Spontaneous diabetes mellitus in transgenic mice expressing human islet amyloid polypeptide.

TLDR

The islet in non‑insulin‑dependent diabetes mellitus is marked by beta‑cell loss and amyloid deposits of the 37‑amino‑acid protein islet amyloid polypeptide (IAPP). The study tests the hypothesis that intracellular IAPP amyloid formation under high expression levels causes beta‑cell destruction. A homozygous transgenic mouse model with high rates of human IAPP expression was created to evaluate this hypothesis. Overexpression of human IAPP in these mice induces beta‑cell death, impaired insulin secretion, and diabetes, with early small amorphous intra‑ and extracellular aggregates present at the time of cell loss, while large amyloid deposits appear later and are not central to cytotoxicity.

Abstract

The islet in non-insulin-dependent diabetes mellitus (NIDDM) is characterized by loss of beta cells and large local deposits of amyloid derived from the 37-amino acid protein, islet amyloid polypeptide (IAPP). We have hypothesized that IAPP amyloid forms intracellularly causing beta-cell destruction under conditions of high rates of expression. To test this we developed a homozygous transgenic mouse model with high rates of expression of human IAPP. Male transgenic mice spontaneously developed 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 of transgenic mice during the development of diabetes mellitus. However, IAPP derived amyloid deposits were found in only a minority of islets at approximately 20 weeks of age, notably after development of diabetes mellitus in male transgenic mice. Approximately 20% of female transgenic mice spontaneously developed diabetes mellitus at 30+ weeks of age, when beta-cell degeneration and both amorphous and amyloid deposits of IAPP were present. We conclude that overexpression of human IAPP causes beta-cell death, impaired insulin secretion, and diabetes mellitus. Large deposits of IAPP derived amyloid do not appear to be important in this cytotoxicity, but early, small amorphous intra- and extracellular aggregates of human IAPP were consistently present at the time of beta-cell death and therefore may be the most cytotoxic form of IAPP.