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
HJ Hiddinga, S Sakagashira… - Journal of diabetes …, 2012 - Wiley Online Library
HJ Hiddinga, S Sakagashira, M Ishigame, P Madde, T Sanke, K Nanjo, YC Kudva, JJ Lee…
Journal of diabetes investigation, 2012•Wiley Online LibraryAbstract Aims/Introduction: Human islet polypeptide S20G mutation (hIAPPS20G) is
associated with earlier onset type 2 diabetes and increased amyloidogenicity and
cytotoxicity in vitro vs wild‐type hIAPP (hIAPPWT), suggesting that amyloidogenesis may be
pathogenic for type 2 diabetes. We compared the contributions of hIAPPS20G and hIAPPWT
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 …
associated with earlier onset type 2 diabetes and increased amyloidogenicity and
cytotoxicity in vitro vs wild‐type hIAPP (hIAPPWT), suggesting that amyloidogenesis may be
pathogenic for type 2 diabetes. We compared the contributions of hIAPPS20G and hIAPPWT
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 …
Abstract
Aims/Introduction: Human islet polypeptide S20G mutation (hIAPPS20G) is associated with earlier onset type 2 diabetes and increased amyloidogenicity and cytotoxicity in vitro vs wild‐type hIAPP (hIAPPWT), suggesting that amyloidogenesis may be pathogenic for type 2 diabetes. We compared the contributions of hIAPPS20G and hIAPPWT 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 hIAPPWT (W allele) and hIAPPS20G (G allele) via homologous recombination and backbred transgenic mice against C57Bl/6 strain 5 generations to minimize genetic variation. Mice (3 month old) were maintained on control (CD) or high fat diet (HFD) for 15 months and studied at 3 month 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 12 months on the high fat diet all mice increased their β cell mass about 3‐fold and were indistinguishable.
Conclusions: Physiologic expression of hIAPPWT and hIAPPS20G in C57Bl/6 mice produces mild glucose intolerance with inappropriately normal insulin secretion that is independent of intraislet amyloid formation. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00166.x, 2011)
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