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The Mode of Action of the Antidiabetic Drug Glimepiride-Beyond Insulin Secretion

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Abstract:

During the past 10 years a multitude of clinical and observational studies have confirmed the efficacy of the antidiabetic drug, glimepiride, in lowering fasting and postprandial blood glucose in lean and obese type 2 diabetic patients even after a single administration per day, only, as well as its high safety and patient's compliance. Additional findings obtained in these studies suggested a number of clinical advantages compared to other sulfonylurea drugs on the market (e.g. glibenclamide), in particular, the lower risk for hypoglycemia, weight gain and atherosclerotic vascular disease as well as the less pronounced hyperinsulinemia. Studies investigating the molecular basis underlying the clinical profile of glimepiride provide strong evidence for multiple molecular targets/mechanisms for the blood glucose-lowering effect of glimepiride operating at both pancreatic ß-cells and extrapancreatic cells. (i) Interaction with the sulfonylurea receptor, SUR, at the ß-cell plasma membrane triggers insulin release. (ii) Interaction with lipid rafts, DIGs, at the plasma membrane of adipose and muscle cells induces the insulin-mimetic activity via the activation of a glycosylphosphatidylinositol- specific phospholipase, redistribution of signaling components and positive cross-talk downstream to the insulin signaling cascade. (iii) Interference with additional molecular mechanisms in extrapancreatic cells (e.g. regulation of adipocytokine release from and differentiation of adipocytes), relying on or independent of SUR and DIGs, contributes to the insulin-sensitizing activity of glimepiride. Differences in the engagement of these targets/mechanisms between glimepiride and glibenclamide are compatible with the more favorable blood glucose-lowering profile and the lower risk for weight gain, hypoglycemic incidences and cardiovascular side effects. The molecular and clinical findings with glimepiride raise doubts that the potential of sulfonylureas for the therapy of type 2 diabetic patients has already been fully explored and feeds the hope for more efficient and nevertheless safe antidiabetic drugs derived from this "old" pharmacophore class in the future.

Keywords: Regulation of glucose and lipid metabolism; adipocytes; insulin resistance; insulin signalling; lipid rafts

Document Type: Review Article

DOI: http://dx.doi.org/10.2174/156801305774962123

Affiliations: Sanofi-Aventis, TD Metabolism, Industrial Park Höchst, Bldg. H821, 65926 Frankfurt am Main, Germany.

Publication date: December 1, 2005

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