IAPP/amylin and β-cell failure: implication of the risk factors of type 2 diabetes

Abstract

In type 2 diabetes (T2D), the most significant pathological change in pancreatic islets is amyloid deposits, of which a major component is islet amyloid polypeptide (IAPP), also called amylin. IAPP is expressed in β-cells and co-secreted with insulin. Together with the inhibitory effects of synthetic human IAPP (hIAPP) on insulin secretion, our studies, using hIAPP transgenic mice, in which glucose-stimulated insulin secretion was moderately reduced without amyloid deposit, and hIAPP gene-transfected β-cell lines, in which insulin secretion was markedly impaired without amyloid, predicted that soluble hIAPP-related molecules would exert cytotoxicity on β-cells. Human IAPP is one of the most aggregation-prone peptides that interact with cell membranes. While it is widely reported that soluble hIAPP oligomers promote cytotoxicity, this is still a hypothesis since the mechanisms are not yet fully defined. Several hIAPP transgenic mouse models did not develop diabetes; however, in models with backgrounds characterized for diabetic phenotypes, β-cell function and glucose tolerance did worsen, compared to those in non-transgenic models with similar backgrounds. Together with these findings, many studies on metabolic and molecular disorders induced by risk factors of T2D suggest that in T2D subjects, toxic IAPP oligomers accumulate in β-cells, impair their function, and reduce mass through disruption of cell membranes, resulting in β-cell failure. IAPP might be central to β-cell failure in T2D. Anti-amyloid aggregation therapeutics will be developed to create treatments with more durable and beneficial effects on β-cell function. KeywordsIAPP/amylin • Type 2 diabetes • Islet amyloid • IAPP oligomer • Risk factors of T2D • β-Cell failure * Azuma Kanatsuka

Curcumin: A small molecule with big functionality against amyloid aggregation in neurodegenerative diseases and type 2 diabetes

“…Indeed, biosynthesis and secretion of IAPP are increased in diabetes and obesity 44 ; and moreover, islet amyloid deposits are present in over 90% of diabetic patients 45 . Multiple mechanisms have been proposed for the pathogenic role of IAPP in T2D, including increased insulin resistance and cytotoxicity in pancreatic beta cells 46 . IAPP, as well as insulin, can control glycemia; however, it has been reported that amylin may have a negative effect on insulin production 47 .…”

“…Ohsawa et al and Degano et al reported that synthetic hIAPP inhibited insulin secretion from pancreatic islets in diabetic rat models, 48,49 whereas other researchers have found no inhibitory effect of IAPP on insulin secretion 50,51 . IAPP β‐cell cytotoxicity related to damaged membranes increases endoplasmic reticulum (ER) stress, produces defects in the autophagy pathway, and induces inflammatory responses leading to T2D 46 . Recently, Li et al demonstrated that soluble hIAPP oligomers containing α‐helical structure induced permeable pores in lipid membranes of cells 52 .…”

Tyrosine carbon dots inhibit fibrillation and toxicity of the human islet amyloid polypeptide

“…4,5 hIAPP oligomers, however, are believed to be the main toxic species, likely through disruption of cell membranes. [6][7][8] In light of the presumed closed relationship between hIAPP aggregation and its pathogenicity, inhibition of hIAPP selfassembly and bril formation have been a major strategy aimed at identifying therapeutic treatments to T2D. 9 Synthetic aggregation inhibitors such as short peptides 9,10 metal nanoparticles [11][12][13] have been reported.…”

Chitosan Oligosaccharides Attenuate Amyloid Formation of hIAPP and Protect Pancreatic β-Cells from Cytotoxicity

“…Mature hIAPP contains 37 amino acids and is one of the most aggregation-prone peptides. It has been reported that aggregated hIAPP formed amyloid deposits in 70-90% of patients with T2D [5]. The amyloidogenic process of hIAPP for diabetes is shown in two aspects.…”