详细记录  
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 Apr 11. [ IF= 8.29 ] ]
URL :10.2337/db12-1394
日期:20130430
摘要:Incretin hormone action on ss-cells stimulates in parallel two different
intracellular cyclic AMP-dependent signaling branches mediated by PKA and EPAC2A.
Both pathways contribute towards potentiation of glucose-stimulated insulin
secretion (GSIS). However, the overall functional role of EPAC2A in ss-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
glucose-stimulated insulin secretion in mice under basal conditions. However,
when mice are exposed to diet-induced insulin resistance, pharmacologic
secretagogue stimulation of ss-cells with an incretin hormone glucagon-like
peptide-1 analogue or with a Fatty Acid Receptor 1/GPR40 selective activator,
EPAC2A is required for the increased ss-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 ss-cells. Our findings advance the rationale for
developing EPAC2A selective pharmacologic activators for ss-cell targeted
pharmacotherapy in type 2 diabetes mellitus.

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