Spontaneous Diabetes in Hemizygous Human Amylin Transgenic Mice that developed neither Islet Amyloid nor Peripheral Insulin Resistance

Abstract

Objectives: (1) Determine whether soluble-misfolded amylin or insoluble-fibrillar amylin may cause, or instead result from diabetes, in human amylin transgenic mice, and (2) the role, if any, that insulin resistance might play in these processes.

Methods: We characterised the phenotypes of independent transgenic mouse lines that display pancreas-specific expression of human amylin or a non-aggregating homolog, [^25,28,29Pro]human amylin, in an FVB/n background.

Results: Diabetes occurred in hemizygous human amylin transgenic mice from 6 weeks after birth. Glucose tolerance was impaired during the mid- and end-diabetic phases, in which progressive β-cell loss paralleled decreasing pancreatic and plasma insulin and amylin. Peripheral insulin resistance was absent, since glucose uptake rates were equivalent in isolated soleus muscles from transgenic and control animals. Even in advanced diabetes, islets lacked amyloid deposits. In islets from non-transgenic mice, glucagon- and somatostatin-cells were present mainly at the periphery and insulin-cells were mainly in the core, whereas by contrast all three cell types were distributed throughout the islet in transgenic animals. [^25,28,29Pro]human amylin transgenic mice developed neither β-cell degeneration nor glucose intolerance.

Conclusions: Over-expression of fibrillogenic human amylin in these human amylin transgenic mice caused β-cell degeneration and diabetes, through mechanisms independent from both peripheral insulin resistance and islet amyloid. These findings are consistent with β-cell death evoked by misfolded but soluble cytotoxic species, such as those formed by human amylin in vitro.