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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



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.


Beta cell mass Gestational diabetes Pregnancy Type 2 diabetes 



C/EBP homologous protein


Endoplasmic reticulum


Human IAPP


hIAPP transgenic


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.

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.


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)


  1. 1.
    Catalano PM, Tyzbir ED, Roman NM, Amini SB, Sims EA (1991) Longitudinal changes in insulin release and insulin resistance in nonobese pregnant women. Am J Obstet Gynecol 165:1667–1672CrossRefGoogle Scholar
  2. 2.
    Buchanan TA, Metzger BE, Freinkel N, Bergman RN (1990) Insulin sensitivity and B cell responsiveness to glucose during late pregnancy in lean and moderately obese women with normal glucose tolerance or mild gestational diabetes. Am J Obstet Gynecol 162:1008–1014CrossRefGoogle Scholar
  3. 3.
    Buchanan TA (2001) Pancreatic B cell defects in gestational diabetes: implications for the pathogenesis and prevention of type 2 diabetes. J Clin Endocrinol Metab 86:989–993CrossRefGoogle Scholar
  4. 4.
    Buchanan TA, Xiang AH (2005) Gestational diabetes mellitus. J Clin Invest 115:485–491CrossRefGoogle Scholar
  5. 5.
    Homko C, Sivan E, Chen X, Reece EA, Boden G (2001) Insulin secretion during and after pregnancy in patients with gestational diabetes mellitus. J Clin Endocrinol Metab 86(2):568–573. CrossRefPubMedGoogle Scholar
  6. 6.
    Xiang AH, Peters RK, Trigo E, Kjos SL, Lee WP, Buchanan TA (1999) Multiple metabolic defects during late pregnancy in women at high risk for type 2 diabetes. Diabetes 48:848–854CrossRefGoogle Scholar
  7. 7.
    Catalano PM, Huston L, Amini SB, Kalhan SC (1999) Longitudinal changes in glucose metabolism during pregnancy in obese women with normal glucose tolerance and gestational diabetes mellitus. Am J Obstet Gynecol 180:903–916CrossRefGoogle Scholar
  8. 8.
    Kautzky-Willer A, Prager R, Waldhausl W et al (1997) Pronounced insulin resistance and inadequate β-cell secretion characterize lean gestational diabetes during and after pregnancy. Diabetes Care 20:1717–1723CrossRefGoogle Scholar
  9. 9.
    Ben-Haroush A, Yogev Y, Hod M (2004) Epidemiology of gestational diabetes mellitus and its association with type 2 diabetes. Diabet Med 21:103–113CrossRefGoogle Scholar
  10. 10.
    Kim C, Newton KM, Knopp RH (2002) Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes Care 25:1862–1868CrossRefGoogle Scholar
  11. 11.
    Naver KV, Lundbye-Christensen S, Gorst-Rasmussen A et al (2011) Parity and risk of diabetes in a Danish nationwide birth cohort. Diabet Med 28:43–47CrossRefGoogle Scholar
  12. 12.
    Araneta MR, Barrett-Connor E (2010) Grand multiparity is associated with type 2 diabetes in Filipino American women, independent of visceral fat and adiponectin. Diabetes Care 33:385–389CrossRefGoogle Scholar
  13. 13.
    Schwartz N, Green MS, Yefet E, Nachum Z (2016) Modifiable risk factors for gestational diabetes recurrence. Endocrine 54:714–722CrossRefGoogle Scholar
  14. 14.
    Plows JF, Yu X, Broadhurst R et al (2017) Absence of a gestational diabetes phenotype in the LepRdb/+ mouse is independent of control strain, diet, misty allele, or parity. Sci Rep 7(1):45130. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Janson J, Ashley RH, Harrison D, McIntyre S, Butler PC (1999) The mechanism of islet amyloid polypeptide toxicity is membrane disruption by intermediate-sized toxic amyloid particles. Diabetes 48:491–498CrossRefGoogle Scholar
  16. 16.
    Matveyenko AV, Gurlo T, Daval M, Butler AE, Butler PC (2009) Successful versus failed adaptation to high-fat diet-induced insulin resistance: the role of IAPP-induced β-cell endoplasmic reticulum stress. Diabetes 58:906–916CrossRefGoogle Scholar
  17. 17.
    Couce M, Kane LA, O’Brien TD et al (1996) Treatment with growth hormone and dexamethasone in mice transgenic for human islet amyloid polypeptide causes islet amyloidosis and β-cell dysfunction. Diabetes 45:1094–1101CrossRefGoogle Scholar
  18. 18.
    Janson J, Soeller WC, Roche PC et al (1996) Spontaneous diabetes mellitus in transgenic mice expressing human islet amyloid polypeptide. Proc Natl Acad Sci U S A 93:7283–7288CrossRefGoogle Scholar
  19. 19.
    Gurlo T, Ryazantsev S, Huang CJ et al (2010) Evidence for proteotoxicity in β cells in type 2 diabetes: toxic islet amyloid polypeptide oligomers form intracellularly in the secretory pathway. Am J Pathol 176(2):861–869. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Geisler JG, Zawalich W, Zawalich K et al (2002) Estrogen can prevent or reverse obesity and diabetes in mice expressing human islet amyloid polypeptide. Diabetes 51:2158–2169CrossRefGoogle Scholar
  21. 21.
    Karnik SK, Chen H, McLean GW et al (2007) Menin controls growth of pancreatic β-cells in pregnant mice and promotes gestational diabetes mellitus. Science 318:806–809CrossRefGoogle Scholar
  22. 22.
    Butler AE, Cao-Minh L, Galasso R et al (2010) Adaptive changes in pancreatic beta cell fractional area and beta cell turnover in human pregnancy. Diabetologia 53:2167–2176CrossRefGoogle Scholar
  23. 23.
    Van Assche FA, Aerts L, De Prins F (1978) A morphological study of the endocrine pancreas in human pregnancy. Br J Obstet Gynaecol 85(11):818–820. CrossRefPubMedGoogle Scholar
  24. 24.
    Meier JJ, Butler AE, Saisho Y et al (2008) β-cell replication is the primary mechanism subserving the postnatal expansion of β-cell mass in humans. Diabetes 57:1584–1594CrossRefGoogle Scholar
  25. 25.
    Tschen SI, Dhawan S, Gurlo T, Bhushan A (2009) Age-dependent decline in β-cell proliferation restricts the capacity of beta-cell regeneration in mice. Diabetes 58:1312–1320CrossRefGoogle Scholar
  26. 26.
    Teta M, Long SY, Wartschow LM, Rankin MM, Kushner JA (2005) Very slow turnover of β-cells in aged adult mice. Diabetes 54:2557–2567CrossRefGoogle Scholar
  27. 27.
    Huang CJ, Haataja L, Gurlo T et al (2007) Induction of endoplasmic reticulum stress-induced β-cell apoptosis and accumulation of polyubiquitinated proteins by human islet amyloid polypeptide. Am J Physiol Endocrinol Metab 293:E1656–E1662CrossRefGoogle Scholar
  28. 28.
    Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC (2003) Beta-cell deficit and increased β-cell apoptosis in humans with type 2 diabetes. Diabetes 52:102–110CrossRefGoogle Scholar
  29. 29.
    Huang CJ, Lin CY, Haataja L et al (2007) High expression rates of human islet amyloid polypeptide induce endoplasmic reticulum stress mediated β-cell apoptosis, a characteristic of humans with type 2 but not type 1 diabetes. Diabetes 56:2016–2027CrossRefGoogle Scholar
  30. 30.
    Mizukami H, Takahashi K, Inaba W et al (2014) Involvement of oxidative stress-induced DNA damage, endoplasmic reticulum stress, and autophagy deficits in the decline of β-cell mass in Japanese type 2 diabetic patients. Diabetes Care 37:1966–1974CrossRefGoogle Scholar
  31. 31.
    Rivera JF, Costes S, Gurlo T, Glabe CG, Butler PC (2014) Autophagy defends pancreatic β-cells from human islet amyloid polypeptide-induced toxicity. J Clin Invest 124:3489–3500CrossRefGoogle Scholar
  32. 32.
    Barkley MS, Geschwind II, Bradford GE (1979) The gestational pattern of estradiol, testosterone and progesterone secretion in selected strains of mice. Biol Reprod 20:733–738CrossRefGoogle Scholar
  33. 33.
    Buchanan TA, Xiang AH, Peters RK et al (2002) Preservation of pancreatic β-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes 51:2796–2803CrossRefGoogle Scholar
  34. 34.
    Baeyens L, Hindi S, Sorenson RL, German MS (2016) β-Cell adaptation in pregnancy. Diabetes Obes Metab 18(Suppl 1):63–70. CrossRefPubMedPubMedCentralGoogle Scholar

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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