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Diabetologia

pp 1–11 | Cite as

Pregnancy in human IAPP transgenic mice recapitulates beta cell stress in type 2 diabetes

  • Tatyana Gurlo
  • Sarah Kim
  • Alexandra E. Butler
  • Chang Liu
  • Lina Pei
  • Madeline Rosenberger
  • Peter C. ButlerEmail author
Article

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.

Keywords

Beta cell mass Gestational diabetes Pregnancy Type 2 diabetes 

Abbreviations

CHOP

C/EBP homologous protein

ER

Endoplasmic reticulum

hIAPP

Human IAPP

hTG

hIAPP transgenic

IAPP

Islet amyloid polypeptide

p-H2AX

Phosphorylated H2A histone family member X

Notes

Acknowledgements

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.

Contribution statement

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.

Funding

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.

Supplementary material

125_2019_4843_MOESM1_ESM.pdf (706 kb)
ESM (PDF 706 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Tatyana Gurlo
    • 1
  • Sarah Kim
    • 1
  • Alexandra E. Butler
    • 1
  • Chang Liu
    • 1
  • Lina Pei
    • 1
  • Madeline Rosenberger
    • 1
  • Peter C. Butler
    • 1
    Email author
  1. 1.Larry L. Hillblom Islet Research Center, David Geffen School of MedicineUniversity of California Los AngelesLos AngelesUSA

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