Critical role of cAMP-GEFII.Rim2 complex in incretin-potentiated insulin secretion

Incretins such as glucagon-like peptide-1 and gastric inhibitory polypeptid e/glucose-dependent insulinotropic peptide are known to potentiate insulin secretion mainly through a cAMP/protein kinase A (PKA) signaling pathway in pancreatic beta -cells, but the mechanism is not clear. We recently found that the cAMP-binding protein eAMP-GEFII (or Epae 2), interacting with Rim2 , a target of the small G protein Rab3, mediates cAMP-dependent, PKA-indepe ndent exocytosis in a reconstituted system. In the present study, we invest igated the role of the cAMP-GEFII.Rim2 pathway in incretin-potentiated insu lin secretion in native pancreatic beta -cells. Treatment of pancreatic isl ets with antisense oligodeoxynucleotides (ODNs) against cAMP-GEFII alone or with the PKA inhibitor H-89 alone inhibited incretin-potentiated insulin s ecretion similar to 50%, while a combination of antisense ODNs and H-89 inh ibited the secretion similar to 80-90% The effect of cAMP-GEFII on insulin secretion is mediated by Rim2 and depends on intracellular calcium as well as on cAMP. Treatment of the islets with antisense ODNs attenuated both the first and second phases of insulin secretion potentiated by the cAMP analo g 8-bromo-cAMP. These results indicate that the PKA-independent mechanism i nvolving the cAMP-GEFII.Rim2 pathway is critical in the potentiation of ins ulin secretion by incretins.