HUMAN ISLET AMYLOID POLYPEPTIDE ACCUMULATES AT SIMILAR SITES IN ISLETS OF TRANSGENIC MICE AND HUMANS

The cellular mechanisms responsible for conversion of islet amyloid po lypeptide (IAPP) into insoluble amyloid deposits in non-insulin-depend ent diabetes mellitus (NIDDM) are not clear. Overexpression of IAPP an d the amino acid sequence of human IAPP (hIAPP) have both been implica ted. To examine factors involved in amyloid formation, transgenic mice expressing the hIAPP or rat IAPP (rIAPP) gene were generated. These m ice had elevated plasma IAPP concentrations, and they were normoglycem ic and normoinsulinemic. No amyloid deposits were detected by light mi croscopy. To examine the ultrastructure of islets, pancreatic tissue w as studied from hIAPP and rIAPP transgenic mice and from age-matched c ontrol mice by immunoelectron microscopy. IAPP was immunolocalized in beta-cell secretory granules of all mice, and the COOH- and NH2-termin al flanking peptides of hIAPP were localized in beta-cell granules of hIAPP mice. Accumulations of nonfibrillar perivascular IAPP-immunoreac tive material were found between capillaries and beta-cells in hIAPP t ransgenic mice but not in rIAPP transgenic or control mice. Similar no nfibrillar masses were identified in islets of an NIDDM patient. Secon dary lysosomes in beta-cells and macrophages of hIAPP transgenic mice showed dense labeling for IAPP. We suggest that hIAPP is degraded more slowly than rIAPP or mouse IAPP by beta-cell lysosomes. Accumulations of IAPP perivascular spaces may represent the early stages of islet a myloid formation.