BACKGROUND & AIMS: Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) activate pathways involved in beta cell survival and proliferation in vitro; we compared the relative importance of exogenous and endogenous GIP receptor (GIPR) and GLP-1 receptor (GLP-1R) activation for beta cell cytoprotection in mice. METHODS: The effects of incretin hormone receptor signaling on beta cell regeneration and survival were assessed in mice following administration of streptozotocin in the absence or presence of the GIPR agonist [D-Ala(2)]-GIP (D-GIP), the GLP-1R agonist exendin-4, or the dipeptidyl peptidase-4 inhibitor sitagliptin. Beta cell survival was assessed in Gipr(-/-) mice given streptozotocin and by gene expression profiling of RNA from islets isolated from Glp1r(-/-) and Gipr(-/-) mice. The antiapoptotic actions of sitagliptin were assessed in wild-type and dual incretin receptor knockout (DIRKO) mice. RESULTS: Administration of exendin-4 for 7 or 60 days improved blood glucose and insulin levels, reduced islet cell apoptosis, and increased pancreatic insulin content and beta cell mass. In contrast, D-GIP was less effective at improving these parameters under identical experimental conditions. Furthermore, Gipr(-/-) mice did not exhibit increased sensitivity to streptozotocin-induced diabetes. Sitagliptin reduced hemoglobin A(1c) levels and increased plasma and pancreatic levels of insulin after streptozotocin administration to wild-type mice. Sitagliptin reduced the levels of activated caspase-3 in wild-type islets but not in beta cells from DIRKO mice. CONCLUSIONS: There are functionally important differences in the pharmacologic and physiologic roles of incretin receptors in beta cells. GLP-1R signaling exerts more robust control of beta cell survival, relative to GIPR activation or dipeptidylpeptidase-4 inhibition in mice in vivo.
BACKGROUND & AIMS:Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) activate pathways involved in beta cell survival and proliferation in vitro; we compared the relative importance of exogenous and endogenous GIP receptor (GIPR) and GLP-1 receptor (GLP-1R) activation for beta cell cytoprotection in mice. METHODS: The effects of incretin hormone receptor signaling on beta cell regeneration and survival were assessed in mice following administration of streptozotocin in the absence or presence of the GIPR agonist [D-Ala(2)]-GIP (D-GIP), the GLP-1R agonist exendin-4, or the dipeptidyl peptidase-4 inhibitor sitagliptin. Beta cell survival was assessed in Gipr(-/-) mice given streptozotocin and by gene expression profiling of RNA from islets isolated from Glp1r(-/-) and Gipr(-/-) mice. The antiapoptotic actions of sitagliptin were assessed in wild-type and dual incretin receptor knockout (DIRKO) mice. RESULTS: Administration of exendin-4 for 7 or 60 days improved blood glucose and insulin levels, reduced islet cell apoptosis, and increased pancreatic insulin content and beta cell mass. In contrast, D-GIP was less effective at improving these parameters under identical experimental conditions. Furthermore, Gipr(-/-) mice did not exhibit increased sensitivity to streptozotocin-induced diabetes. Sitagliptin reduced hemoglobin A(1c) levels and increased plasma and pancreatic levels of insulin after streptozotocin administration to wild-type mice. Sitagliptin reduced the levels of activated caspase-3 in wild-type islets but not in beta cells from DIRKO mice. CONCLUSIONS: There are functionally important differences in the pharmacologic and physiologic roles of incretin receptors in beta cells. GLP-1R signaling exerts more robust control of beta cell survival, relative to GIPR activation or dipeptidylpeptidase-4 inhibition in mice in vivo.
Authors: Jeremy A Lavine; Carly R Kibbe; Mieke Baan; Sirinart Sirinvaravong; Heidi M Umhoefer; Kimberly A Engler; Louise M Meske; Kaitlyn A Sacotte; Daniel P Erhardt; Dawn Belt Davis Journal: Am J Physiol Endocrinol Metab Date: 2015-09-22 Impact factor: 4.310
Authors: Scott B Widenmaier; Su-Jin Kim; Gary K Yang; Thomas De Los Reyes; Cuilan Nian; Ali Asadi; Yutaka Seino; Timothy J Kieffer; Yin Nam Kwok; Christopher H S McIntosh Journal: PLoS One Date: 2010-03-09 Impact factor: 3.240
Authors: Jonathan E Campbell; John R Ussher; Erin E Mulvihill; Jelena Kolic; Laurie L Baggio; Xiemen Cao; Yu Liu; Benjamin J Lamont; Tsukasa Morii; Catherine J Streutker; Natalia Tamarina; Louis H Philipson; Jeffrey L Wrana; Patrick E MacDonald; Daniel J Drucker Journal: Nat Med Date: 2015-12-07 Impact factor: 53.440
Authors: Allison L Brill; Jaclyn A Wisinski; Mark T Cadena; Mary F Thompson; Rachel J Fenske; Harpreet K Brar; Michael D Schaid; Renee L Pasker; Michelle E Kimple Journal: Mol Endocrinol Date: 2016-04-06
Authors: Meghan Sauvé; Kiwon Ban; M Abdul Momen; Yu-Qing Zhou; R Mark Henkelman; Mansoor Husain; Daniel J Drucker Journal: Diabetes Date: 2010-01-22 Impact factor: 9.461