Beta cell-specific deficiency of the stimulatory G protein alpha-subunit Gsalpha leads to reduced beta cell mass and insulin-deficient diabetes.
The G protein alpha-subunit G(s)alpha is required for hormone-stimulated cAMP generation. In pancreatic beta cells, G(s)alpha mediates the signaling of glucagon-like peptide 1 and other incretin hormones, which are implicated as important regulators of beta cell survival and insulin release. Studies have suggested that G(s)alpha/cAMP mediates these actions by stimulating insulin receptor substrate 2 (IRS2) expression. Mice with beta cell-specific G(s)alpha deficiency (betaGsKO) were generated by mating G(s)alpha-floxed mice to rat insulin II promoter-cre recombinase mice. betaGsKO mice had poor survival and postnatal growth with low serum insulin-like growth factor 1 levels. betaGsKO mice also developed severe hyperglycemia and glucose intolerance with severe hypoinsulinemia and reduced islet insulin content and glucose-stimulated insulin release. betaGsKO mice had markedly reduced average islet size and beta cell mass, which was partially explained by reduced beta cell size. In addition, betaGsKO mice had significantly reduced beta cell proliferation and increased beta cell apoptosis and markedly reduced expression of the cell cycle protein cyclin D2. The effects on beta 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 G(s)alpha/cAMP pathways are critical regulators of beta cell function and proliferation that can work through IRS2-independent mechanisms.
Xie
Tao
T
Metabolic Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Chen
Min
M
Zhang
Qing-Hong
QH
Ma
Zheng
Z
Weinstein
Lee S
LS
D000818:Animals; D002452:Cell Count; D049109:Cell Proliferation; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000172:deficiency* / Q000235:genetics; D006128:Growth / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000201:enzymology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
D018398:Homeodomain Proteins; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526296:Irs1 protein, rat; D010750:Phosphoproteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D019205:GTP-Binding Protein alpha Subunits, Gs