Pancreas-specific Gsalpha deficiency has divergent effects on pancreatic alpha- and beta-cell proliferation.
The ubiquitously expressed G protein alpha-subunit G(s)alpha mediates 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 beta-cell-specific G(s)alpha deficiency (betaGsKO) develop severe early-onset insulin-deficient diabetes with a severe defect in beta-cell proliferation. We have now generated mice with G(s)alpha deficiency throughout the whole pancreas by mating G(s)alpha-floxed mice with Pdx1-cre transgenic mice (PGsKO). PGsKO mice also developed severe insulin-deficient diabetes at a young age, confirming the important role of G(s)alpha signaling in beta-cell growth and function. Unlike in betaGsKO mice, islets in PGsKO mice had a relatively greater proportion of alpha-cells, which were spread throughout the interior of the islet. Similar findings were observed in mice with pancreatic islet cell-specific G(s)alpha deficiency using a neurogenin 3 promoter-cre recombinase transgenic mouse line. Studies in the alpha-cell line alphaTC1 confirmed that reduced cAMP signaling increased cell proliferation while increasing cAMP produced the opposite effect. Therefore, it appears that G(s)alpha/cAMP signaling has opposite effects on pancreatic alpha- and beta-cell proliferation, and that impaired GLP1 action in alpha- and beta-cells via G(s)alpha 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 G(s)alpha in the exocrine pancreas as well.
Xie
Tao
T
Signal Transduction Section, Metabolic Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Chen
Min
M
Weinstein
Lee S
LS
D000704:Analysis of Variance; D000818:Animals; D001823:Body Composition / Q000502:physiology; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004435:Eating / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics / Q000378:metabolism*; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000378:metabolism*; D005951:Glucose Tolerance Test; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010179:Pancreas / Q000378:metabolism*; D011863:Radioimmunoassay; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology
D007328:Insulin; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000242:Cyclic AMP; D019205:GTP-Binding Protein alpha Subunits, Gs