Mechanisms of beta-cell failure in diabetes

糖尿病β细胞衰竭的机制

• 批准号: nhmrc : 427616
• 负责人: A/Pr David Laybutt
• 金额: $ 35.81万
• 依托单位: Garvan Institute of Medical Research
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2007
• 资助国家: 澳大利亚
• 起止时间: 2007-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/mechanisms-beta-cell-failure-diabetes/94439
• 关键词: Mechanisms; beta; cell; failure; diabetes

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.

目前2型糖尿病的流行是一个重大的全球健康问题，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的关系已经确立，但大多数超重的人不会患上2型糖尿病，因为他们的胰岛β细胞通过胰岛素分泌增加来补偿。β细胞代偿的失败是糖尿病发生的根本原因。β细胞是一种高度专业化的细胞，具有独特的代谢特征和分化，专门针对使这些细胞能够感知循环血糖水平的波动并相应地分泌胰岛素。我们认为，在易感个体中，由于肥胖和胰岛素抵抗增加而导致的血糖(高血糖)和血脂水平逐渐上升，导致适当分泌胰岛素所必需的独特基因表达模式的丧失。这会加剧高血糖，导致进一步的β细胞去分化，最终导致β细胞通过细胞凋亡而死亡。我们最近在几种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细胞衰竭和进展到糖尿病是重要的：1)β细胞表型的丧失(去分化)是衰竭的β细胞失去胰岛素分泌功能的基础。2)高血糖对胰岛β细胞去分化的进程起着重要的调节作用。3)关键候选基因产物的过度表达在高血糖与β细胞分泌丧失之间起着不可或缺的作用。4)内质网应激是糖尿病β细胞死亡的必要条件。我们的研究将对我们理解为什么β细胞在糖尿病中失败做出重大贡献，并旨在为糖尿病的治疗提供新的治疗靶点。