1568-P: Liver-specific Expression of Activated G Protein Gsα Leads to Hyperglycemia with Reduced Pancreatic α-Cell Mass and Function

Gsα couples hormones to stimulate intracellular cAMP generation. We previously showed that mice with liver-specific Gsα deficiency (LGsKO) have improved glucose tolerance and enlarged pancreatic islets. Here we generated mice with liver-specific expression of an activated Gsα by breeding mice containing a Lox-STOP-Lox-GsαR201C transgene with albumin-Cre mice (LGsR201C). Compared to controls, male LGsR201C mice had normal survival but increased hepatic cAMP levels and gluconeogenetic gene expression, confirming the activation of liver Gsα/cAMP signaling in these mice. Consequently, LGsR201C mice showed elevated blood glucose, enhanced glucose response to pyruvate administration and hyperglycemic response to glucagon. LGsR201C mice had glucose intolerance and lacked insulin response to i.p. glucose injection, although having normal pancreatic β-cell mass and intact glucose-stimulated insulin secretion from isolated islets ex vivo . On the other hand, LGsR201C mice exhibited normal insulin sensitivity but lacked counterregulatory action of glucagon responding to lower blood glucose levels in vivo and had less pancreatic α-cell mass, reduced islet glucagon content and impaired arginine-stimulated glucagon secretion from isolated islets. Notably, LGsR201C mice showed significantly lower serum levels in all tested 17 amino acids. RNAseq analysis revealed that an array of genes was oppositely regulated in LGsR201C vs. LGsKO mice, including the genes of several amino acid transporters upregulated in the liver and islets of LGsR201C mice and downregulated in the liver of LGsKO mice. Thus, our data indicate that activation of Gsα/cAMP signaling in the liver triggers a liver-islet circuit that plays divergent roles in the control of pancreatic islet α- and β-cell biogenesis and functions. Disclosure M. Gupta: None. H. Sun: None. D. Layton: None. J. Zhang: None. J. Lee: None. M. Chen: None. L. Weinstein: None. Funding NIDDK Intramural Research Program