Tatyana Gurlo1, Sarah Kim1, Alexandra E Butler1, Chang Liu1, Lina Pei1, Madeline Rosenberger1, Peter C Butler2. 1. Larry L. Hillblom Islet Research Center, David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Avenue, 32-150 CHS, Los Angeles, CA, 90095-7073, USA. 2. Larry L. Hillblom Islet Research Center, David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Avenue, 32-150 CHS, Los Angeles, CA, 90095-7073, USA. pbutler@mednet.ucla.edu.
Abstract
AIMS/HYPOTHESIS: Islet amyloid polypeptide (IAPP) misfolding and toxic oligomers contribute to beta cell loss and stress in type 2 diabetes. Pregnancy-related diabetes predicts subsequent risk for type 2 diabetes but little is known about the impact of pregnancy on beta cell mass, turnover and stress. Availability of human pancreas tissue in pregnancy is limited and most widely used mouse models of type 2 diabetes do not develop pregnancy-related diabetes, possibly because rodent IAPP is not prone to form toxic oligomers. We hypothesised that mice transgenic for human IAPP (hIAPP) are prone to pregnancy-related diabetes with beta cell responses reflective of those in type 2 diabetes. METHODS: We evaluated the impact of a first and second pregnancy on glucose homeostasis, beta cell mass and turnover and markers of beta cell stress in hIAPP transgenic (hTG) mice. RESULTS: Pregnancy induced both endoplasmic reticulum stress and oxidative stress and compromised autophagy in beta cells in hTG mice, which are characteristic of beta cells in type 2 diabetes. Beta cell stress persisted after pregnancy, resulting in subsequent diabetes before or during a second pregnancy. CONCLUSIONS/ INTERPRETATION: High expression of hIAPP in response to pregnancy recapitulates mechanisms contributing to beta cell stress in type 2 diabetes. We hypothesise that, in individuals prone to type 2 diabetes, pregnancy-induced increased expression of IAPP inflicts beta cell damage that persists and is compounded by subsequent additive stress such as further pregnancy. The hTG mouse model is a novel model for pregnancy-related diabetes.
AIMS/HYPOTHESIS: Islet amyloid polypeptide (IAPP) misfolding and toxic oligomers contribute to beta cell loss and stress in type 2 diabetes. Pregnancy-related diabetes predicts subsequent risk for type 2 diabetes but little is known about the impact of pregnancy on beta cell mass, turnover and stress. Availability of human pancreas tissue in pregnancy is limited and most widely used mouse models of type 2 diabetes do not develop pregnancy-related diabetes, possibly because rodent IAPP is not prone to form toxic oligomers. We hypothesised that micetransgenic for humanIAPP (hIAPP) are prone to pregnancy-related diabetes with beta cell responses reflective of those in type 2 diabetes. METHODS: We evaluated the impact of a first and second pregnancy on glucose homeostasis, beta cell mass and turnover and markers of beta cell stress in hIAPPtransgenic (hTG) mice. RESULTS:Pregnancy induced both endoplasmic reticulum stress and oxidative stress and compromised autophagy in beta cells in hTG mice, which are characteristic of beta cells in type 2 diabetes. Beta cell stress persisted after pregnancy, resulting in subsequent diabetes before or during a second pregnancy. CONCLUSIONS/ INTERPRETATION: High expression of hIAPP in response to pregnancy recapitulates mechanisms contributing to beta cell stress in type 2 diabetes. We hypothesise that, in individuals prone to type 2 diabetes, pregnancy-induced increased expression of IAPP inflicts beta cell damage that persists and is compounded by subsequent additive stress such as further pregnancy. The hTG mouse model is a novel model for pregnancy-related diabetes.
Entities:
Keywords:
Beta cell mass; Gestational diabetes; Pregnancy; Type 2 diabetes
Authors: Jacqueline F Rivera; Safia Costes; Tatyana Gurlo; Charles G Glabe; Peter C Butler Journal: J Clin Invest Date: 2014-07-18 Impact factor: 14.808
Authors: Tatyana Gurlo; Sergey Ryazantsev; Chang-jiang Huang; Michael W Yeh; Howard A Reber; O Joe Hines; Timothy D O'Brien; Charles G Glabe; Peter C Butler Journal: Am J Pathol Date: 2009-12-30 Impact factor: 4.307