Horm Metab Res 1996; 28(9): 464-468
DOI: 10.1055/s-2007-979838

© Georg Thieme Verlag Stuttgart · New York

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

W. Kramer, G. Müller, K. Geisen
  • Hoechst AG, Frankfurt, TD Metabolic Diseases G 838, Frankfurt, Germany
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Publication History

Publication Date:
23 April 2007 (online)


Glimepiride was compared with glibenclamide for its insulin secretion stimulating and β-cell membrane depolarizing activity as well as for its binding kinetics to β-cell membranes and for its β-cell membrane binding proteins. Steady state, kinetic and competitive binding studies revealed a 3- to 4-fold lower binding affinity of glimepiride to isolated β-cell membranes and intact β-cells compared to glibenclamide. Direct photoaffinity labeling of β-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.