Spontaneous Diabetes in Hemizygous Human Amylin Transgenic Mice That Developed Neither Islet Amyloid nor Peripheral Insulin Resistance

  1. Winifred P.S. Wong1,
  2. David W. Scott1,
  3. Chia-Lin Chuang1,
  4. Shaoping Zhang12,
  5. Hong Liu1,
  6. Athena Ferreira1,
  7. Etuate L. Saafi1,
  8. Yee Soon Choong1 and
  9. Garth J.S. Cooper123
  1. 1School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand
  2. 2Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
  3. 3MRC Immunochemistry Unit, Department of Biochemistry, University of Oxford, Oxford, U.K
  1. Corresponding author: Prof. Garth J.S. Cooper, g.cooper{at}auckland.ac.nz

Abstract

OBJECTIVES—We sought to 1) Determine whether soluble-misfolded amylin or insoluble-fibrillar amylin may cause or result from diabetes in human amylin transgenic mice and 2) determine the role, if any, that insulin resistance might play in these processes.

RESEARCH DESIGN AND METHODS—We characterized the phenotypes of independent transgenic mouse lines that display pancreas-specific expression of human amylin or a nonaggregating homolog, [25,28,29Pro]human amylin, in an FVB/n background.

RESULTS—Diabetes occurred in hemizygous human amylin transgenic mice from 6 weeks after birth. Glucose tolerance was impaired during the mid- and end-diabetic phases, in which progressive β-cell loss paralleled decreasing pancreatic and plasma insulin and amylin. Peripheral insulin resistance was absent because glucose uptake rates were equivalent in isolated soleus muscles from transgenic and control animals. Even in advanced diabetes, islets lacked amyloid deposits. In islets from nontransgenic mice, glucagon and somatostatin cells were present mainly at the periphery and insulin cells were mainly in the core; in contrast, all three cell types were distributed throughout the islet in transgenic animals. [25,28,29Pro]human amylin transgenic mice developed neither β-cell degeneration nor glucose intolerance.

CONCLUSIONS—Overexpression of fibrillogenic human amylin in these human amylin transgenic mice caused β-cell degeneration and diabetes through mechanisms independent from both peripheral insulin resistance and islet amyloid. These findings are consistent with β-cell death evoked by misfolded but soluble cytotoxic species, such as those formed by human amylin in vitro.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 15 July 2008.

    Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted June 30, 2008.
    • Received December 29, 2006.
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  1. Diabetes vol. 57 no. 10 2737-2744
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