SPONTANEOUS DIABETES-MELLITUS IN TRANSGENIC MICE EXPRESSING HUMAN ISLET AMYLOID POLYPEPTIDE

The islet in non-insulin-dependent diabetes mellitus (NIDDM) is charac terized by loss of beta cells and large local deposits of amyloid deri ved from the 37-amino acid protein, islet amyloid polypeptide (IAPP). We have hypothesized that IAPP amyloid forms intracellularly causing b eta-cell destruction under conditions of high rates of expression, To test this we developed a homozygous transgenic mouse model with high r ates of expression of human IAPP. Male transgenic mice spontaneously d eveloped diabetes mellitus by 8 weeks of age,which was associated with selective beta-cell death and impaired insulin secretion. Small intra - and extracellular amorphous IAPP aggregates were present in islets o f transgenic mice during the development of diabetes mellitus, However , IAPP derived amyloid deposits were found in only a minority of islet s at approximate to 20 weeks of age, notably after development of diab etes mellitus in male transgenic mice, Approximately 20% of female tra nsgenic mice spontaneously developed diabetes mellitus at 30+ weeks of age, when beta-cell degeneration and both amorphous and amyloid depos its of IAPP were present, We conclude that overexpression of human IAP P causes beta-cell death, impaired insulin secretion, and diabetes mel litus. Large deposits of IAPP derived amyloid do not appear to be impo rtant in this cytotoxicity, but early, small amorphous intra- and extr acellular aggregates of human IAPP were consistently present at the ti me of beta-cell death and therefore may be the most cytotoxic form of IAPP.