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The ubiquitously expressed G protein α-subunit G s α mediates 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 β-cell-specific G s α deficiency (βGsKO) develop severe early-onset insulin-deficient diabetes with a severe defect in β-cell proliferation. We have now generated mice with G s α deficiency throughout the whole pancreas by mating G s α-floxed mice with Pdx1-cre transgenic mice (PGsKO). PGsKO mice also developed severe insulin-deficient diabetes at a young age, confirming the important role of G s α signaling in β-cell growth and function. Unlike in βGsKO mice, islets in PGsKO mice had a relatively greater proportion of α-cells, which were spread throughout the interior of the islet. Similar findings were observed in mice with pancreatic islet cell-specific G s α deficiency using a neurogenin 3 promoter-cre recombinase transgenic mouse line. Studies in the α-cell line αTC1 confirmed that reduced cAMP signaling increased cell proliferation while increasing cAMP produced the opposite effect. Therefore, it appears that G s α/cAMP signaling has opposite effects on pancreatic α- and β-cell proliferation, and that impaired GLP1 action in α- and β-cells via G s α 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 G s α in the exocrine pancreas as well.

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