Identification of key signaling molecules downstream of cAMP that regulate insulin secretion

Abstract

In the pancreatic islet, the unique heterotrimeric G protein α‐subunit, Gαz, inhibits adenylate cyclase, reducing cyclic adenosine monophosphate (cAMP) levels. cAMP is an important potentiator of glucose‐stimulated insulin secretion (GSIS) and Gαz‐null islets have enhanced GSIS. To further delineate the mechanisms downstream of cAMP that impact GSIS, an exon array analysis was performed in islets isolated from 10‐week‐old male Gαz‐null and control mice. Candidate genes were flagged as being differentially expressed in Gαz‐null islets. To further test the mechanism for gene regulation, highly glucose‐and cAMP‐responsive Ins‐1 832/3 insulinoma cells were treated with various stable cAMP analogs. PGC‐1α was induced greater than 4‐fold with increasing 8‐CPT‐cAMP dose and 8‐fold with increasing 8‐CPT‐cAMP treatment time. 8‐CPT‐cAMP activates both the Epac and PKA pathways. Treatment with an Epac‐specific cAMP analog, 8‐CPT‐2′‐O‐Me‐cAMP, had no effect on PGC‐1α suggesting PKA as the specific activator downstream of cAMP. Thus, PGC‐1α may play an important role in cAMP dependent insulin secretion and further functional characterization of PGC‐1α in the β‐cell may help explain the phenotype of increased GSIS in Gαz‐null islets. This work was funded by JDRF grant 17–2011‐608 (to M.E.K).