AIMS/HYPOTHESIS: Glucokinase activators (GKAs) are currently being developed as new therapies for type 2 diabetes and have been shown to enhance beta cell survival and proliferation in vitro. Here, we report the effects of chronic GKA treatment on the development of hyperglycaemia and beta cell loss in the male Zucker diabetic fatty (ZDF) rat, a model of type 2 diabetes with severe obesity. METHODS: Cell protection by GKA was studied in MIN6 and INS-1 cells exposed to hydrogen peroxide. Glucose homeostasis and beta cell mass were evaluated in ZDF rats dosed for 41 days with Cpd-C (a GKA) or glipizide (a sulfonylurea) as food admixtures at doses of approximately 3 and 10 mg kg(-1) day(-1). RESULTS: Incubation of MIN6 and INS-1 832/3 insulinoma cell cultures with GKA significantly reduced cell death and impairment of intracellular NADH production caused by exposure to hydrogen peroxide. Progression from prediabetes (normoglycaemia and hyperinsulinaemia) to overt diabetes (hyperglycaemia and hypoinsulinaemia) was significantly delayed in male ZDF rats by in-feed treatment with Cpd-C, but not glipizide. Glucose tolerance, tested in the fifth week of treatment, was also significantly improved by Cpd-C, as was pancreatic insulin content and beta cell area. In a limited immunohistochemical analysis, Cpd-C modestly and significantly enhanced the rate of beta cell proliferation, but not rates of beta cell apoptosis relative to untreated ZDF rats. CONCLUSIONS/ INTERPRETATION: These findings suggest that chronic activation of glucokinase preserves beta cell mass and delays disease in the ZDF rat, a model of insulin resistance and progressive beta cell failure.
AIMS/HYPOTHESIS: Glucokinase activators (GKAs) are currently being developed as new therapies for type 2 diabetes and have been shown to enhance beta cell survival and proliferation in vitro. Here, we report the effects of chronic GKA treatment on the development of hyperglycaemia and beta cell loss in the male Zucker diabetic fatty (ZDF) rat, a model of type 2 diabetes with severe obesity. METHODS: Cell protection by GKA was studied in MIN6 and INS-1 cells exposed to hydrogen peroxide. Glucose homeostasis and beta cell mass were evaluated in ZDFrats dosed for 41 days with Cpd-C (a GKA) or glipizide (a sulfonylurea) as food admixtures at doses of approximately 3 and 10 mg kg(-1) day(-1). RESULTS: Incubation of MIN6 and INS-1 832/3 insulinoma cell cultures with GKA significantly reduced cell death and impairment of intracellular NADH production caused by exposure to hydrogen peroxide. Progression from prediabetes (normoglycaemia and hyperinsulinaemia) to overt diabetes (hyperglycaemia and hypoinsulinaemia) was significantly delayed in male ZDFrats by in-feed treatment with Cpd-C, but not glipizide. Glucose tolerance, tested in the fifth week of treatment, was also significantly improved by Cpd-C, as was pancreatic insulin content and beta cell area. In a limited immunohistochemical analysis, Cpd-C modestly and significantly enhanced the rate of beta cell proliferation, but not rates of beta cell apoptosis relative to untreated ZDFrats. CONCLUSIONS/ INTERPRETATION: These findings suggest that chronic activation of glucokinase preserves beta cell mass and delays disease in the ZDFrat, a model of insulin resistance and progressive beta cell failure.
Authors: Shay Porat; Noa Weinberg-Corem; Sharona Tornovsky-Babaey; Rachel Schyr-Ben-Haroush; Ayat Hija; Miri Stolovich-Rain; Daniela Dadon; Zvi Granot; Vered Ben-Hur; Peter White; Christophe A Girard; Rotem Karni; Klaus H Kaestner; Frances M Ashcroft; Mark A Magnuson; Ann Saada; Joseph Grimsby; Benjamin Glaser; Yuval Dor Journal: Cell Metab Date: 2011-04-06 Impact factor: 27.287
Authors: E A Davis; A Cuesta-Muñoz; M Raoul; C Buettger; I Sweet; M Moates; M A Magnuson; F M Matschinsky Journal: Diabetologia Date: 1999-10 Impact factor: 10.122
Authors: Won-Ho Kim; June Woo Lee; Young Ho Suh; Shin Hee Hong; Joo Sun Choi; Joo Hyun Lim; Ji Hyun Song; Bin Gao; Myeong Ho Jung Journal: Diabetes Date: 2005-09 Impact factor: 9.461
Authors: Franz M Matschinsky; Mark A Magnuson; Dorothy Zelent; Tom L Jetton; Nicolai Doliba; Yi Han; Rebecca Taub; Joseph Grimsby Journal: Diabetes Date: 2006-01 Impact factor: 9.461
Authors: Ishrat Jahan; Kathryn L Corbin; Avery M Bogart; Nicholas B Whitticar; Christopher D Waters; Cara Schildmeyer; Nicholas W Vann; Hannah L West; Nathan C Law; Jeffrey S Wiseman; Craig S Nunemaker Journal: Endocrinology Date: 2018-11-01 Impact factor: 4.736
Authors: D J Baker; G P Wilkinson; A M Atkinson; H B Jones; M Coghlan; A D Charles; B Leighton Journal: Br J Pharmacol Date: 2014-04 Impact factor: 8.739
Authors: Rachel E Stamateris; Rohit B Sharma; Douglas A Hollern; Laura C Alonso Journal: Am J Physiol Endocrinol Metab Date: 2013-05-14 Impact factor: 4.310
Authors: Derek M Erion; Amanda Lapworth; Paul A Amor; Guoyun Bai; Nicholas B Vera; Ronald W Clark; Qingyun Yan; Yimin Zhu; Trenton T Ross; Julie Purkal; Matthew Gorgoglione; Guodong Zhang; Vinicius Bonato; Levenia Baker; Nicole Barucci; Theresa D'Aquila; Alan Robertson; Robert J Aiello; Jiangli Yan; Jeff Trimmer; Timothy P Rolph; Jeffrey A Pfefferkorn Journal: PLoS One Date: 2014-05-23 Impact factor: 3.240
Authors: Min Lu; Pingping Li; Gautam Bandyopadhyay; William Lagakos; Walter E Dewolf; Taylor Alford; Mark Joseph Chicarelli; Lance Williams; Deborah A Anderson; Brian R Baer; Maralee McVean; Marion Conn; Murielle M Véniant; Peter Coward Journal: PLoS One Date: 2014-02-12 Impact factor: 3.240