β cell-specific deficiency of the stimulatory G protein α-subunit G s α leads to reduced β cell mass and insulin-deficient diabetes

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Abstract
The G protein α-subunit Gsα is required for hormone-stimulated cAMP generation. In pancreatic β cells, Gsα mediates the signaling of glucagon-like peptide 1 and other incretin hormones, which are implicated as important regulators of β cell survival and insulin release. Studies have suggested that Gsα/cAMP mediates these actions by stimulating insulin receptor substrate 2 (IRS2) expression. Mice with β cell-specific Gsα deficiency (βGsKO) were generated by mating Gsα-floxed mice to rat insulin II promoter-cre recombinase mice. βGsKO mice had poor survival and postnatal growth with low serum insulin-like growth factor 1 levels. βGsKO mice also developed severe hyperglycemia and glucose intolerance with severe hypoinsulinemia and reduced islet insulin content and glucose-stimulated insulin release. βGsKO mice had markedly reduced average islet size and β cell mass, which was partially explained by reduced β cell size. In addition, βGsKO mice had significantly reduced β cell proliferation and increased β cell apoptosis and markedly reduced expression of the cell cycle protein cyclin D2. The effects on β cell mass and proliferation, but not apoptosis, were present from birth. Unexpectedly expression of Irs2 and the downstream gene Pdx1 were unaffected. These results show that Gsα/cAMP pathways are critical regulators of β cell function and proliferation that can work through IRS2-independent mechanisms.