Islet Amyloid in Type 2 Diabetes, and the Toxic Oligomer Hypothesis

Abstract

Type 2 diabetes (T2DM) is characterized by insulin resistance, defective insulin secretion, loss of beta-cell mass with increased beta-cell apoptosis and islet amyloid. The islet amyloid is derived from islet amyloid polypeptide (IAPP, amylin), a protein coexpressed and cosecreted with insulin by pancreatic beta-cells. In common with other amyloidogenic proteins, IAPP has the propensity to form membrane permeant toxic oligomers. Accumulating evidence suggests that these toxic oligomers, rather than the extracellular amyloid form of these proteins, are responsible for loss of neurons in neurodegenerative diseases. In this review we discuss emerging evidence to suggest that formation of intracellular IAPP oligomers may contribute to beta-cell loss in T2DM. The accumulated evidence permits the amyloid hypothesis originally developed for neurodegenerative diseases to be reformulated as the toxic oligomer hypothesis. However, as in neurodegenerative diseases, it remains unclear exactly why amyloidogenic proteins form oligomers in vivo, what their exact structure is, and to what extent these oligomers play a primary or secondary role in the cytotoxicity in what are now often called unfolded protein diseases.

The role of caspase-8 in amyloid-induced beta cell death in human and mouse islets

“…Islet amyloid formation in patients with type 2 diabetes contributes to progressive beta cell death [3][4][5]. Unlike in type 2 diabetes, amyloid forms rapidly in cultured [6][7][8] and transplanted human islets [9,10], and this is associated with beta cell dysfunction and death in vitro [6][7][8], and with islet graft failure leading to recurrence of hyperglycaemia in animal models of type 1 diabetes [10][11][12].…”

“…Islet amyloid is typically found extracellular, adjacent to beta cells [6-8, 13, 20, 21], but intracellular hIAPP aggregates also form in humans and transgenic rodent models [9,13,18,21]. Small hIAPP aggregates appear to be the major mediators of beta cell death [3,4,22].…”

Is type 2 diabetes an amyloidosis and does it really matter (to patients)?

“…Human amylin's physiological conformation is one of random coil, but it undergoes rapid conformational change into β-conformers when placed in physiological solutions [35]. Based on the available evidence, many workers have concluded that small oligomers formed by aggregated human amylin [36,37] are probably the species that could ultimately cause diabetes [38,39]. Others, among them Zraika and colleagues, believe that the cytotoxicity of larger amyloid fibrils must be considered [11,15], as indeed it must.…”

“…Zraika et al have argued that mature amyloid fibrils, rather than small, soluble cytotoxic oligomers [37][38][39]43], could play the main role in beta cell degeneration and diabetes causation. As noted, they have pointed to the numerous weaknesses and shortcomings of the currently available evidence, and in so doing have indicated further lines of investigation that might improve our understanding.…”

“…In brief, there is much evidence that aggregating amylin evokes cytotoxicity through an apoptotic mechanism [48] mediated via a pathway comprising initial activation of a cell membranebound Fas/Fas ligand/Fas-associated death domaincontaining protein/caspase-8 complex [41,42,49], followed by a three-pronged downstream cascade comprising cJun amino-terminal kinase 1/cJun [41], activating transcription factor 2/p38 mitogen-activated protein kinase [50] and p53/ p21 wild-type p53-activated fragment 1/p21 cyclindependent kinase-interacting protein 1 pathways [48], which results ultimately in activation of caspase-3 [41] and cell death. Haataja et al, in a review [38], have reported on their parallel studies of an amylin-mediated pathway, whereby activation of a mechanism related to endoplasmic reticulum stress might also contribute to islet beta cell degeneration.…”