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

Abstract

The role of islet amyloidosis in the onset and progression of Type 2 diabetes remains obscure. Islet amyloid polypeptide is a 37 amino-acid, beta-cell peptide which is co-stored and co-released with insulin. Human islet amyloid polypeptide refolds to a β-conformation and oligomerises to form insoluble fibrils; proline substitutions in rodent islet amyloid polypeptide prevent this molecular transition. Pro-islet amyloid polypeptide (67 amino acids in man) is processed in secretory granules. Refolding of islet amyloid polypeptide may be prevented by intragranular heterodimer formation with insulin (but not proinsulin). Diabetes-associated abnormal proinsulin processing could contribute to de-stabilisation of granular islet amyloid polypeptide. Increased pro-islet amyloid polypeptide secretion as a consequence of islet dysfunction could promote fibrillogenesis; the propeptide forms fibrils and binds to basement membrane glycosamino-glycans. Islet amyloid polypeptide gene polymorphisms are not universally associated with Type 2 diabetes. Transgenic mice expressing human islet amyloid polypeptide gene have increased islet amyloid polypeptide concentrations but develop islet amyloid only against a background of obesity and/or high fat diet. In transgenic mice, obese monkeys and cats, initially small perivascular deposits progressively increase to occupy 80% islet mass; the severity of amyloidosis in animal models is related to the onset of hyperglycaemia, suggesting that islet amyloid and the associated destruction of islet cells cause diabetes. In human diabetes, islet amyloid can affect less than 1% or up to 80% of islets indicating that islet amyloidosis largely results from diabetes-related pathologies and is not an aetiological factor for hyperglycaemia. However, the associated progressive betacell destruction leads to severe islet dysfunction and insulin requirement. [Diabetologia (2004) 47:157-169]

Differences between amyloid toxicity in alpha and beta cells in human and mouse islets and the role of caspase-3

“…Growing evidence suggests that hIAPP aggregates are toxic to beta cells and contribute to loss of beta cell mass in type 2 diabetes [3][4][5]. Furthermore, we have previously shown that amyloid formation in human [8] and hIAPP-expressing mouse islets [16] during culture is associated with beta cell death and that prevention of amyloid formation enhances survival and function of cultured islets [8,16].…”

“…Type 2 diabetes is characterised by progressive beta cell dysfunction, decreased beta cell mass, and islet amyloid deposition [1][2][3][4][5]. Islet amyloid formation caused by aggregation of human islet amyloid polypeptide (hIAPP, amylin) [6,7] is associated with beta cell apoptosis and contributes to progressive beta cell death in type 2 diabetes [3][4][5].…”

“…Islet amyloid formation caused by aggregation of human islet amyloid polypeptide (hIAPP, amylin) [6,7] is associated with beta cell apoptosis and contributes to progressive beta cell death in type 2 diabetes [3][4][5]. Interestingly, islet amyloid also forms in human islets during culture [8] and following transplantation into mouse models of type 1 diabetes [9].…”

Small Interfering RNA–Mediated Suppression of Proislet Amyloid Polypeptide Expression Inhibits Islet Amyloid Formation and Enhances Survival of Human Islets in Culture

“…The decrease in ␤-cell mass in type 2 diabetes results primarily from increased ␤-cell death via apoptosis (40,41), and formation of toxic IAPP aggregates is thought to be an important contributor to the progressive loss of ␤-cells in this disease (1,16,42). It remains unclear whether aggregation of IAPP and amyloid formation is a cause of ␤-cell loss or simply a marker of ␤-cell death and dysfunction.…”

Impaired NH2-Terminal Processing of Human Proislet Amyloid Polypeptide by the Prohormone Convertase PC2 Leads to Amyloid Formation and Cell Death

“…Islet amyloid deposits are a pathological characteristic of the pancreas in type 2 diabetes that likely contribute to the progressive loss of ␤-cells in this disease (4,5). Islet amyloid is formed by aggregation of islet amyloid polypeptide (IAPP; amylin) (6,7), a 37-amino acid hormone that is colocalized and cosecreted with insulin from ␤-cells (8,9).…”