Weight gain, in the range of 3-4 kg over the first 6-12 months of therapy is usual with drugs such as glibenclamide and chlorpropamide, as was seen in the UKPDS. Similar effects are usually seen with newer agents, such as glipizide and gliclazide, although some studies report no weight gain with glipizide, this may be because these studies were of short duration (Simonson et al., 1997; Cefalu et al., 1998). Such drugs should therefore be considered as second-line agents in obese patients with type 2 diabetes, usually as add-on therapy to metformin, and only used as monotherapy only if metformin is contraindicated or poorly tolerated. The mechanisms whereby sulphonylureas cause weight gain are not fully understood, and have not been studied in detail. Improved metabolic control, with reduction of glycosuria has been suggested as one possible mechanism, but weight gain also occurs in patients without glycosuria. Studies of energy intake and metabolic rate in diabetic patients on sulphonylureas versus met-formin show little difference in energy expenditure, but this is slightly lower in those on sulphonylureas after adjusting for fat free mass (Chong et al., 1995). Hyperglycaemia itself is correlated with basal metabolic rate, perhaps due to the energy costs of increased gluconeogenesis and futile glucose cycling; so part of the weight gain could be due to a reduction in metabolic rate related to improvements in hyperglycaemia during therapy (Efendic et al., 1985; Franssi-lakallunki and Groop, 1992). Hyperinsulinaemia, leading to increased deposition of lipid in adipose tissue might also increase metabolic efficiency. Hypogly-caemia is said to increase hunger, and is a known side-effect of sulphonylureas, but hypoglycaemia is uncommon in poorly controlled obese patients with type 2 diabetes. A recent report suggesting that the sulphonylurea receptor is expressed in adipocytes and increases expression of lipogenic enzymes such as fatty acid synthase could be of relevance, but the clinical significance of this in-vitro observation remains uncertain (Shi et al., 1999). Receptors for sulphonylureas are also present in the hypothalamus and other appetite-regulating areas of the central nervous system, but the possibility of direct effects on appetite and/or central nervous system (CNS) modulation of energy expenditure by sulphony-lureas and related compounds has not been systematically investigated (Treherne and Ashford, 1991).

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