An oral hypoglycaemic drug (see hypoglycaemics, oral) that lowers blood glucose levels and is used to treat type 2 diabetes mellitus. Possible adverse effects include loss of appetite, a metallic taste in the mouth, nausea, vomiting, and diarrhoea.
Insulin-dependent and non-insulindependent diabetes have a varied pathological pattern and are caused by the interaction of several genetic and environmental factors.
Insulin-dependent diabetes mellitus (IDDM) (juvenile-onset diabetes, type 1 diabetes) describes subjects with a severe de?ciency or absence of insulin production. Insulin therapy is essential to prevent KETOSIS – a disturbance of the body’s acid/base balance and an accumulation of ketones in the tissues. The onset is most commonly during childhood, but can occur at any age. Symptoms are acute and weight loss is common.
Non-insulin-dependent diabetes mellitus (NIDDM) (maturity-onset diabetes, type 2 diabetes) may be further sub-divided into obese and non-obese groups. This type usually occurs after the age of 40 years with an insidious onset. Subjects are often overweight and weight loss is uncommon. Ketosis rarely develops. Insulin production is reduced but not absent.
A new hormone has been identi?ed linking obesity to type 2 diabetes. Called resistin – because of its resistance to insulin – it was ?rst found in mice but has since been identi?ed in humans. Researchers in the United States believe that the hormone may, in part, explain how obesity predisposes people to diabetes. Their hypothesis is that a protein in the body’s fat cells triggers insulin resistance around the body. Other research suggests that type 2 diabetes may now be occurring in obese children; this could indicate that children should be eating a more-balanced diet and taking more exercise.
Diabetes associated with other conditions (a) Due to pancreatic disease – for example, chronic pancreatitis (see PANCREAS, DISORDERS OF); (b) secondary to drugs – for example, GLUCOCORTICOIDS (see PANCREAS, DISORDERS OF); (c) excess hormone production
– for example, growth hormone (ACROMEGALY); (d) insulin receptor abnormalities; (e) genetic syndromes (see GENETIC DISORDERS).
Gestational diabetes Diabetes occurring in pregnancy and resolving afterwards.
Aetiology Insulin-dependent diabetes occurs as a result of autoimmune destruction of beta cells within the PANCREAS. Genetic in?uences are important and individuals with certain HLA tissue types (HLA DR3 and HLA DR4) are more at risk; however, the risks associated with the HLA genes are small. If one parent has IDDM, the risk of a child developing IDDM by the age of 25 years is 1·5–2·5 per cent, and the risk of a sibling of an IDDM subject developing diabetes is about 3 per cent.
Non-insulin-dependent diabetes has no HLA association, but the genetic in?uences are much stronger. The risks of developing diabetes vary with di?erent races. Obesity, decreased exercise and ageing increase the risks of disease development. The risk of a sibling of a NIDDM subject developing NIDDM up to the age of 80 years is 30–40 per cent.
Diet Many NIDDM diabetics may be treated with diet alone. For those subjects who are overweight, weight loss is important, although often unsuccessful. A diet high in complex carbohydrate, high in ?bre, low in fat and aiming towards ideal body weight is prescribed. Subjects taking insulin need to eat at regular intervals in relation to their insulin regime and missing meals may result in hypoglycaemia, a lowering of the amount of glucose in the blood, which if untreated can be fatal (see below).
Oral hypoglycaemics are used in the treatment of non-insulin-dependent diabetes in addition to diet, when diet alone fails to control blood-sugar levels. (a) SULPHONYLUREAS act mainly by increasing the production of insulin;
(b) BIGUANIDES, of which only metformin is available, may be used alone or in addition to sulphonylureas. Metformin’s main actions are to lower the production of glucose by the liver and improve its uptake in the peripheral tissues.
Complications The risks of complications increase with duration of disease.
Diabetic hypoglycaemia occurs when amounts of glucose in the blood become low. This may occur in subjects taking sulphonylureas or insulin. Symptoms usually develop when the glucose concentration falls below 2·5 mmol/l. They may, however, occur at higher concentrations in subjects with persistent hyperglycaemia – an excess of glucose – and at lower levels in subjects with persistent hypo-glycaemia. Symptoms include confusion, hunger and sweating, with coma developing if blood-sugar concentrations remain low. Re?ned sugar followed by complex carbohydrate will return the glucose concentration to normal. If the subject is unable to swallow, glucagon may be given intramuscularly or glucose intravenously, followed by oral carbohydrate, once the subject is able to swallow.
Although it has been shown that careful control of the patient’s metabolism prevents late complications in the small blood vessels, the risk of hypoglycaemia is increased and patients need to be well motivated to keep to their dietary and treatment regime. This regime is also very expensive. All risk factors for the patient’s cardiovascular system – not simply controlling hyperglycaemia – may need to be reduced if late complications to the cardiovascular system are to be avoided.
Diabetes is one of the world’s most serious health problems. Recent projections suggest that the disorder will affect nearly 240 million individuals worldwide by 2010 – double its prevalence in 1994. The incidence of insulin-dependent diabetes is rising in young children; they will be liable to develop late complications.
Although there are complications associated with diabetes, many subjects live normal lives and survive to an old age. People with diabetes or their relatives can obtain advice from Diabetes UK (www.diabetes.org.uk).
Increased risks are present of (a) heart disease, (b) peripheral vascular disease, and (c) cerebrovascular disease.
Diabetic eye disease (a) retinopathy, (b) cataract. Regular examination of the fundus enables any abnormalities developing to be detected and treatment given when appropriate to preserve eyesight.
Nephropathy Subjects with diabetes may develop kidney damage which can result in renal failure.
Neuropathy (a) Symmetrical sensory polyneuropathy; damage to the sensory nerves that commonly presents with tingling, numbness of pain in the feet or hands. (b) Asymmetrical motor diabetic neuropathy, presenting as progressive weakness and wasting of the proximal muscles of legs. (c) Mononeuropathy; individual motor or sensory nerves may be affected. (d) Autonomic neuropathy, which affects the autonomic nervous system, has many presentations including IMPOTENCE, diarrhoea or constipation and postural HYPOTENSION.
Skin lesions There are several skin disorders associated with diabetes, including: (a) necrobiosis lipoidica diabeticorum, characterised by one or more yellow atrophic lesions on the legs;
(b) ulcers, which most commonly occur on the feet due to peripheral vascular disease, neuropathy and infection. Foot care is very important.
Diabetic ketoacidosis occurs when there is insu?cient insulin present to prevent KETONE production. This may occur before the diagnosis of IDDM or when insu?cient insulin is being given. The presence of large amounts of ketones in the urine indicates excess ketone production and treatment should be sought immediately. Coma and death may result if the condition is left untreated.
Symptoms Thirst, POLYURIA, GLYCOSURIA, weight loss despite eating, and recurrent infections (e.g. BALANITIS and infections of the VULVA) are the main symptoms.
However, subjects with non-insulindependent diabetes may have the disease for several years without symptoms, and diagnosis is often made incidentally or when presenting with a complication of the disease.
Treatment of diabetes aims to prevent symptoms, restore carbohydrate metabolism to as near normal as possible, and to minimise complications. Concentration of glucose, fructosamine and glycated haemoglobin in the blood are used to give an indication of blood-glucose control.
Insulin-dependent diabetes requires insulin for treatment. Non-insulin-dependent diabetes may be treated with diet, oral HYPOGLYCAEMIC AGENTS or insulin.
Insulin All insulin is injected – mainly by syringe but sometimes by insulin pump – because it is inactivated by gastrointestinal enzymes. There are three main types of insulin preparation: (a) short action (approximately six hours), with rapid onset; (b) intermediate action (approximately 12 hours); (c) long action, with slow onset and lasting for up to 36 hours. Human, porcine and bovine preparations are available. Much of the insulin now used is prepared by genetic engineering techniques from micro-organisms. There are many regimens of insulin treatment involving di?erent combinations of insulin; regimens vary depending on the requirements of the patients, most of whom administer the insulin themselves. Carbohydrate intake, energy expenditure and the presence of infection are important determinants of insulin requirements on a day-to-day basis.
A new treatment for diabetes, pioneered in Canada and entering its preliminary clinical trials in the UK, is the transplantation of islet cells of Langerhans from a healthy person into a patient with the disorder. If the transplantation is successful, the transplanted cells start producing insulin, thus reducing or eliminating the requirement for regular insulin injections. If successful the trials would be a signi?cant advance in the treatment of diabetes.
Scientists in Israel have developed a drug, Dia Pep 277, which stops the body’s immune system from destroying pancratic ? cells as happens in insulin-dependent diabetes. The drug, given by injection, o?ers the possibility of preventing type 1 diabetes in healthy people at genetic risk of developing the disorder, and of checking its progression in affected individuals whose ? cells are already perishing. Trials of the drug are in progress.... diabetes mellitus
Sulphonylureas The main group of hypoglycaemic agents, these act on the beta cells to stimulate insulin release; consequently they are e?ective only when there is some residual pancreatic beta-cell activity (see INSULIN). They also act on peripheral tissues to increase sensitivity, although this is less important. All sulphonylureas may lead to HYPOGLYCAEMIA four hours or more after food, but this is relatively uncommon, and usually an indication of overdose.
There are several di?erent sulphonylureas; apart from some di?erences in their duration or action (and hence in their suitability for individual patients) there is little di?erence in their e?ectiveness. Only chlorpropamide has appreciably more side-effects – mainly because of its prolonged duration of action and consequent risk of hypoglycaemia. There is also the common and unpleasant chlorpropamide/ alcohol-?ush phenomenon when the patient takes alcohol. Selection of an individual sulphonylurea depends on the patient’s age and renal function, and often just on personal preference. Elderly patients are particularly prone to the risks of hypoglycaemia when long-acting drugs are used. In these patients chlorpropamide, and preferably glibenclamide, should be avoided and replaced by others such as gliclazide or tolbutamide.
These drugs may cause weight gain and are indicated only if poor control persists despite adequate attempts at dieting. They should not be used during breast feeding, and caution is necessary in the elderly and in those with renal or hepatic insu?ciency. They should also be avoided in porphyria (see PORPHYRIAS). During surgery and intercurrent illness (such as myocardial infarction, COMA, infection and trauma), insulin therapy should be temporarily substituted. Insulin is generally used during pregnancy and should be used in the presence of ketoacidosis.
Side-effects Chie?y gastrointestinal disturbances and headache; these are generally mild and infrequent. After drinking alcohol, chlorpropamide may cause facial ?ushing. It also may enhance the action of antidiuretic hormone (see VASOPRESSIN), very rarely causing HYPONATRAEMIA.
Sensitivity reactions are very rare, usually occurring in the ?rst six to eight weeks of therapy. They include transient rashes which rarely progress to erythema multiforme (see under ERYTHEMA) and exfoliate DERMATITIS, fever and jaundice; chlorpropamide may also occasionally result in photosensitivity. Rare blood disorders include THROMBOCYTOPENIA, AGRANULOCYTOSIS and aplastic ANAEMIA.
Biguanides Metformin, the only available member of this group, acts by reducing GLUCONEOGENESIS and by increasing peripheral utilisation of glucose. It can act only if there is some residual insulin activity, hence it is only of value in the treatment of non-insulin dependent (type 2) diabetics. It may be used alone or with a sulphonylurea, and is indicated when strict dieting and sulphonylurea treatment have failed to control the diabetes. It is particularly valuable in overweight patients, in whom it may be used ?rst. Metformin has several advantages: hypoglycaemia is not usually a problem; weight gain is uncommon; and plasma insulin levels are lowered. Gastrointestinal side-effects are initially common and persistent in some patients, especially when high doses are being taken. Lactic acidosis is a rarely seen hazard occurring in patients with renal impairment, in whom metformin should not be used.
Other antidiabetics Acarbose is an inhibitor of intestinal alpha glucosidases (enzymes that process GLUCOSIDES), delaying the digestion of starch and sucrose, and hence the increase in blood glucose concentrations after a meal containing carbohydrate. It has been introduced for the treatment of type 2 patients inadequately controlled by diet or diet with oral hypoglycaemics.
Guar gum, if taken in adequate doses, acts by delaying carbohydrate absorption, and therefore reducing the postprandial blood glucose levels. It is also used to relieve symptoms of the DUMPING SYNDROME.... hypoglycaemic agents
Pioglitazone acts by reducing peripheral insulin resistance.
Side effects may include gastrointestinal disturbances, weight gain, and anaemia.... pioglitazone
Rosiglitazone acts by reducing peripheral insulin resistance.
Side effects may include gastrointestinal disturbances, weight gain, and anaemia.... rosiglitazone
Antidiabetic drugs include insulin, which must be administered by injection, and oral hypoglycaemics such as glibenclamide and metformin. Acarbose and guar gum reduce or slow absorption of carbohydrate from the intestines after meals. Repaglinide stimulates insulin release from the pancreas for a short time and may be taken directly before meals. Rosiglitazone reduces resistance to the effects of insulin in the tissues and may be used together with other hypoglycaemics.... antidiabetic drugs
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