Pancreas-specific Gsα deficiency has divergent effects on pancreatic α- and β-cell proliferation

The ubiquitouslyexpressed G proteina-subunit Gsamediates the intracellular cAMP response to glucagon-like peptide 1 (GLP1) and other incretin hormones in pancreatic islet cells. We have shown previously that mice with b-cell-specific Gsa deficiency (bGsKO) develop severe early-onset insulindeficient diabetes with a severe defect in b-cell proliferation. We have now generated micewith Gsadeficiency throughout the whole pancreas by mating Gsa-floxed mice with Pdx1-cre transgenic mice(PGsKO). PGsKO mice also developedsevere insulin-deficient diabetes at a young age, confirming the important role of Gsa signaling in b-cell growth and function. Unlike in bGsKO mice, islets in PGsKO mice had a relatively greater proportion of a-cells, which were spread throughout the interiorof the islet. Similarfindingswereobserved in mice with pancreatic islet cell-specific Gsa deficiency using a neurogenin 3 promoter-cre recombinase transgenic mouse line. Studies in the a-cell line aTC1 confirmed that reduced cAMP signaling increased cell proliferation while increasing cAMP produced the opposite effect. Therefore, it appears that Gsa/cAMP signaling has opposite effects on pancreatic a- and b-cell proliferation, and that impaired GLP1 action in a- and b-cells via Gsa signaling may be an important contributor to the reciprocal effects on insulin and glucagon observed in type 2 diabetics. In addition, PGsKO mice show morphological changes in exocrine pancreas and evidence for malnutrition and dehydration, indicating an important role for Gsa in the exocrine pancreas as well.