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

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 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.

Rutin suppresses human-amylin/hIAPP misfolding and oligomer formation in-vitro , and ameliorates diabetes and its impacts in human-amylin/hIAPP transgenic mice

“…These findings indicate that the pharmacophore responsible for these effects resides solely in the quercetin structure. These data are consistent with a rutin interaction with soluble hA oligomers that prevents or restricts their conversion into cytotoxic structures and thus shields islet β-cells from Fas-evoked destruction [8][9][10].…”

“…It is a small protein that can spontaneously misfold and aggregate to form structures that elicit death by apoptosis in islet β-cells, as well as β-cell/islet degeneration and failure of insulin secretion in animal models [7,8]. Amylin-mediated cytotoxicity is identified as a potential target for developing new anti-diabetic molecules that act by suppressing β-cell death.…”

“…For ligand-binding experiments, rutin or raffinose were dissolved in water and added to amylin solutions at 1:1 ratios prior to mass spectral analysis, with no prior incubation period. The construction, characterisation, husbandry and measurement of glucose concentrations in tail-vein blood of hA-transgenic mice in such studies were performed as previously described [8,9,12].…”

Chemical and Biological Aspects of Extracts from Medicinal Plants with Antidiabetic Effects

“…The exocrine section releases digestive enzymes, aiding in the digestion of food [2]. The endocrine pancreas is dispersed in the exocrine parenchyma with clusters of cells, the islets of Langerhans, which include four major cell types: α-, β-, δ-, and PP-cells (pancreatic polypeptide).…”

Membrane Curvature-sensing and Curvature-inducing Activity of Islet Amyloid Polypeptide and Its Implications for Membrane Disruption

“…However, rat IAPP (rIAPP), which does not readily form fibrils (19), has also been seen to cause membrane leakage in vitro (16) and confer some (albeit strongly reduced) cytotoxicity in vivo (12). Also, the nonamyloidogenic hIAPP (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) fragment as well as a number of nonamyloidogenic full-length variants of IAPP have been observed to cause leakage of synthetic membranes (13,15,20), and hIAPP (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) and rIAPP (1)(2)(3)(4)(5)…”