Extensive islet amyloid formation is induced by development of type II diabetes mellitus and contributes to its progression: pathogenesis of diabetesin a mouse model

Aims/hypothesis. Type II (non-insulin-dependent) diabetes mellitus is a mul tifactorial disease in which pancreatic islet amyloid is a characteristic h istopathological finding. Islet amyloid fibrils consist of the beta-eel pro tein "islet amyloid polypeptide" (IAPP)/"amylin". Unlike human IAPP (hIAPP) , mouse IAPP cannot form amyloid. In previously generated transgenic mice, high expression of hIAPP as such did not induce islet amyloid formation. To further explore the potential diabetogenic role of amyloidogenic IAPP, we introduced a diabetogenic trait ("ob" mutation) in hIAPP transgenic mice. Methods. Plasma concentrations of IAPP, insulin and glucose were determined at 3.5 (t1), 6 (t2), and 16-19 months of age (t3). At t3, the mice were ki lled and the pancreas was analysed (immuno)histochemically. Results. In non-transgenic ob/ob mice, insulin resistance caused a compensa tory increase in insulin production, normalizing the initial hyperglycaemia . In transgenic ob/ob mice, concurrent increase in hIAPP production resulte d in extensive islet amyloid formation (more often and more extensive than in transgenic non-ob/ob mice), insulin insufficiency and persistent hypergl ycaemia: At t3, plasma insulin levels in transgenic ob/ob mice with amyloid were fourfold lower than in non-transgenic ob/ob mice (p < 0.05), and plas ma glucose concentrations in transgenic obi sb mice were almost twofold hig her (p < 0.05). In addition, the degree of islet amyloid formation in ob/ob mice was positively correlated to the glucose:insulin ratio (r(s) = 0.53, p < 0.05). Conclusion/interpretation. Islet amyloid is a secondary diabetogenic factor which can be both a consequence of insulin resistance and a cause of insul in insufficiency.