Regulation of glucose and incretin-stimulated insulin secretion by cAMP-EPAC2-TRPM2

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In pancreatic beta-cells, closure of ATP-sensitive-K+ (K-ATP) channel is an initial process triggering glucose-stimulated insulin secretion. However theoretically, closure of K-ATP channel　alone should be insufficient to shift membrane potential toward threshold level to set on insulin secretion. Opening of background nonselective-cation channels (NSCCs) facilitates excitability of the membrane.　We here show that a class of NSCC is activated by both glucose and incretin hormones, GLP-1 and GIP, via cAMP/EPAC-mediated NSCC (TRPM2 channel) pathway. Our data demonstrate that glucose metabolism leads to opening of TRPM2 channel and closure of K-ATP channel simultaneously. Glucose- and incretin-activated NSCC works in concert to effectively induce membrane depolarization to initiate insulin secretions. The present study reveals a newly confirmed beta-cell mechanism through which glucose and incretin evoke insulin secretion and provides a innovative target to treat type 2 diabetes.