Tetracycline treatment retards the onset and slows the progression of diabetes in human amylin/hIAPP transgenic mice

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 employed 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 characterised 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 non-diabetic hemizygous animals also had large islet-amyloid areas showing that amyloid itself was not intrinsically cytotoxic. Administration of tetracycline dosage-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 β-cell dysfunction followed by β-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.