Endocrine Abstracts

The critical contribution of deficient insulin secretion to the pathogenesis of type 2 diabetes is beyond doubt. The normal beta-cell response to obesity-associated insulin resistance is hypersecretion of insulin that maintains blood glucose levels within the normal range. This is associated with both expansion of beta-cell mass and enhanced beta-cell function. Type 2 diabetes only develops in subjects that are unable to sustain the beta-cell compensatory response. This is associated with a progressive deterioration of beta-cell function, particularly impairment of glucose stimulated insulin secretion (GSIS), and a loss of beta-cell mass through an increased rate of apoptosis. Thus, type 2 diabetes arises in subjects with islets that are susceptible to dysfunction and apoptosis under conditions of high demand. Stress within the endoplasmic reticulum (ER) organelle of the cell has been proposed as a mechanism for beta-cell dysfunction and death in type 2 diabetes. ER stress activates a signalling cascade known as the unfolded protein response (UPR) – the role of which is both to alleviate the ER stress through the upregulation of protein folding enzymes and chaperones and, paradoxically, to activate apoptosis via deleterious UPR signalling if the stress is too severe or prolonged. Recent findings suggest that upregulation of the adaptive UPR is linked with beta-cell compensation and protection against obesity-associated diabetes. Conversely, in genetically susceptible islets, suppression of ER adaptation and loss of beta-cell differentiation underlies beta-cell failure and progression to diabetes. Factors leading to failure of ER adaptation include chronic hyperglycaemia, inflammation and hypoxia. This knowledge is critically important to understanding the mechanisms responsible for the switch from beta-cell compensation to failure in type 2 diabetes.