Islet amyloid formation associated with hyperglycemia in transgenic mice with pancreatic beta cell expression of human islet amyloid polypeptide.

TLDR

Pancreatic islet amyloid deposits are a hallmark of non‑insulin‑dependent diabetes mellitus and consist of islet amyloid polypeptide (IAPP). The study used transgenic mice expressing human IAPP in pancreatic β‑cells to investigate whether islet amyloid contributes to the pathogenesis of type 2 diabetes. In this model, ~80 % of older male transgenic mice developed human IAPP‑positive fibrillar amyloid between β‑cells and capillaries, whereas females rarely showed amyloid and non‑transgenic controls had none. Approximately half of the amyloid‑positive males were hyperglycemic, and all younger amyloid‑positive males exhibited severe hyperglycemia, demonstrating a strong association between amyloid formation and hyperglycemia.

Abstract

Pancreatic islet amyloid deposits are a characteristic pathologic feature of non-insulin-dependent diabetes mellitus and contain islet amyloid polypeptide (IAPP; amylin). We used transgenic mice that express human IAPP in pancreatic beta cells to explore the potential role of islet amyloid in the pathogenesis of non-insulin-dependent diabetes mellitus. Extensive amyloid deposits were observed in the pancreatic islets of approximately 80% of male transgenic mice > 13 months of age. Islet amyloid deposits were rarely observed in female transgenic mice (11%) and were never seen in nontransgenic animals. Ultrastructural analysis revealed that these deposits were composed of human IAPP-immunoreactive fibrils that accumulated between beta cells and islet capillaries. Strikingly, approximately half of the mice with islet amyloid deposits were hyperglycemic (plasma glucose > 11 mM). In younger (6- to 9-month-old) male transgenic mice, islet amyloid deposits were less commonly observed but were always associated with severe hyperglycemia (plasma glucose > 22 mM). These data indicate that expression of human IAPP in beta cells predisposes male mice to the development of islet amyloid and hyperglycemia. The frequent concordance of islet amyloid with hyperglycemia in these mice suggests an interdependence of these two conditions and supports the hypothesis that islet amyloid may play a role in the development of hyperglycemia.