Characterization of the Molecular Mode of Action of the Sulfonylurea, Glimepiride, at β-Cells

Abstract

Glimepiride was compared with glibenclamide for its insulin secretion stimulating and beta-cell membrane depolarizing activity as well as for its binding kinetics to beta-cell membranes and for its beta-cell membrane binding proteins. Steady state, kinetic and competitive binding studies revealed a 3- to 4-fold lower binding affinity of glimepiride to isolated beta-cell membranes and intact beta-cells compared to glibenclamide. Direct photoaffinity labeling of beta-cell membrane proteins with the radiolabeled sulfonylureas identified a 65-kDa binding protein for glimepiride and a 140-kDa binding protein for glibenclamide which may be the basis for the different binding characteristics of the two sulfonylureas. The inhibition of binding and photoaffinity labeling of glimepiride and glibenclamide to the 65- and 140-kDa protein, respectively, by glibenclamide and glimepiride can be explained with allosteric interactions between two distinct sulfonylurea binding proteins, subunits of a KATP protein complex, each regulating the open/closed-state of a common separate pore-forming subunit by allosteric interactions. Whole-cell patch clamp experiments with RINm5F cells demonstrated a 3- to 4-fold lower depolarization activity of glimepiride compared to glibenclamide which correlates well with the lower binding affinity of glimepiride. The lower binding affinity and depolarization activity of glimepiride were not reflected in vitro in perifused islets and the isolated perfused pancreas of the rat. This discrepancy remains to be elucidated. The binding, depolarisation and insulin releasing characteristics of glimepiride and glibenclamide suggest that different sulfonylureas can interact with different components of KATP.

Development and Functional Characterization of Insulin-releasing Human Pancreatic Beta Cell Lines Produced by Electrofusion

“…For example, the amino acids leucine, KIC, alanine, and arginine caused significant increases in insulin release from each cell line. Similarly, blockade of K-ATP channels with glibenclamide or tolbutamide enhanced insulin release as in native beta cells (31). The intestinal hormones glucose-dependent insulinotropic polypeptide (GIP), GLP-1, and CCK-8 trigger insulin release via diverse signal transduction pathways including adenylate cyclase, elevation of intracellular Ca 2ϩ , and stimulation of the mitogen-activated protein kinase (32-34).…”

Meglitinide Analogues in Adolescent Patients With HNF1A-MODY (MODY 3)

“…19 Glimepiride is a third-generation sulfonylurea preparation, and an additional, extrapancreatic glucose-lowering effect has been suggested with its use. 20 It displays a lower incidence of hypoglycemia than glibenclamide because it has a lesser effect on fasting insulin levels. 21 Glimepiride' s plasma half-life is almost equal to that of glibenclamide, and it can also be given once daily.…”

Cardiovascular Safety Evaluation in the Development of New Drugs for Diabetes Mellitus

“…These insulin-providing agents bind to the β-cell sulfonylurea receptor of the pancreatic β-cell and block ATP channels, resulting in insulin release mediated via the activation of calcium-dependent proteins. 22,23 In animal models, sulfonylureas have been shown to bind to receptors in the heart and negatively impact ischemic preconditioning responses. [24][25][26][27][28] Adverse contractile responses to ischemia and on infarct size, as well, have been noted.…”