Abstract
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.
Key words
Non-Insulin-Dependent Diabetes Mellitus (NIDDM) - Sulfonylureas - Glibenclamide -
Sulfonylurea Receptor - KATP Channels - Insulin Secretion
