Mechanisms of beta-cell failure in diabetes

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The current epidemic of type 2 diabetes represents a major global health problem, with over 7% of the Australians suffering the disease. While there is a well-established relationship between obesity and insulin resistance, the majority of overweight individuals do not develop type 2 diabetes because their pancreatic beta-cells compensate with enhanced insulin secretion. It is the failure of beta-cell compensation that is fundamental to the development of diabetes. The beta-cell is a highly specialised cell with a unique metabolic profile and differentiation specifically geared towards making these cells able to sense fluctuations in circulating glucose levels and secrete insulin accordingly. We propose that in susceptible individuals, a gradual rise in blood glucose (hyperglycaemia) and lipid levels resulting from increasing obesity and insulin resistance leads to a loss of the unique expression pattern of genes necessary for appropriate insulin secretion. This exacerbates hyperglycaemia, which causes further beta-cell dedifferentiation and eventually the death of beta-cells by apoptosis. We have recently found evidence in several models of diabetes that supports this hypothesis. We propose to use animal studies and cell culture systems to investigate the following hypotheses important for our understanding of beta-cell failure and progression to diabetes: 1) The loss of beta-cell phenotype (dedifferentiation) underlies the loss of insulin secretory function in failing beta-cells. 2) Hyperglycaemia plays a critical role regulating the progression to beta-cell dedifferentiation. 3) The overexpression of key candidate gene products play an integral role linking hyperglycaemia to the loss of beta-cell secretion. 4) Endoplasmic reticulum stress is necessary for beta-cell death in diabetes. Our studies will make a major contribution to our understanding of why beta-cells fail in diabetes and aim to provide novel therapeutic targets in the treatment of diabetes.