TITLE

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

AUTHOR(S)
Aitken, Jacqueline F.; Loomes, Kerry M.; Scott, David W.; Reddy, Shivanand; Phillips, Anthony R. J.; Prijic, Gordana; Fernando, Chathurini; Zhang, Shaoping; Broadhurst, Ric; L'Huillier, Phil; Cooper, Garth J. S.
PUB. DATE
January 2010
SOURCE
Diabetes;Jan2010, Vol. 59 Issue 1, p161
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
OBJECTIVE--Aggregation of human amylin/islet amyloid polypeptide (hA/hIAPP) into small soluble β-sheet-containing oligomers is linked to islet p-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 p-cell dysfunction followed by progressive p-ceil loss. Islet amyloid was absent from hemizygous animals with earlyonset 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 mneliorate their diabetic phenotype. Fibrillar mnyloid was neither necessary nor sufficient to cause diabetes and indeed was positively correlated with longevity therein, whereas early-to nfid-stage diabetes was associated with islet β-cells dysfunction followed by β-cells 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. Diabetes 59:161-171, 2010
ACCESSION #
47995262

 

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