2187-P: G_sα Deficiency in Pancreatic a Cells Leads to Enlarged Islets

Pancreatic β-cell dysfunction leads to diabetes with reduced β-cell mass and impaired glucose-stimulated insulin secretion. The G protein α subunit G_sα couples receptors to generate cAMP, which mediates the insulinotropic effects of incretin hormones, such as GLP-1. We previously reported that β-cell-specific G_sα deficiency causes insulin-deficient diabetes due to reduced islet size and β-cell mass, and that mice with whole pancreatic G_sα deficiency develop insulin deficient diabetes and reduced β-cell mass, but also showed increased proliferation of α-cells, indicating that G_sα plays divergent roles in pancreatic α-and β-cell growth. In the present study, we generated mice with α-cell-specific G_sα deficiency (αGsKO) by mating G_sα-floxed mice with glucagon-cre mice and studied the metabolic consequences. Deletion of G_sα in α-cells did not affect growth, blood glucose, or serum insulin or glucagon levels. However, αGsKO mice displayed enlarged islet size of normal architecture with significant increases in both α- and β-cell numbers, accompanied with increased β-cell proliferation and reduced apoptosis. This increased β-cell proliferation could be detected as early as at 3 days after birth. Consistent with this, αGsKO mice showed increased insulin response to acute glucose loading (3mg/g i.p.), although they had unaltered glucose tolerance when given a lower dose of glucose (2 mg/g i.p.). The results of RT-PCR on pancreatic islets isolated from aged mice (9-10 months old) showed that expression of Maf B and Pax6, transcription factors required for β-cell development, tended to be increased; whereas cell cycle factors, such as Cyclin D1, D2, and CDK4, tended to be decreased. Taken together, our results show that G_sα/cAMP signaling pathway in pancreatic α-cells is critical for both α- and β-cell growth as well as for maintenance of β-cell mass.