title: Human IAPP amyloidogenic properties and pancreatic β-cell death.
abstract: A hallmark of type 2 diabetes mellitus (T2DM) is the presence of extracellular amyloid deposits in the islets of Langerhans. These deposits are formed by the human islet amyloid polypeptide, hIAPP (or amylin), which is a hormone costored and cosecreted with insulin. Under normal conditions, the hormone remains in solution but, in the pancreas of T2DM individuals, it undergoes misfolding giving rise to oligomers and cross-β amyloid fibrils. Accumulating evidence suggests that the amyloid deposits that accompany type 2 diabetes mellitus are not just a trivial epiphenomenon derived from the disease progression. Rather, hIAPP aggregation induces processes that impair the functionality and viability of β-cells and may lead to apoptosis. The present review article aims to summarize a few aspects of the current knowledge of this amyloidogenic polypeptide. In the first place, the physicochemical properties which condition its propensity to misfold and form aggregates. Secondly, how these properties confer hIAPP the capacity to interfere with some signaling of the pancreatic β-cell, interact with membranes, form channels or affect natural ion channels, including calcium channels. Finally, how misfolded hIAPP cytotoxicity results in apoptosis. A number of pathophysiological changes of the T2DM islet can be related to the amyloidogenic properties of hIAPP. However, in a certain way, the in vivo aggregation of the polypeptide also reflects a failure of chaperones and, in general, of cellular proteostasis, supporting the view that T2DM may also be considered as a conformational disorder.
authors.affiliation: Department of Biochemistry, Centro de Investigación y de Estudios Avanzados del I.P.N. (CINVESTAV), Ave, Politécnico 2508, PO Box 14-740, 07000 México D.F., Mexico. Electronic address: msfernandez@cinvestav.mx.
authors.forename: Marta S
authors.initials: MS
authors.lastname: Fernández
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D058228:Islet Amyloid Polypeptide / Q000235:genetics / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology
chemical_list: D007328:Insulin; D058228:Islet Amyloid Polypeptide
keywords: Amylin; Amyloid; Human islet amyloid polypeptide; Ion-channels; T2DM; Type 2 diabetes mellitus; hIAPP; β-Cell death