Mechanisms of beta-cell failure in diabetes

目前2型糖尿病的流行是一个主要的全球健康问题，超过7%的澳大利亚人患有这种疾病。虽然肥胖和胰岛素抵抗之间有明确的关系，但大多数超重的人不会患上2型糖尿病，因为他们的胰腺β细胞通过增加胰岛素分泌来进行补偿。细胞补偿的失败是糖尿病发展的根本原因。β细胞是一种高度特化的细胞，具有独特的代谢特征和分化，专门用于使这些细胞能够感知循环葡萄糖水平的波动并相应地分泌胰岛素。我们提出，在易感个体中，由于肥胖和胰岛素抵抗的增加，血糖（高血糖）和脂质水平逐渐升高，导致适当胰岛素分泌所需的独特基因表达模式的丧失。这加剧了高血糖，导致β细胞进一步去分化，并最终通过凋亡导致β细胞死亡。我们最近在几个糖尿病模型中发现了支持这一假设的证据。我们建议使用动物研究和细胞培养系统来研究以下假设，这些假设对于我们理解β细胞衰竭和糖尿病的进展非常重要：1)β细胞表型的丧失（去分化）是β细胞衰竭中胰岛素分泌功能丧失的基础。2)高血糖在β细胞去分化过程中起着重要的调节作用。3)关键候选基因产物的过表达在高血糖与β细胞分泌缺失之间起着不可或缺的作用。内质网应激是糖尿病β细胞死亡的必要条件。我们的研究将为我们理解β细胞在糖尿病中失败的原因做出重大贡献，并旨在为糖尿病的治疗提供新的治疗靶点。

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.