The pathogenic mechanism of diabetes varies with the degree of overexpression and oligomerization of human amylin in the pancreatic islet β cells

The aggregation of human amylin (hA) to form cytotoxic structures has been closely associated with the causation of type 2 diabetes. We sought to advance understanding of how altered expression and aggregation of hA might link β‐cell degeneration with diabetes onset and progression, by comparing phenotypes between homozygous and hemizygous hA‐transgenic mice. The homozygous mice displayed elevated islet hA that correlated positively with measures of oligomer formation ( r =0.91; P <0.0001). They also developed hyperinsulinemia with transient insulin resistance during the prediabetes stage and then underwent rapid β‐cell loss, culminating in severe juvenile‐onset diabetes. The prediabetes stage was prolonged in the hemizygous mice, wherein β‐cell dysfunction and extensive oligomer formation occurred in adulthood at a much later stage, when hA levels were lower ( r = –0.60; P <0.0001). This is the first report to show that hA‐evoked diabetes is associated with age, insulin resistance, progressive islet dysfunction, and β‐cell apoptosis, which interact variably to cause the different diabetes syndromes. The various levels of hA elevation cause different extents of oligomer formation in the disease stages, thus eliciting early‐ or adult‐onset diabetes syndromes, reminiscent of type 1 and 2 diabetes, respectively. Thus, the hA‐evoked diabetes phenotypes differ substantively according to degree of amylin overproduction. These findings are relevant to the understanding of the pathogenesis and the development of experimental therapeutics for diabetes.—Zhang, S., Liu, H., Chuang, C. L., Li, X., Au, M., Zhang, L., Phillips, A. R. J., Scott, D. W., Cooper, G.J. S. The pathogenic mechanism of diabetes varies with the degree of overexpression and oligomerization of human amylin in the pancreatic islet β cells. FASEB J. 28, 5083–5096 (2014). www.fasebj.org