Toxic oligomers and islet beta cell death: guilty by association or convicted by circumstantial evidence?

Abstract

Type 2 diabetes is a progressive disease characterised by islet amyloid deposits in the majority of patients. Amyloid formation is considered a significant factor in deterioration of islet function and reduction in beta cell mass, and involves aggregation of monomers of the normally soluble beta cell peptide, human islet amyloid polypeptide (hIAPP) into oligomers, fibrils and, ultimately, mature amyloid deposits. Despite extensive in vitro studies, the process of hIAPP aggregation in vivo is poorly understood, though it is widely reported to promote cytotoxicity. Recently, studies have suggested that only the early stages of fibril assembly, and in particular small hIAPP oligomers, are responsible for beta cell cytotoxicity. This challenges the prior concept that newly formed fibrils and/or mature fibrillar amyloid are cytotoxic. Herein, evidence both for and against the toxic hIAPP oligomer hypothesis is presented; from this, it is apparent that what exactly causes beta cell death when hIAPP aggregates remains debatable. Moreover, substantially more work with more specific reagents and techniques than are currently available will be required to identify conclusively the toxic species resulting from hIAPP aggregation. Keeping an open mind on the nature of the cytotoxic insult has implications for therapeutic developments and clinical care in type 2 diabetes.

Fig. 1

Stages of islet amyloid formation. Human IAPP is a 37-amino-acid peptide; residues 20–29 (shaded) are particularly important for conversion of the molecule to beta sheet conformation and assembly into fibrils. Fibril formation in vitro can be measured using the thioflavin-T-binding assay, which typically shows a lag phase and a sigmoidal increase to a steady state. This reflects the assembly of fibrils. The exact process of assembly from monomer to fibril in vivo is unknown. A simplified version of events is depicted below the graph. Initially IAPP monomers are in random structure. Off-pathway oligomers may also be formed but are not depicted in the diagram. Under particular conditions the monomer assumes a beta conformation (depicted by the red rod), forms dimers, small oligomers and larger multimers. This occurs during the lag phase of the thioflavin T assay. As the assemblies extend, (a) protofilaments (4 nm diameter, visible by electron microscopy), are formed which themselves assemble into (b) fibrils (2–4 protofilaments, 10 nm diameter); these assemblies are thioflavin T positive. Progressive fibril formation leads to (c) islet amyloid deposits (green), which can occupy a large proportion of the islet, replacing insulin-producing cells (insulin is shown in red) in type 2 diabetes. Scale bars: a, b 100 nm; c 50 μm