Pathways leading to β-cell dysfunction and death in type 1 and type 2 diabetes

Abstract

The failure of β-cells to provide sufficient amounts of insulin to maintain blood glucose levels within a narrow physiological range is central to the development of all forms of diabetes. β-cell failure is characterised by both functional defects and loss of β-cell mass through apoptosis; however, the underlying mechanisms are not well defined. The broad aim of this thesis was to gain further insight into the mechanisms leading to β-cell dysfunction and death in type 1 and type 2 diabetes. Pro-inflammatory cytokines and saturated fatty acids are suggested mediators of β-cell apoptosis in type 1 diabetes and type 2 diabetes, respectively. Endoplasmic reticulum (ER) stress is induced by cytokines and saturated fatty acids in vitro. Studies in this thesis tested the hypothesis that ER stress provides a common mechanism for β-cell death induced by cytokines and the saturated fatty acid, palmitate. The research demonstrated for the first time that chemical chaperones are able to relieve ER stress in β-cells. This was associated with protection against death induced by palmitate, but not by cytokines. These findings indicated that ER stress activation is selectively necessary for palmitate- and not for cytokine-mediated β-cell death. The studies suggest that improving ER folding capacity is a promising therapeutic strategy for type 2 diabetes. Previous studies have found that β-cell dysfunction in animal models of diabetes is associated with increased expression of the helix-loop-helix protein Id1. Studies in this thesis investigated the role of Id1 in insulin secretion and glucose homeostasis. The research demonstrates a novel role of Id1 as a negative regulator of insulin secretion. Studies with Id1 knockout mice demonstrated that Id1 expression plays an essential role in the aetiology of glucose intolerance, insulin secretory dysfunction and β-cell dedifferentiation under conditions of insulin resistance and chronic lipid oversupply. The findings suggest that Id1 expression may provide a molecular link between chronic lipid oversupply and β-cell dedifferentiation and dysfunction. Id1 may therefore represent a new target for therapeutic interventions aimed at improving β-cell dysfunction and restoring disordered glucose homeostasis.