Islet amyloid formation associated with hyperglycemia in transgenic mice with pancreatic beta cell expression of human islet amyloid polypeptide.

Abstract

Pancreatic islet amyloid deposits are a characteristic pathologic feature of non-insulin-dependent diabetes mellitus and contain islet amyloid polypeptide (IAPP; amylin). We Amyloid deposits are found in the pancreatic islets of most individuals with non-insulin-dependent diabetes mellitus (NIDDM) (1-3). The major component of islet amyloid is a 37-amino acid peptide, islet amyloid polypeptide (IAPP; amylin) (4-6), which is a normal secretory product of the pancreatic f3 cell (7,8). Formation of islet amyloid deposits from IAPP may contribute to the progressive deterioration of ,3-cell function observed in this disease (9), since IAPP-derived amyloid has been shown to be toxic to islet cells in vitro (10) and the degree of amyloid deposition is associated with the severity of hyperglycemia in monkeys (11). The mechanism leading to IAPP deposition as islet amyloid is unknown. The sequence of human IAPP (hIAPP) contains an amyloidogenic region (amino acids 20-29) that is thought to be essential for fibril formation (12, 13); however, this sequence does not appear to be the sole prerequisite since nondiabetic individuals do not usually develop islet amyloid (1-3). Thus, some additional unrecognized factor(s) must be present in NIDDM that potentiates islet amyloid formation.IAPP-derived islet amyloid has never been observed in rodents, presumably because rodent IAPP, unlike hIAPP, does not contain the necessary amyloidogenic sequence (13).The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

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.…”

“…No correlation has been observed between an increase in circulating IAPP concentrations and either glucose intolerance or T2DM in man other than that which would be expected as a result of increased insulin resistance [10,16,84]. In addition, insulin and IAPP are co-ordinately regulated in terms of gene expression [85] and circulating concentrations in glucose intolerance and diabetes in man [16,84,86,87]; disassociation of the two beta-cell products does how-ever occur during treatment with steroids [97,98,99] when expression of insulin is reduced and IAPP enhanced.…”

“…No such clear sex differences in diabetes susceptibility are seen in humans or in cats and monkeys. The fact that increased dietary fat promotes islet amyloidosis in islets of transgenic mice in vivo [97] suggests that the role of lipids in the genesis of amyloid fibrils is important in addition to the increased insulin resistance and beta-cell secretion observed in obesity. In vitro, fatty acids promote IAPP fibrillogenesis of synthetic hIAPP and biosynthetic IAPP in hIAPP mouse islets [100,101] and the degree of amyloidosis in hIAPP TM in vivo was shown to be proportional to the percentage of fat in the diet [102].…”

DPP-4 inhibition improves glucose tolerance and increases insulin and GLP-1 responses to gastric glucose in association with normalized islet topography in mice with β-cell-specific overexpression of human islet amyloid polypeptide

“…Hemizygous transgenic mice with islet β-cell expression of hIAPP on a C57BL/6J/6xDBA/2 background were generated as previously described (21). Transgenic status was determined by PCR using oligonucleotide primers directed against the hIAPP transgene (22).…”

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

“…***p < 0.001 compared with untreated controls. 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.…”