FORMATION OF ISLET AMYLOID FIBRILS IN BETA-SECRETORY GRANULES OF TRANSGENIC MICE EXPRESSING HUMAN ISLET AMYLOID POLYPEPTIDE AMYLIN

To investigate the relationship between human islet amyloid polypeptid e (IAPP)/amylin expression and islet amyloid deposits in the pathogene sis of human non-insulin-dependent diabetes mellitus (NIDDM), we devel oped transgenic mice using a human IAPP cDNA connected to an insulin p romoter. Ribonucleic acid blotting and immunohistochemistry revealed t he expression of the transgene in the pancreatic beta cells. Immunogol d electron microscopy showed that beta-secretory granules contained th e human C-terminal nanking peptide of the IAPP precursor. Reverse-phas e HPLC demonstrated human and mouse IAPP amide in the pancreas. Electr on microscopy showed the accumulation of fibril-like material in a con siderable number of beta-secretory granules. These results suggest tha t in transgenic mice, the human IAPP precursor is expressed in beta ce lls and becomes normally sorted into beta-secretory granules in which normal conversion to mature human IAPP takes place. The human IAPP mol ecules, because of their amyloidogenesis, aggregate into amyloid fibri ls in secretory granules. Glucose tolerance was normal at 7 months old and islet amyloid was not observed. A longer time may be required for islet amyloid deposits and hyperglycemia to develop in mice. Our work ing hypothesis is that in human NIDDM, IAPP aggregates into amyloid fi brils in beta-secretory granules, and that the fibrils are released in to the extracellular space and islet amyloid deposits become substanti al with time.