Pancreas - specific G a deficiency h s as divergent effects on pancreatic a - and b - cell proliferation

The ubiquitously expressed G protein a-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 mice with Gsa deficiency throughout the whole pancreas by mating Gsa-floxed mice with Pdx1-cre transgenic mice (PGsKO). PGsKOmice also developed severe 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 interior of the islet. Similar findings were observed in mice Journal of Endocrinology (2010) 206, 261–269 0022–0795/10/0206–261 q 2010 Society for Endocrinology Printed in Great 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 aand b-cell proliferation, and that impaired GLP1 action in aand 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. Journal of Endocrinology (2010) 206, 261–269