Type 2 diabetes as a protein misfolding disease

Abstract

Type 2 diabetes (T2D) is a highly prevalent and chronic metabolic disorder. Recent evidence suggests that formation of toxic aggregates of the islet amyloid polypeptide (IAPP) might contribute to β-cell dysfunction and disease. However, the mechanism of protein aggregation and associated toxicity remains unclear. Misfolding, aggregation, and accumulation of diverse proteins in various organs is the hallmark of the group of protein misfolding disorders (PMDs), including highly prevalent illnesses affecting the central nervous system (CNS) such as Alzheimer's disease (AD) and Parkinson's disease (PD). In this review we discuss the current understanding of the mechanisms implicated in the formation of protein aggregates in the endocrine pancreas and associated toxicity in the light of the long-standing knowledge from neurodegenerative disorders associated with protein misfolding.

Keywords: amyloid; islet amyloid polypeptide; prions; protein misfolding; type 2 diabetes; β cells.

Figure 1. IAPP propensity to form amyloid aggregates

A: The figure shows a schematic representation of the typical kinetics of human IAPP aggregation compared with other PMD-associated proteins. In our experience, at low micromolar concentrations, physiological temperature and pH, IAPP forms aggregates in minutes, whereas Aβ needs hours and α-synuclein needs days to bypass the lag phase before aggregating exponentially. B: Amyloidogenicity of IAPP from human, rhesus monkey, cat and mouse was studied in silico using a structure-based algorithm originally described by Eisenberg and colleagues [157]. The amino acid sequence is plotted along the X-axis. Each histogram bar represents one hexa-peptide starting at the indicated position in the sequence and is colored according to its Rosetta energy. Orange-red segments with energy below the indicated energetic threshold of −23 kcal/mol (gray line), are predicted to form fibrils.

Figure 2. Molecular pathways implicated in β-cell damage mediated by the formation and accumulation of IAPP aggregates

Illustration of major cellular pathways implicated in the toxicity of IAPP aggregates against β-cells. Figure elements are not drawn to scale. Abbreviations: ER, endoplasmic reticulum; ROS, reactive oxygen species; UPS, ubiquitin proteasome system.