Mechanism Of Action

Sulfonylureas and meglitinides (repaglinide and nateglinide) bind to a subunit of a potassium channel (KATP-channel) on beta cells named SURl (for sulfonylurea). SURl is a subunit of a potassium channel of the inward rectifier (IR) type, together with the channel-forming subunit named Kir6.2 (4). This channel is physiologically regulated by adenosine triphosphate (ATP). ATP is generated by oxidative phosphorylation in the mitochondria and is derived from glucose metabolism. ATP closes the KATP-channel, which normally allows efflux of K+ from the beta cell, thereby generating the normal hyperpolarized membrane potential. Closure of the KATP-channel depolarizes the cell and activates voltage-driven Ca2+ channels. The ensuing influx of Ca2+ into the cell promotes fusion of insulin granules with the cell membrane, causing insulin release (5). Sulfonylureas and the "glinides," i.e., the meglitinides repaglinide and nateglinide, promote closure of the KATP-channel complex by binding to the SURl subunit. They can thereby enhance the effect of ATP, but also cause closure of the channels on their own. Sulfonylureas, therefore, cause an increase in basal insulin secretion and enhance glucose- or nutrient-induced insulin secretion. The degree to which basal and meal-stimulated insulin release is enhanced may differ between compounds.

Recently glimepiride and glybenclamide were shown to activate the nuclear transcription factor PPARy in vitro, which is thought to mediate the insulin-sensitizing action of thiazolidinediones (6). Their maximal potency was about 60% of that of pioglitazone. This provides a novel explanation for insulin-sensitizing actions of SUs, which may thus be caused by a partial agonism at these nuclear receptors. Two clinical studies reported that glimepiride increases adiponectin and reduced inflammatory cytokines such as TNFa, which is increased by activation of PPARy (7).

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