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

Abstract

OBJECTIVEAggregation 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 METHODSWe chronically treated hemizygous hA/hIAPP transgenic mice with oral tetracycline to determine its effects on rates of diabetes initiation, progression, and survival.RESULTSHomozygous 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.CONCLUSIONSThis 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.

Is type 2 diabetes an amyloidosis and does it really matter (to patients)?

“…Human amylin's physiological conformation is one of random coil, but it undergoes rapid conformational change into β-conformers when placed in physiological solutions [35]. Based on the available evidence, many workers have concluded that small oligomers formed by aggregated human amylin [36,37] are probably the species that could ultimately cause diabetes [38,39]. Others, among them Zraika and colleagues, believe that the cytotoxicity of larger amyloid fibrils must be considered [11,15], as indeed it must.…”

“…Zraika et al have argued that mature amyloid fibrils, rather than small, soluble cytotoxic oligomers [37][38][39]43], could play the main role in beta cell degeneration and diabetes causation. As noted, they have pointed to the numerous weaknesses and shortcomings of the currently available evidence, and in so doing have indicated further lines of investigation that might improve our understanding.…”

“…There is emerging evidence, discussed below, that targeting amylin misfolding to suppress diabetes might well be an attainable goal in the not-too-distant future [39].…”

“…Many such lines, for example those in which the transgene was inserted into a C57BL background, do not develop spontaneous diabetes [51][52][53]. However, other lines, whose genetic background is FVB/N, develop spontaneous diabetes and islet amyloid [39,54,55], presenting an opportunity to probe the relationship between these two phenomena and to measure the impact of experimental therapies on both.…”

“…We have now developed lines of human amylin transgenic mice in which hemizygous animals develop spontaneous diabetes with high penetrance (∼95%) [39]. Diabetes in these mice is caused by initial islet beta cell dysfunction followed later by progressive beta cell loss and progressively worsening hyperglycaemia.…”