Abstract

Glucose metabolism stimulates Cdc42-Pak1 activity and initiates F-actin cytoskeleton remodeling in pancreatic β-cells so that cytoplasmic secretory granules can translocate to the plasma membrane where insulin exocytosis occurs. Since glucose metabolism also generates cAMP in β-cells, the crosstalk of cAMP signaling with Cdc42-Pak1 activation might be of fundamental importance to glucose-stimulated insulin secretion (GSIS). Previously, the cAMP-regulated guanine nucleotide exchange factor Epac2 was established to mediate a potentiation of GSIS by cAMP-elevating agents. Here we report that non-diabetic (ND) human islets and INS-1 832/13 β-cells treated with the selective Epac activator 8-pCPT-2'-O-Me-cAMP-AM exhibited Cdc42-Pak1 activation at 1 mM glucose, and that the magnitude of this effect was equivalent to that which was measured during stimulation with 20 mM glucose in the absence of 8-pCPT-2'-O-Me-cAMP-AM. Conversely, the cAMP antagonist Rp-8-Br-cAMPS-pAB prevented glucose-stimulated Cdc42-Pak1 activation, thereby blocking GSIS while also increasing cellular F-actin content. Although islets from type 2 diabetic (T2D) donors had profound defects in glucose-stimulated Cdc42-Pak1 activation and insulin secretion, these defects were rescued by the Epac activator so that GSIS was restored. Collectively, these findings indicate an unexpected role for cAMP as a permissive or direct metabolic coupling factor in support of GSIS that is Epac2 and Cdc42-Pak1 regulated.