INTRACELLULAR AND EXTRACELLULAR AMYLOID FIBRILS ARE FORMED IN CULTURED PANCREATIC-ISLETS OF TRANSGENIC MICE EXPRESSING HUMAN ISLET AMYLOID POLYPEPTIDE

Islet amyloid polypeptide (IAPP) is the constituent peptide of amyloid deposits found in the islets of non-insulin-dependent diabetic patien ts. Formation of islet amyloid is associated with a progressive destru ction of insulin-producing beta cells. Factors responsible for the con version of IAPP into insoluble amyloid fibrils are unknown. Both the a mino acid sequence of human IAPP (hIAPP) and hypersecretion of hIAPP h ave been implicated as factors for amyloid fibril formation in man. We have generated transgenic mice using rat insulin promoter-hIAPP or ra t IAPP (rIAPP) gene constructs. No fibrillar islet amyloid was detecta ble in vivo in these normoglycemic mice, although small amorphous peri vascular accumulations of IAPP were observed in hIAPP mice only. To de termine the effects of glucose on IAPP secretion and fibrillogenesis, pancreatic islets from transgenic and control mice were examined in vi tro. Islet IAPP secretion and content were increased in transgenic isl ets compared with control islets. IAPP-immunoreactive fibrils were for med at both intra- and extracellular sites in isolated hIAPP islets cu ltured with glucose at 11.1 and 28 mM for only 7 days. At 28 mM glucos e, fibrils were present in deep invaginations of beta cells as observe d in non-insulin-dependent diabetic patients. No fibrils were present at low glucose concentrations in hIAPP islets or at any glucose concen tration in rIAPP or control islets. Thus, glucose-induced expression a nd secretion of hlAPP in transgenic mouse islets can lead to formation of amyloid fibrils similar to that found in non-insulin-dependent dia betes mellitus.