题名：Pancreatic beta-Cell Response to Increased Metabolic Demand and to Pharmacologic Secretagogues Requires EPAC2A.
作者：SONG WJ; MONDAL P; LI Y; LEE SE; HUSSAIN MA;
来源：Diabetes. 2013 Aug;62(8):2796-807. doi: 10.2337/db12-1394. Epub 2013 Apr 11. [ IF= 7.89 ] ]
摘要：Incretin hormone action on beta-cells stimulates in parallel two different
intracellular cyclic AMP-dependent signaling branches mediated by protein kinase
A and exchange protein activated by cAMP islet/brain isoform 2A (EPAC2A). Both
pathways contribute toward potentiation of glucose-stimulated insulin secretion
(GSIS). However, the overall functional role of EPAC2A in beta-cells as it
relates to in vivo glucose homeostasis remains incompletely understood.
Therefore, we have examined in vivo GSIS in global EPAC2A knockout mice.
Additionally, we have conducted in vitro studies of GSIS and calcium dynamics in
isolated EPAC2A-deficient islets. EPAC2A deficiency does not impact GSIS in mice
under basal conditions. However, when mice are exposed to diet-induced insulin
resistance, pharmacologic secretagogue stimulation of beta-cells with an incretin
hormone glucagon-like peptide-1 analog or with a fatty acid receptor 1/G
protein-coupled receptor 40 selective activator, EPAC2A is required for the
increased beta-cell response to secretory demand. Under these circumstances,
EPAC2A is required for potentiating the early dynamic increase in islet calcium
levels after glucose stimulation, which is reflected in potentiated first-phase
insulin secretion. These studies broaden our understanding of EPAC2A function and
highlight its significance during increased secretory demand or drive on
beta-cells. Our findings advance the rationale for developing EPAC2A-selective
pharmacologic activators for beta-cell-targeted pharmacotherapy in type 2