title: Deletion of GαZ protein protects against diet-induced glucose intolerance via expansion of β-cell mass.
abstract: Insufficient plasma insulin levels caused by deficits in both pancreatic β-cell function and mass contribute to the pathogenesis of type 2 diabetes. This loss of insulin-producing capacity is termed β-cell decompensation. Our work is focused on defining the role(s) of guanine nucleotide-binding protein (G protein) signaling pathways in regulating β-cell decompensation. We have previously demonstrated that the α-subunit of the heterotrimeric G(z) protein, Gα(z), impairs insulin secretion by suppressing production of cAMP. Pancreatic islets from Gα(z)-null mice also exhibit constitutively increased cAMP production and augmented glucose-stimulated insulin secretion, suggesting that Gα(z) is a tonic inhibitor of adenylate cyclase, the enzyme responsible for the conversion of ATP to cAMP. In the present study, we show that mice genetically deficient for Gα(z) are protected from developing glucose intolerance when fed a high fat (45 kcal%) diet. In these mice, a robust increase in β-cell proliferation is correlated with significantly increased β-cell mass. Further, an endogenous Gα(z) signaling pathway, through circulating prostaglandin E activating the EP3 isoform of the E prostanoid receptor, appears to be up-regulated in insulin-resistant, glucose-intolerant mice. These results, along with those of our previous work, link signaling through Gα(z) to both major aspects of β-cell decompensation: insufficient β-cell function and mass.
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53705, USA. mkimple@medicine.wisc.edu
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Kimple
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Moss
authors.forename: Harpreet K
authors.initials: HK
authors.lastname: Brar
authors.forename: Taylor C
authors.initials: TC
authors.lastname: Rosa
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Truchan
authors.forename: Renee L
authors.initials: RL
authors.lastname: Pasker
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Casey
mesh_terms: D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D048429:Cell Size; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D018149:Glucose Intolerance / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D004041:Dietary Fats; D044385:GTP-Binding Protein alpha Subunits; D007328:Insulin; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D000262:Adenylyl Cyclases