Pregnancy in human IAPP transgenic mice recapitulates beta cell stress in type 2 diabetes
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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.
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.
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.
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.
KeywordsBeta cell mass Gestational diabetes Pregnancy Type 2 diabetes
C/EBP homologous protein
Islet amyloid polypeptide
Phosphorylated H2A histone family member X
We would like to thank the members of Larry L. Hillblom Islet Research Center at UCLA: B. Lui for editorial assistance, and K. Zeng and M. Cory for technical support. We are thankful to UCLA undergraduate student E. Beebe for help with image analysis.
TG contributed to the study design, coordinated breeding and tissue collection, performed imaging, image analysis, data analysis and interpretation and wrote the manuscript. SK performed image acquisition and quantitative analysis and contributed to the interpretation of the data. AEB contributed to image analysis and interpretation, critical discussion and reviewing the manuscript. CL contributed to the planning of the study, animal work, tissue collection, tissue staining and image analysis. LP contributed to imaging and image analysis and interpretation of the data. MR contributed to tissue staining, imaging and data analysis. PCB designed the study, interpreted data and wrote the manuscript. All authors contributed to the content and critical revision of the manuscript and agreed to submit the manuscript for publication. TG and PCB are the guarantors of the work.
The present studies were supported by funding from the United States Public Health Services National Institute of Health grant (DK059579) and the Larry L. Hillblom Foundation (2014-D-001-NET).
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
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