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

• Published in: Diabetes (New York, N.Y.) Vol. 57; no. 10; pp. 2737 - 2744
• Main Authors: Wong, Winifred P S, Scott, David W, Chuang, Chia-Lin, Zhang, Shaoping, Liu, Hong, Ferreira, Athena, Saafi, Etuate L, Choong, Yee Soon, Cooper, Garth J S
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.10.2008
• Subjects: Amyloid - genetics; Amyloid - metabolism; Amyloid - physiology; Animals; Apoptosis - physiology; Biological and medical sciences; Blood Glucose - metabolism; Cell death; Development and progression; Diabetes; Diabetes mellitus; Diabetes Mellitus - metabolism; Diabetes Mellitus - pathology; Diabetes Mellitus - physiopathology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme-Linked Immunosorbent Assay; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Glucagon - metabolism; Glucose; Glucose - metabolism; Glucose Tolerance Test; Glycoproteins; Humans; Immunohistochemistry; Insulin resistance; Insulin Resistance - physiology; Islet Amyloid Polypeptide; Islet Studies; Islets of Langerhans - metabolism; Islets of Langerhans - pathology; Islets of Langerhans - ultrastructure; Medical sciences; Mice; Mice, Inbred Strains; Mice, Transgenic; Microscopy, Electron, Transmission; Pancreas; Pathogenesis; Physiological aspects; Polypeptides; Research design; Somatostatin - metabolism; Transgenic animals; Endocrinopathy; Human; Diabetes mellitus; Rodentia; Amylin; Langerhans islet; Transgenic animal; Metabolic diseases; Target tissue resistance; Vertebrata; Mammalia; Mouse; Insulin resistance; Amyloid; Endocrine pancreas
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db06-1755

Spontaneous Diabetes in Hemizygous Human Amylin Transgenic Mice That Developed Neither Islet Amyloid nor Peripheral Insulin Resistance Winifred P.S. Wong 1 , David W. Scott 1 , Chia-Lin Chuang 1 , Shaoping Zhang 1 2 , Hong Liu 1 , Athena Ferreira 1 , Etuate L. Saafi 1 , Yee Soon Choong 1 and Garth J.S. Cooper 1 2 3 1 School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand 2 Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand 3 MRC Immunochemistry Unit, Department of Biochemistry, University of Oxford, Oxford, U.K 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, [ 25,28,29 Pro]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. [ 25,28,29 Pro]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. DIABETES