CHRONIC OVERPRODUCTION OF ISLET AMYLOID POLYPEPTIDE AMYLIN IN TRANSGENIC MICE - IYSOSOMAL LOCALIZATION OF HUMAN ISLET AMYLOID POLYPEPTIDE AND LACK OF MARKED HYPERGLYCEMIA OR HYPERINSULINEMIA

Type 2 (non-insulin-dependent) diabetes mellitus is characterised by h yperglycaemia, peripheral insulin resistance, impaired insulin secreti on and pancreatic islet amyloid formation. The major constituent of is let amyloid is islet amyloid polypeptide (amylin). Islet amyloid polyp eptide is synthesized by islet beta cells and co-secreted with insulin . The ability of islet amyloid polypeptide to form amyloid fibrils is related to its species-specific amino acid sequence. Islet amyloid ass ociated with diabetes is only found in man, monkeys, cats and racoons. Pharmacological doses of islet amyloid polypeptide have been shown to inhibit insulin secretion as well as insulin action on peripheral tis sues (insulin resistance). To examine the role of islet amyloid polype ptide in the pathogenesis of Type 2 diabetes, we have generated transg enic mice with the gene encoding either human islet amyloid polypeptid e (which can form amyloid) or rat islet amyloid polypeptide, under con trol of an insulin promoter. Transgenic islet amyloid polypeptide mRNA was detected in the pancreas in all transgenic mice. Plasma islet amy loid polypeptide levels were significantly elevated (up to 15-fold) in three out of five transgenic lines, but elevated glucose levels, hype rinsulinaemia and obesity were not observed. This suggests that insuli n resistance is not induced by chronic hypersecretion of islet amyloid polypeptide. Islet amyloid polypeptide immunoreactivity was localized to beta-cell secretory granules in all mice. Islet amyloid polypeptid e immunoreactivity in beta-cell lysosomes was seen only in mice with t he human islet amyloid polypeptide gene, as in human beta cells, and m ight represent an initial step in intracellular formation of amyloid f ibrils. These transgenic mice provide a unique model with which to exa mine the physiological function of islet amyloid polypeptide and to st udy intracellular and extracellular handling of human islet amyloid po lypeptide in pancreatic islets.