Mechanisms of islet amyloidosis toxicity in type 2 diabetes

Abstract

Amyloid formation by the neuropancreatic hormone, islet amyloid polypeptide (IAPP or amylin), one of the most amyloidogenic sequences known, leads to islet amyloidosis in type 2 diabetes and to islet transplant failure. Under normal conditions, IAPP plays a role in the maintenance of energy homeostasis by regulating several metabolic parameters, such as satiety, blood glucose levels, adiposity and body weight. The mechanisms of IAPP amyloid formation, the nature of IAPP toxic species and the cellular pathways that lead to pancreatic β-cell toxicity are not well characterized. Several mechanisms of toxicity, including receptor and non-receptor-mediated events, have been proposed. Analogs of IAPP have been approved for the treatment of diabetes and are under investigation for the treatment of obesity.

Figure 1. Amyloid formation by IAPP

(A) Schematic diagram of amyloid formation (solid blue curve). During the lag phase monomers associate to form oligomeric species which then assemble to nucleate an exponential growth phase. Secondary nucleation and off-pathway steps such as formation of amorphous aggregates are omitted for clarity. Amyloid formation can be accelerated by the addition of small amounts of preformed fibrils (dashed red curve). (B) The primary sequence of human IAPP. The peptide has a free N-terminus, an amidated C-terminus and an intramolecular disulfide bond between residues 2 and 7.

Figure 2. Physiological and pathophysiological effects of IAPP

According to this scheme, amyloidosis by adaptive IAPP leads to the production of cytotoxic species. The toxic species of IAPP may form either intracellularly or extracellularly, leading to a series of parallel, overlapping and potentially additive or synergistic pathogenic pathways.