Glucose metabolism sulphonylureas effect

Fig. 20. Hypothetical model of how insulin secretion is regulated. The most important event is the depolarization of the B-cell which causes Ca"+ influx along L-type Ca2+ channels and subsequent increase in cytosolic Ca"+. Depolarization is produced by nutrient (glucose) metabolism via an increase in B-cell ATP and/or ATP/ADP ratio which closes KAXP channels. Also, sulphonylureas, at a distinct location, close KATP channels. The increase in [Ca2+]j activates CaCaMK. Ca2+ uptake appears to be modulated by nutrient metabolism (redox state of NAD(P)H and GSH). Insulin release in response to depolarization is also modulated by factors affecting PLC and adenylate cyclase. Here, production of IP3 leads to release of stored Ca2+ from the endoplasmic reticiulum. DAG activates PKC whereas cAMP activates PKA. CaMK, PKC and PKA cause protein phosphorylations which finally cause granule movement and exocytosis. But there will also be other effects of phosphorylations related to stimulus-secretion coupling, e.g. a possible interaction with voltage-dependent Ca2+ channels.

The sulphonylurea and other sulfonamide-related compounds such as chlorpropamide and tolbutamide were the first synthetic compounds used in medicine as antidiabetics. Among their actions they stimulate the remaining beta-cells of the pancreas to grow and secrete insulin which, with a restricted diet, controls blood glucose levels and permits normal metabolism to occur. Clearly they can only be effective in those diabetics whose pancreas still has the capacity to produce some insulin, so their use is confined to type 2 diabetes. 

The blood glucose-lowering effects of some of the sulphonylureas are increased by some, but not all, sulfonamides, due to inhibition of their metabolism. However, sulfaphenazole, which was shown to have an important pharmacokinetic interaction with tolbutamide, is no longer used clinically, and other sulfonamides appear less likely to interact. Nevertheless, occasionally and unpredicta-... 

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