The β-cell assassin: IAPP cytotoxicity

Abstract

Islet amyloid polypeptide (IAPP) forms cytotoxic oligomers and amyloid fibrils in islets in type 2 diabetes (T2DM). The causal factors for amyloid formation are largely unknown. Mechanisms of molecular folding and assembly of human IAPP (hIAPP) into β-sheets, oligomers and fibrils have been assessed by detailed biophysical studies of hIAPP and non-fibrillogenic, rodent IAPP (rIAPP); cytotoxicity is associated with the early phases (oligomers/multimers) of fibrillogenesis. Interaction with synthetic membranes promotes β-sheet assembly possibly via a transient α-helical molecular conformation. Cellular hIAPP cytotoxicity can be activated from intracellular or extracellular sites. In transgenic rodents overexpressing hIAPP, intracellular pro-apoptotic signals can be generated at different points in β-cell protein synthesis. Increased cellular trafficking of proIAPP, failure of the unfolded protein response (UPR) or excess trafficking of misfolded peptide via the degradation pathways can induce apoptosis; these data indicate that defects in intracellular handling of hIAPP can induce cytotoxicity. However, there is no evidence for IAPP overexpression in T2DM. Extracellular amyloidosis is directly related to the degree of β-cell apoptosis in islets in T2DM. IAPP fragments, fibrils and multimers interact with membranes causing disruption in vivo and in vitro. These findings support a role for extracellular IAPP in β-sheet conformation in cytotoxicity. Inhibitors of fibrillogenesis are useful tools to determine the aberrant mechanisms that result in hIAPP molecular refolding and islet amyloidosis. However, currently, their role as therapeutic agents remains uncertain.

Islet prohormone processing in health and disease

“…Evidence for altered aggregation properties of proIAPP processing intermediates suggests errors in proIAPP processing as a potential mechanism for amyloid‐induced islet failure . In cell lines lacking PC expression, transfection of hproIAPP resulted in increased intracellular amyloid deposition .…”

“…IAPP species with less propensity to form fibrils may spend more time in toxic oligomeric phases prior to fibril formation. In addition, incompletely processed forms may have a higher tendency to bind to heparan sulphate proteoglycans, a component of islet amyloid, potentially enhancing amyloid plaque deposition . As IAPP aggregates drive inflammation and β‐cell dysfunction, a deleterious cycle may perpetuate, wherein (pro)IAPP aggregates lead to β‐cell dysfunction and exacerbate processing defects, leading to the production of more incompletely processed forms of proIAPP and further aggregation and islet dysfunction.…”

The receptor for advanced glycation endproducts is a mediator of toxicity by IAPP and other proteotoxic aggregates: Establishing and exploiting common ground for novel amyloidosis therapies

“…A reduction in weight induced by IAPP has been reported for obese rats and humans, and animal studies have led to the hypothesis that weight loss occurs through a mode of action that is similar to that found in cases of enhanced leptin sensitivity . As the focus of this review is on proteotoxicity rather than normal function of IAPP, the interested reader is referred to several recent reviews that discuss the proposed function(s) of IAPP in more depth …”

“…Fully processed IAPP is stored in the halo region of the insulin secretory granule, while insulin is found in the dense core of the granule . The concentration of IAPP in the granule is only about 1–2% that of insulin, but this is a much higher concentration than required to promote aggressive amyloid formation in vitro . This suggests that there are factors that inhibit irreversible aggregation of IAPP in the granule.…”

“…Defining whether islet amyloid has an intracellular or extracellular origin might affect drug design, and is thus of practical, as well as academic interest. The interested reader is referred to the recent review by Clark and co‐workers for a more in‐depth discussion of the issue of intra‐ vs. extracellular islet amyloid formation …”