TRPM5 Activity is Potentiated with Glimepiride and Acts in Tandem with K ATP Channels to Stimulate Glucose‐Induced Insulin Secretion

TRPM5 is a calcium‐activated monovalent cation channel expressed in the pancreatic beta‐cells where it is involved in the regulation of glucose‐induced insulin secretion. Screening of a large library of bioactive drug‐like compounds revealed that glimepiride displays TRPM5‐potentiating activity. Glimepiride is a third generation sulfolylurea drug and is used in clinical practice to stimulate insulin secretion in type II diabetic patients. It is an optimized sulfonylurea drug compound with improved pharmacological effects compared to earlier drugs in this class. One of the main advantages of glimepiride is the reduced observation of hypoglycemic events during treatment. The interaction of glimepiride with K ATP channels, the bona fide target of sulfonylureas, cannot fully explain the differences in observed effects between glimepiride and earlier sulfonylureas as glyburide and tolbutamide. We used a series of in vitro and in vivo experiments to examine the interaction between glimepiride and TRPM5. We measured the TRPM5 currents evoked by glimepiride in a HEK‐cell overexpression system. In isolated pancreatic islets from WT, Trpm5 −/− and K ATP functional knockout mice, we measured the changes in intracellular calcium dynamics. Ultimately we observed the effects of glimepiride in vivo . Glimepiride increases TRPM5‐mediated currents in HEK cells. In isolated islets, we observe calcium activity in the presence of glimepiride in a lower concentration range compared to Trpm5 −/− islets. Furthermore in islets isolated form K ATP pore mutant mice, we observed increased calcium activity in the beta‐cells during application of glimepiride. Ultimately, in Trpm5 −/− mice, glimepiride has less antihyperglycemic effects after a glucose injection compared to WT mice, indicating there is an important role for TRPM5 in the signal transduction of glimepiride in the beta‐cells. The action on TRPM5 is downstream of increases in [Ca 2+ ] i , and therefore glucose‐dependent. Our data suggest an explanation for the reduced hypoglycemic effect of glimepiride. Taken together the promiscuity of glimepride leads to a synergetic action on K ATP channels and TRPM5 channels to stimulate insulin secretion from pancreatic beta‐cells. This new information confirms the hypothesis that targeting TRPM5 is a valid approach to stimulate insulin secretion and in fact, is unknowingly already widely used. Support or Funding Information Koenraad Philippaert is a FWO [PEGASUS] 2 Marie Skłodowska‐Curie Fellow and received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska‐Curie grant agreement (665501) with the Research Foundation Flanders (FWO).