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- Title
The pathogenic mechanism of diabetes varies with the degree of overexpression and oligomerization of human amylin in the pancreatic islet β cells.
- Authors
Shaoping Zhang; Hong Liu; Chia Lin Chuang; Xiaoling Li; Au, Maggie; Lin Zhang; Phillips, Anthony R. J.; Scott, David W.; Cooper, Garth J. S.
- Abstract
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 pheno-types 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.
- Subjects
DIABETES; AMYLIN; TYPE 2 diabetes; DISEASE progression; OLIGOMERS
- Publication
FASEB Journal, 2014, Vol 28, Issue 12, p5083
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.14-251744