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Colin Dayan

and Gareth Williams



Diagnosis—use of HbA1c for screening and diagnosis. Estimation of urinary C-peptide: creatinine ratio to distinguish MODY from type 1 diabetes.

Types of diabetes—description of ‘ketone-prone’ diabetes

Management—comment on withdrawal of some thiazolidinediones (troglitazone, rosiglitazone) for safety reasons. Discussion of use of saxagliptin in patients with severe chronic renal failure. Increased emphasis on intensive dietary support in type 2 diabetes and updated discussion of approach to medication.

Monitoring—discussion of change from reporting HbA1c as a percentage to in mmol HbA1c per mol of haemoglobin (mmol/mol).

Surgery in patients with diabetes—recommendations amended in line with new UK guidelines.

Diabetic ketoacidosis—emphasis on value of bedside finger-prick testing for blood ketones in diagnosis and management; modified treatment algorithm to advise fixed rate insulin infusion with addition of 10% dextrose infusion when blood glucose falls to less than 14 mmol/litre.

Updated on 30 Nov 2011. The previous version of this content can be found here.
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date: 25 March 2017

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, affecting more than 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). HbA1C has recently been proposed as an alternative test for diabetes diagnosis.

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 18 loci are involved, with the HLA class II locus IDDM2 having by far the greatest effect. Environmental factors that have been implicated but not confirmed 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. Increasing rates of obesity and sedentary activity has lead to very marked (2—3-fold) increase in incidence of type 1 diabetes worldwide, especially in developing countries. 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 (see Chapter 14.10).

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 mass 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 with greatly enhanced flexibility.

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).

Incretin mimetics (e.g. exenatide or liragultide) are increasingly being used as an alternative to insulin therapy to avoid weight gain and hypoglycaemia.

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 HbA1c 48 mmol/mol (6.5%) or less (‘good’ control defined as below 53 mmol/mol (7%), ‘poor’ control as over 64 mmol/mol (8%)), but, particularly in type 1 diabetes, these targets are often not achievable.

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 urine or blood analysis 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 or 0.1 U/kg, and continued (if necessary in combination with 10% dextrose infusion) until ketosis has resolved; (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. For further discussion see Chapter 13.11.2.

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 but drugs for neuropathic pain including specific antidepressants and anticonvulsants are of more value. 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—see Chapter 21.10.1.

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.

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