title: Targeted expression of islet neogenesis associated protein to beta cells enhances glucose tolerance and confers resistance to streptozotocin-induced hyperglycemia.
abstract: Islet neogenesis associated protein (INGAP) stimulates experimental pancreatic islet growth, as evidenced by elevated markers of beta cell mass, in rodents, dogs and primates. Previous analyses of mice that have a transgenic expression of INGAP targeted to the exocrine pancreas have indicated additional biological activity attributed to INGAP. In this study we report on mice with a targeted expression of INGAP to the islet beta cell. The beta cell transgenic mice (IP-INGAP) showed enhanced normalization of blood glucose during IPGTT. Further, IP-INGAP mice had a significant delay in development of hyperglycemia following a diabetogenic dose of streptozotocin. INGAP conferred beta cell protection and enhanced islet function. Analysis of oxidative stress genes in IP-INGAP mice revealed a decrease in islet expression of the NADPH oxidase, NOX1, in both basal state and in response to pro-inflammatory cytokine stimulation. These data are consistent with a pleiotropic role for INGAP and reveal new pathways to target in the discovery of improved diabetic therapies.
authors.affiliation: Strelitz Diabetes Center, Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA 23507, USA.
authors.forename: Tien-Jyun
authors.initials: TJ
authors.lastname: Chang
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Weaver
authors.forename: Angela
authors.initials: A
authors.lastname: Bowman
authors.forename: Kendall
authors.initials: K
authors.lastname: Leone
authors.forename: Rebekah
authors.initials: R
authors.lastname: Raab
authors.forename: Aaron I
authors.initials: AI
authors.lastname: Vinik
authors.forename: Gary L
authors.initials: GL
authors.lastname: Pittenger
authors.forename: David A
authors.initials: DA
authors.lastname: Taylor-Fishwick
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced* / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D006943:Hyperglycemia / Q000139:chemically induced* / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics; D000074624:NADPH Oxidase 1; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013311:Streptozocin; D014158:Transcription, Genetic
chemical_list: D001786:Blood Glucose; D007328:Insulin; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins; C000612141:REG3A protein, human; D011994:Recombinant Proteins; C490253:Reg3b protein, mouse; D013311:Streptozocin; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614711:NOX1 protein, mouse; D053148:Caspase 3; D005947:Glucose