Expression of wild-type and mutant S20G hIAPP in physiologic knock-in mouse models fails to induce islet amyloid formation, but induces mild glucose intolerance

Henry J. Hiddinga, Setsuya Sakagashira, Masayuki Ishigame, Pranathi Madde, Tokio Sanke, Kishio Nanjo, Yogish C. Kudva, James J. Lee, Jan van Deursen, Norman L. Eberhardt

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Aims/Introduction: Human islet polypeptide S20G mutation (hIAPP S20G) is associated with earlier onset type 2 diabetes and increased amyloidogenicity and cytotoxicity in vitro vs wild-type hIAPP (hIAPP WT), suggesting that amyloidogenesis may be pathogenic for type 2 diabetes. We compared the contributions of hIAPP S20G and hIAPP WT toward intra islet amyloid formation and development of type 2 diabetes in a unique physiologic knock-in mouse model. Materials and Methods: We replaced the mouse IAPP gene (M allele) with hIAPP WT (W allele) and hIAPP S20G (G allele) via homologous recombination and backbred transgenic mice against C57Bl/6 strain 5 generations to minimize genetic variation. Mice (3month old) were maintained on control (CD) or high fat diet (HFD) for 15months and studied at 3month intervals by oral glucose tolerance testing (OGTT) and pancreas histology to assess glucose homeostastis, amyloidogeneisis, islet mass, β cell replication, and apoptosis. Results: IAPP blood levels were indistinguishable in all mice. WW and GW mice maintained on both diets lacked intraislet amyloid at all ages. On both diets relative to MM controls WW and GW mice exhibit glucose intolerance (P<0.008) with no differences in insulin secretion. However, GW mice secreted significantly more insulin (P<0.03 that WW mice on both diets throughout the study. By 12months on the high fat diet all mice increased their β cell mass about 3-fold and were indistinguishable. Conclusions: Physiologic expression of hIAPP WT and hIAPP S20G in C57Bl/6 mice produces mild glucose intolerance with inappropriately normal insulin secretion that is independent of intraislet amyloid formation.

Original languageEnglish (US)
Pages (from-to)138-147
Number of pages10
JournalJournal of Diabetes Investigation
Volume3
Issue number2
DOIs
StatePublished - Apr 2012

Keywords

  • Islet amyloid polypeptide
  • Transgenic mice
  • Type 2 diabetes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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