Islet amyloid-associated diabetes in obese A(vy)/a mice expressing human islet amyloid polypeptide.

Abstract

We have previously shown that hemizygous transgenic mice expressing human islet amyloid polypeptide (hIAPP) in pancreatic beta-cells have no diabetic phenotype, whereas in the homozygous state, they developed severe, early-onset hyperglycemia associated with impaired insulin secretion and beta-cell death. We investigated the possibility that when the hemizygous mice are crossed onto an obese, insulin-resistant strain such as agouti viable yellow (A(vy)/a), they would exhibit a phenotype more akin to human type 2 diabetes. The hIAPP-expressing A(vy) males (TG-Y) displayed fasting hyperglycemia at 90 days of age and by 1 year progressed to severe hyperglycemia relative to their nontransgenic counterparts. Plasma insulin concentrations and pancreatic insulin content dropped 10- to 20-fold, suggesting severe impairment of beta-cell function. Histopathological findings revealed beta-cell degeneration and loss consistent with the drop in the plasma insulin concentration. In addition, large deposits of IAPP amyloid were present in TG-Y islets. We conclude that in transgenic mice expressing hIAPP, insulin resistance can induce overt, slow-onset diabetes associated with islet amyloid and decreased beta-cell mass.

Islet amyloid: a complication of islet dysfunction or an aetiological factor in Type 2 diabetes?

“…Amyloid deposition in obese or fat-fed hIAPP TM is more frequent in males [96,97], is reversed by oestrogen treatment in obese male animals [98] and is increased in hIAPP females by oophorectomy despite no change in circulating concentrations of IAPP [99]. No such clear sex differences in diabetes susceptibility are seen in humans or in cats and monkeys.…”

“…Transgenic mice overexpressing the gene for human IAPP (hIAPP TM) have increased circulating IAPP which can be up to 30 times higher than the endogenous mouse IAPP [49, 91,92,93,94]; these are not necessarily associated with amyloidosis suggesting that increased concentration is not adequate alone to induce changes in peptide conformation [95,96]. Amyloid deposition in obese or fat-fed hIAPP TM is more frequent in males [96,97], is reversed by oestrogen treatment in obese male animals [98] and is increased in hIAPP females by oophorectomy despite no change in circulating concentrations of IAPP [99].…”

Amyloid fibril formation is progressive and correlates with beta-cell secretion in transgenic mouse isolated islets

“…of transgenic mice expressing the gene for human islet amyloid polypeptide (hIAPP) is associated with a substantial decrease in the mass of islet beta-cells and an increased frequency of hyperglycaemia [6,7,8,9]. This could be explained by the proposed cytotoxic role of amyloid: fibrils formed from human synthetic islet amyloid polypeptide (IAPP) have been shown to be cytotoxic to pancreatic islet cells in vitro [10].…”

Islet amyloid polypeptide in the islets of Langerhans: friend or foe?

“…Data from [62,67,68,83] cells develops hyperglycaemia and islet amyloid when given a high-fat diet [77]. Although islet amyloid formation in other similar transgenic mouse strains seems to depend on additional factors (e. g. genetic background [78,79], dose of the transgene [80], or induction of insulin resistance by treatment with steroids and growth hormone [81]), this raises the possibility that lipid perturbations are involved in the dissociation of IAPP and insulin expression. A 4.5-fold increase in the ratio of circulating fasting plasma IAPP to insulin occurs in NMRI mice fed a high-fat diet for 6 months [82].…”