Aitken, JacquelineLoomes, KerryScott, DWReddy, ShivanandPhillips, AnthonyVirijevic, GFernando, CZhang, ShaopingBroadhurst, RL'Huillier, PJCooper, Garth2012-02-232009DIABETES 59(1):161-171 Jan 20100012-1797http://hdl.handle.net/2292/11663OBJECTIVE--Aggregation of human amylin/islet amyloid polypeptide (hA/hIAPP) into small soluble [beta]-sheet-containing oligomers is linked to islet [beta]-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 [beta]-cell loss. Hemizygous transgenic animals also developed spontaneous diabetes, although severity was less and progression rates slower. Pathogenesis was characterized by initial islet [beta]-cell dysfunction followed by progressive [beta]-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 isletamyloid 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. CONCLUSIONS--This is the first report to show that treating hA/hIAPP transgenic mice with a modifier of hA/hIAPP misfolding can ameliorate their diabetic phenotype. Fibrillar amyloid was neither necessary nor sufficient to cause diabetes and indeed was positively correlated with longevity therein, whereas early-to mid-stage diabetes was associated with islet [beta]-cell dysfunction followed by [beta]-cell loss. Interventions capable of suppressing misfolding in soluble hA/hIAPP oligomers rather than mature fibrils may have potential for treating or preventing type 2 diabetes.Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. Details obtained from http://www.sherpa.ac.uk/romeo/issn/0012-1797/https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htmhttps://creativecommons.org/licenses/by-nc-nd/3.0/Journal Article10.2337/db09-0548Copyright: American Diabetes Association19794060http://purl.org/eprint/accessRights/OpenAccess1939-327X