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Sulphonylureas block the ATP-sensitive potassium channels on the |3-islet cell plasma membrane. This results in the release of stored insulin in response to glucose. They do not increase insulin formation. Sulphonylureas appear to enhance insulin action on liver, muscle and adipose tissue by increasing insulin receptor number and by enhancing the postreceptor complex enzyme reactions mediated by insulin. The principal result is decreased hepatic glucose output and increased glucose uptake in muscle. They are ineffective in totally insulin-deficient patients and for successful therapy probably require about 30% of normal ß-cell function to be present. Their main adverse effects are hypo-glycaemia and weight gain.

Secondary failure (after months or years) occurs due to declining ß-cell function and to insulin resistance.

Biguanides. These agents have been in use since 1957. Metformin is the only biguanide in current use, and is a major agent in the management of Type 2 diabetes. Its cellular mode of action is uncertain but the most important effect is reduction of hepatic glucose production. Other effects include enhancement of peripheral insulin sensitivity increaseing glucose uptake in peripheral tissues; biguanides are ineffective in the absence of insulin. Rare complications are hypoglycaemia and lactic acidosis. Secondary failure is not a problem. Metformin can be used in combination with either insulin or other oral hypoglycaemic agents.

Thiazolidinediones. Pioglitazone and rosiglitazone reduce peripheral insulin resistance, leading to a reduction of blood glucose concentration. These drugs stimulate the nuclear hormone receptor, peroxisome proliferator-activated receptor (PPARy), which causes differentation of adipocytes.8 They should be initiated only by a physician experienced in treating Type 2 diabetes and should always be used in combination with metformin or with a sulphonylurea (if metformin is inappropriate). The drugs can cause 3-4 kg weight gain in the first year of use, with peripheral oedema in 3-4% of patients. Other adverse effects of the class have included abnormal liver function, and relevant tests should be monitored during the first year.

8 The importance of PPARy in insulin sensitivity was confirmed with the finding, in Cambridge, of two families presenting with severe insulin resistance in whom rare mutations of the PPARy gene caused loss of PPARy activity (Barroso I, Gurnell M, Crowley VE, et al 1989 Dominant negative mutations in human PPARy associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 402: 880-882.)

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Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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