
|Immune insulin resistance|
|Low insulin requirements, recurrent hypoglycaemia||Weight loss|
|Loss of hypoglycaemia awareness|
|Endocrine diseases: adrenocortical failure, hypothyroidism, growth hormone deficiency, hypopituitarism|
|Erratic glycaemic profile, frequent hyper- and hypoglycaemia (‘brittle’ diabetes)||Pancreatic damage|
|Injection site problems (lipohypertrophy)|
|Recurrent or chronic infections: tuberculosis, sinusitis|
For all three characteristics, always consider: unsuitable insulin regime; poor diabetes education; deliberate noncompliance; appetite disorders (anorexia nervosa, food bingeing).
It is now clear that poor compliance, often aggravated by deliberate interference with treatment, is responsible in many of these patients. Most are young women who tend to be obese and are generally hyperglycaemic despite apparently high insulin dosages; when tested under controlled conditions, however, their intravenous and subcutaneous insulin requirements are unremarkable. Many are probably omitting insulin or taking only small doses: common motives include escape from difficulties at school or home, or wanting to stay thin (disturbances of body image are common in this group). Coexistent eating disorders, such as anorexia and bulimia nervosa, are commonly seen in these individuals. Initially, such patients may appear to lead charmed lives despite frequent hospital admissions but many die prematurely (especially from ketoacidosis or hypoglycaemia); significant diabetic complications frequently develop during their twenties or thirties.
Management can be extremely difficult. Patients with sustained poor control should be admitted selectively for intensive education, observation, and exclusion of other possible causes. In some cases, it may be necessary to confirm that insulin is effective at conventional doses (for more information see the paper by Schade and Duckworth listed in ‘Further reading’). Even close supervision in hospital does not exclude ingenious interference with insulin treatment or glucose monitoring. Intensified insulin schedules or continuous subcutaneous insulin infusion may help in some cases and increasingly whole pancreas transplantation is being considered as an option if patients are willing to take the associated risks (see below).
Whole pancreatic transplantation, usually performed in conjunction with renal transplantation for patients with diabetic nephropathy, can achieve good results including long-term withdrawal of exogenous insulin (> 5 years) in up to 70% of cases. The whole gland or a segment is transplanted into the pelvis and anastomosed to the iliac vessels; to avoid damage from pancreatic exocrine secretions, the pancreatic duct is drained either into the gut or into the bladder (when urinary amylase excretion can indicate the health of the graft). Outcomes for both the pancreas and the kidney are better when simultaneous transplantation is performed as the early treatment of rejection, which is easier to identify in the kidney by serum creatinine and or biopsy, preserves both organs and the improved glycaemic control from the pancreas is beneficial to the kidney. Problems are the need for lifelong immunosuppression (required anyway for renal transplantation) and the global shortage of donor organs. An increasing number of pancreas transplants alone are being performed in type 1 diabetes but the balance of risks (especially of malignancy and infection from the immunosuppression) and benefits (from improved glycaemic control) is difficult to assess. The exact indication for this procedure, where available, remains but it is generally performed for persistent poor metabolic control with or without recurrent ketoacidosis. Although there are attendant risks from the surgery and immunosuppression, recurrent ketoacidosis and poor metabolic control itself carries a not insignificant risk of death.
Introduction of an improved immunosuppressive regimen (which omits glucocorticoids) by Shapiro and colleagues reported in 2000 has lead to a resurgence in pancreatic islet transplantation. The most widely used method is by transcutaneous injection into the portal vein of islets isolated from a donor pancreas; these colonize and function well in the liver, the first stop for insulin secreted physiologically. Even with less toxic immunosuppression, two or three donor pancreases are currently needed for each recipient, and only 10% of patients are insulin independent at 5 years. Nevertheless, up to 90% of patients report significant reductions in the rate of hypoglycaemia; hence recurrent severe hypoglycaemia unresponsive to changes in insulin therapy or the use of CSII remains the main indication for this procedure.
Prevention of type 1 diabetes by aborting insulitis during the long prediabetic phase by immunosuppression in high-risk subjects, or preserving islet cell function in newly diagnosed patients, is a major goal of current research. Trials in the 1980s demonstrated that ciclosporin can achieve this, but the cost in terms of side effects of continuous therapy is too high. Newer immunomodulatory agents, such as nondepleting anti-CD3, that regulate rather than suppress immune responses, may ultimately improve the risk–benefit ratio to the point of acceptability but are not currently available.
Much effort is also being invested in promoting the regeneration of β cells either from pancreatic tissue or more generic stem cells. These studies remain at a preliminary stage, but potentially offer a renewable therapy. Although they may not require immunosuppression for allograft rejection, it remains to be seen whether such new cells would be retargeted by the autoimmune process in subjects with type 1 diabetes.
Management of type 2 diabetes
Dietary and lifestyle measures form an essential foundation for the management of type 2 diabetes and must be maintained throughout, even though fewer than 10% of patients can be controlled satisfactorily for more than a year by these means alone.
Patients who fail to meet the glycaemic targets set out in Table 3 should generally follow the steps outlined below, although compromises may be more appropriate in older people or those at risk of hypoglycaemia. Progress should be reviewed every 3 months or so if blood glucose is unacceptably high; the inexorable deterioration of β-cell function in type 2 diabetes means that there is no point in delaying decisions to increase drug doses or add insulin.
The first-line oral hypoglycaemic agent for dietary failure is metformin, particularly for obese patients (those with a BMI >30 kg/m2). Full effect takes 3 or more months to be achieved, so doses should not be increased too rapidly.
The addition to metformin of a sulphonylurea or a thiazolidinedione represents second-line treatment. The place of triple therapy (typically with the addition a thiazolidinedione as the third drug) is uncertain but in some cases very marked and prolonged improvements are seen in glycaemic control. Some diabetologists would consider adding acarbose at this stage, although the chances of lowering glucose adequately are remote.
Long-acting insulin with a first-line oral agent: although seemingly illogical, a bedtime injection of isophane can control blood glucose overnight and before breakfast, and this apparently helps oral hypoglycaemic agents to act more effectively during the day. The combination of metformin (three times daily with meals) with bedtime isophane often achieves good glycaemic control, while limiting the weight gain that commonly follows the introduction of insulin in type 2 patients. Isophane with a sulphonylurea or pioglitazone may increase weight; the combination of rosiglitazone with insulin should be avoided because of the risk of heart failure from fluid retention.
Insulin therapy can range from once or twice daily long-acting insulin in subjects with residual insulin, to the more intensified basal and prandial regimens used in type 1 diabetes. Large dosages (150 to 300 U/day) may be needed to achieve good glycaemic control in obese, highly insulin-resistant subjects. Rapidly acting and very long-acting analogues have been promoted in type 2 diabetes but meta-analyses do not suggest a major advantage over conventional insulins. The recent 4T study (Treating to Target in Type 2 Diabetes) confirmed that intensified regimes with prandial insulin achieve lower HbA1c levels than once or twice daily therapy but, as expected, they are associated with an increased incidence of hypoglycaemia.
Obesity (and therefore insulin resistance) may worsen when insulin treatment is started. The average weight gain is around 6 kg; possible reasons include reduced loss of energy through glycosuria, a tendency to relax dietary restriction when a more effective means of lowering glycaemia is introduced, and sometimes overeating during hypoglycaemic episodes. Increasing insulin resistance may lead to escalating insulin dosages. The possible hazards of insulin-induced obesity are not clear but could theoretically include vascular disease, which may be hinted at by the lower frequency of cardiovascular events among patients treated with metformin in the United Kingdom Prospective Diabetes Study trial. At present, however, the consensus is probably to aim for the glycaemic targets set out in Table 3 (which will reduce the risks of microvascular complications) and to accept an increase in weight, while actively treating other cardiovascular risk factors. The increasing use of incretin mimetics in place of insulin conversion may challenge this practice, although the long-term safety and efficacy of these drugs is not known.
Antiobesity drugs (including orlistat, sibutramine) could have an important impact in many type 2 patients although their exact role remains to be determined. Rimonabant, a canabinoid receptor (CB1)antagonist which reduced appetite and increase insulin sensitivity, has been withdrawn because of exacerbation of depression and anxiety. Additional appetite modulating agents currently in preclinical testing include neuropeptide Y receptor (NPY5R) antagonists, melanocortin-4 receptor agonists, and low molecular weight leptin and peptide YY mimetics. Bariatric surgery is the most effective means of lowering weight and fat mass in obesity. Up to 80% of subjects with impaired glucose tolerance or established type 2 diabetes will revert to normoglycaemia following bariatric procedures. Those with long-standing type 2 diabetes requiring insulin treatment are the least likely to respond. The optimal place of this invasive approach in diabetes management remains to be defined.
Monitoring diabetic control
Treatment targets for blood glucose in type 1 and type 2 diabetes have been selected to reduce the risk of chronic diabetic complications. Avoiding acute episodes of hyper- and hypoglycaemia is also important.
Blood glucose concentration can be easily and quickly measured in small drops of blood (a few microlitres or less), using various test strips; the ability to perform such measurements is an essential skill for all professionals delivering diabetes care and for most diabetic patients. Test strips contain glucose oxidase (which catalyses the oxidation of glucose to gluconic acid) together with a detection system to measure specific reaction products, either electrochemically or colorimetrically (using dyes sensitive to hydrogen peroxide). The signal is read by a reflectance meter or electrically, and converted into the glucose concentration in the sample. Colour-based test strips can also be read by eye against a printed standard scale, although this may be difficult for partially sighted or colour-blind patients.
A drop of blood is obtained by pricking the sides of the fingertip, avoiding the sensitive pads; various lancets and automatic finger-pricking devices are available. Blood must cover the reaction area completely and be left in contact for exactly the period stipulated; modern meters read out automatically at this point, whereas older strips must be wiped dry and left for the colour to develop. Failure to follow the manufacturer’s instructions is the main cause of inaccurate readings, which are disturbingly frequent. With attention to detail, readings correspond closely to laboratory measurements of glucose (which also employ the glucose oxidase reaction) but are not reliable enough to be used for diagnosing diabetes.
Type 2 diabetes treated with diet and oral agents can be monitored using fasting glucose and values in the mid-afternoon or 2 h postprandially (both of which correlate with overall glucose level) measured once or twice per week. Recent trials indicate that glucose monitoring per se does not improve glycaemic control in type 2 diabetes and home monitoring is not essential in patients treated with diet alone or a single oral agent.
Insulin-treated patients need more frequent monitoring to adjust insulin dosages. Bed-time and pre-meal testing (4-point) as well as ideally 2 hour post-prandial (7-point) testing is recommended. Fasting glucose is determined by the previous evening’s long-acting insulin, while values before the evening meal reflect mainly the morning’s long-acting dose. Prandial short-acting insulin dosages can be titrated from the glucose rise 90 to 120 min after eating. Readings can be scattered across these time points on different days; most patients can be persuaded to check their glucose levels once or twice per day but to achieve tight glycaemic control targets without hypoglycaemia more frequent blood glucose testing is required.
Written records help to bring out general patterns in glucose control and many modern meters can be downloaded to display the pattern in different formats. Patients must also be encouraged to check their glucose if they feel unwell and, crucially, at frequent intervals during intercurrent illness. Occasional tests during the night (especially between 02.00 and 04.00) are useful in patients at risk of nocturnal hypoglycaemia, including those injecting long-acting or premixed insulins in the early evening.
Checking the self-monitoring technique and the patient’s action plan when glucose levels fall outside the target range is a core part of the patient’s diabetic education.
These tests measure the nonenzymatic reaction of glucose with circulating proteins (see below), and therefore reflect longer-term blood glucose levels. Glycated (glycosylated) haemoglobin (HbA1) results from the combination of glucose with the N-terminal valine residue of the B chain of adult Hb (HbA), and can be separated from unaltered HbA by electrophoretic and other methods. HbA1 includes the stable HbA1c fraction, which is most closely related to average blood glucose levels over the preceding 6 to 8 weeks.
The various assay methods for HbA1c are now standardized to match the methodology used in the Diabetes Control and Complications Trial (DCCT), which defined the long-term risks of diabetic microvascular complications (see below). For assays conforming to DCCT standards, nondiabetic HbA1c ranges from 3.5 to 5.5% of total HbA, with good control defined as values less than 7% and poor control as more than 8%; some poorly compliant patients have HbA1c concentrations of 14 to 16%. HbA1c measurements are a useful index of medium-term glycaemic control, but may be invalidated by abnormal red cell turnover (values are spuriously low in haemolysis, bleeding, and pregnancy), in renal failure (carbamylated HbA coelutes with HbA1c, falsely raising levels), and with abnormal haemoglobins such as hetero- or homozygous sickle cell disease (HbF also comigrates with HbA1). Modern analytical methods for HbA1c detect the presence of abnormal haemoglobins and hence spurious results are usually highlighted by the laboratory.
Serum albumin also undergoes glycation, which is measured by the fructosamine reaction. As albumin turns over faster than haemoglobin, the fructosamine concentration reflects mean blood glucose over the previous 1 to 2 weeks. Assays are cheap but not standardized between laboratories, and are generally less reliable and reproducible than measurements of HbA1c.
Urinary glucose concentrations can be measured easily using glucose oxidase test strips, but are of limited use: urinary glucose concentration depends on the renal threshold (which can lie between 7 and 13 mmol/litre), urine output, and the time since the bladder was last emptied. Crucially, hypoglycaemia cannot be detected. Urinary glucose measurements are acceptable in type 2 diabetic patients with a normal renal threshold who are not receiving hypoglycaemic medication (insulin or sulphonylureas) and in patients who decline to prick their fingers.
Urinary ketone measurements can be useful for predicting impending ketoacidosis, particularly during intercurrent illness when blood glucose is high. Moderate ketonuria can be caused by fasting or undereating, including during infections. Some modern blood testing meters can also often also measure blood ketones with appropriate testing strips.
Structures for diabetes care
Diabetes is best managed by the combined efforts of a well-trained primary care team and a team of specialists with complementary and overlapping skills: physician, specialist diabetes nurse, dietitian, and chiropodist. The specialist diabetes nurse has a crucial role in educating patients about diabetes and its practical management, and in starting and adjusting therapy. Many patients are more receptive and responsive to information given by primary care teams and specialist nurses than by doctors. For complex cases, there must be frequent contact with and easy access to other specialists (ophthalmologist, vascular surgeon, renal physician, obstetrician, and clinical psychologist), ideally in the setting of combined clinics. Each member of the team has a particular niche but all must agree common strategies (such as dietary advice for obesity) to avoid giving the patients conflicting or inconsistent information.
Diabetes care can be delivered effectively by well-informed general practitioners or practice nurses, hospital-based clinics, community mini-clinics, or shared care schemes that bridge the primary and secondary sectors. Because of the unpredictable course and potential complications of diabetes, all patients must be thoroughly reviewed each year and be rapidly referred for specialist help if the need arises. A check list for the annual review is suggested in Table 6.
Living and coping with diabetes is a considerable burden that is poorly appreciated by many doctors and nurses. Careful education about diabetes, its complications, and its practical management can provide great reassurance to patients and also reduce emergency hospital admissions and complications such as foot ulceration and amputation.
Diabetes education is most effectively provided by a trained practice nurse or specialist diabetes nurse, but all members of the diabetes care team should understand the key messages, and check and reinforce these whenever possible. Evidence suggests that education in a group setting is often more effective than on a one to one basis and may promote informal support networks. Key elements of the education programme include:
- ◆ causes of hyperglycaemia and diabetic symptoms
- ◆ own treatment: diet and lifestyle; drawing up and injecting insulin; oral agents; recognizing and treating hypoglycaemia
- ◆ self-monitoring technique; targets and danger levels; how to respond to poor control
- ◆ ‘sick-day’ rules: monitoring during intercurrent illness; how to adjust own treatment; when and how to call for help.
Several very intensive training courses have been developed such as the Diabetes Adjustment For Normal Eating (DAFNE) course for type 1 diabetes; effectiveness when applied at a wide variety of training centres has been confirmed for some but not all courses and likely depends on the enthusiasm, skills and attention to detail of individual trainers.
Employment, driving, and insurance
Because of the risk of hypoglycaemia, patients treated with insulin (type 1 or 2) are generally barred from driving heavy goods and public service vehicles. Licensing for taxi drivers varies between local authorities. Until recently, insulin-treated individuals were also barred from active service in the police, fire service, or armed forces, and from work as airline pilots or cabin staff; but this policy is increasingly being revised in favour of individual case-based assessments, following new legislation regarding discrimination against people with disabilities. In the armed forces, although there remains reluctance to recruit subjects already on insulin, military personnel who develop diabetes can request to have their particular circumstances reviewed. Specific diabetic complications, notably sight-threatening retinopathy, may preclude particular jobs or pastimes.
Patients must inform the driving licence authorities and their driving insurer that they have diabetes, and those receiving insulin or with clinically significant retinopathy may require periodic medical confirmation of fitness to drive. Frequent hypoglycaemia, especially with decreased awareness of symptoms, is a bar to driving. Currently the use of GLP-1 agonists carries no specific restrictions in the UK except for heavy goods vehicle or public service vehicle drivers taking these agents in conjunction with sulphonylureas, in which case the driving authority will make an assessment on individual basis.
Special life insurance policies are available from companies endorsed by patient-centred organizations such as Diabetes UK and the American Diabetes Association. Many patients find it valuable to join these organizations.