Tetracycline Treatment Retards the Onset and Slows the Progression of Diabetes in Human Amylin/Islet Amyloid Polypeptide Transgenic Mice

Tetracycline Treatment Retards the Onset and Slows the Progression of Diabetes in Human Amylin/Islet Amyloid Polypeptide Transgenic Mice Jacqueline F. Aitken 1 , 2 , Kerry M. Loomes 1 , 2 , David W. Scott 1 , 3 , Shivanand Reddy 1 , Anthony R.J. Phillips 1 , 2 , 4 , Gordana Prijic 1 , Chathurini Fernando 1 , Shaoping Zhang 1 , 2 , Ric Broadhurst 5 , Phil L'Huillier 5 and Garth J.S. Cooper 1 , 2 , 3 , 6 1 School of Biological Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand; 2 Maurice Wilkins Centre for Molecular Biodiscovery, Faculty of Science, University of Auckland, Auckland, New Zealand; 3 Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand; 4 Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand; 5 AgResearch, Ruakura, Hamilton, New Zealand; 6 Department of Pharmacology, Medical Sciences Division, University of Oxford, Oxford, U.K. Corresponding author: Garth J.S. Cooper, g.cooper{at}auckland.ac.nz . J.F.A., K.M.L., and D.W.S. contributed equally to this article. Abstract OBJECTIVE Aggregation of human amylin/islet amyloid polypeptide (hA/hIAPP) into small soluble β-sheet–containing oligomers is linked to islet β-cell degeneration and the pathogenesis of type 2 diabetes. Here, we used tetracycline, which modifies hA/hIAPP oligomerization, to probe mechanisms whereby hA/hIAPP causes diabetes in hemizygous hA/hIAPP-transgenic mice. RESEARCH DESIGN AND METHODS We chronically treated hemizygous hA/hIAPP transgenic mice with oral tetracycline to determine its effects on rates of diabetes initiation, progression, and survival. RESULTS Homozygous mice developed severe spontaneous diabetes due to islet β-cell loss. Hemizygous transgenic animals also developed spontaneous diabetes, although severity was less and progression rates slower. Pathogenesis was characterized by initial islet β-cell dysfunction followed by progressive β-cell loss. Islet amyloid was absent from hemizygous animals with early-onset diabetes and correlated positively with longevity. Some long-lived nondiabetic hemizygous animals also had large islet-amyloid areas, showing that amyloid itself was not intrinsically cytotoxic. Administration of tetracycline dose-dependently ameliorated hyperglycemia and polydipsia, delayed rates of diabetes initiation and progression, and increased longevity compared with water-treated controls. CONCL