Epac2A Makes a New Impact in β-Cell Biology

Abstract

The high-fat diet (HFD)-fed mouse model of obesity-related type 2 diabetes mellitus (T2DM) continues to provide new insights concerning the molecular basis for pancreatic β-cell compensation under conditions of diet-induced insulin resistance. In the new study by Song et al. (1), β-cell compensation to preserve glucose-stimulated insulin secretion (GSIS) under conditions of the HFD is shown to be lost in mice in which there is a knockout (KO) of Rapgef4 , the gene coding for a cAMP-regulated guanine nucleotide exchange factor designated as Epac2A. These findings obtained with mice fed the HFD suggest that Epac2A activators might be of use for the treatment of T2DM, or that aberrant Epac2A signaling in the β-cell might predispose to T2DM. Protein kinase A (PKA)-independent signaling properties of cAMP are mediated by Epac2A in β-cells, and Epac2A acts as a cofactor with PKA in order to mediate the potentiation of GSIS by cAMP-elevating hormone glucagon-like peptide 1 (GLP-1) (2–5). Since GLP-1 is the prototype of a new class of insulin secretagogues for use in the treatment of T2DM (6), speculation exists concerning what additional roles Epac2A might play in β-cell biology. Song et al. (1) now report that when mice are fed an HFD (7), there exists β-cell compensation in which Epac2A enables GSIS to occur in the absence of administered GLP-1. Thus, Epac2A expression in islets is of importance to the cAMP-dependent potentiation of GSIS by GLP-1 (Fig. 1 A ), while also being of importance to the maintenance of GSIS under conditions of an HFD (Fig. 1 B ). These new findings concerning Epac2A …