Pancreatic beta-cell dysfunction in diabetes

糖尿病中的胰腺β细胞功能障碍

• 批准号: nhmrc : 325618
• 负责人: A/Pr David Laybutt
• 金额: $ 25.96万
• 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: 2005
• 资助国家: 澳大利亚
• 起止时间: 2005-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/pancreatic-beta-cell-dysfunction-diabetes/97241
• 关键词: Pancreatic; beta; cell; dysfunction; diabetes

In Australia over 7% of the population have type 2 diabetes. This epidemic represents a major health problem. The majority of overweight individuals do not develop diabetes because their insulin-secreting pancreatic beta-cells adequately compensate with over-secretion. It is the failure of this so called, beta-cell compensation, that is fundamental to the development of diabetes. We propose that in susceptible individuals, a gradual rise in blood glucose levels resulting from obesity and insulin resistance leads to beta-cell failure and overt diabetes. This project will investigate the mechanisms responsible for beta-cell failure in a mouse model with a similar time-dependent progression to obesity and type 2 diabetes as that seen in humans. C57BL-KsJ db-db mice progress from a pre-diabetic phase of insulin over-secretion, obesity and insulin resistance to a diabetic state characterised by the appearance of high blood glucose and lipid levels and the loss of insulin secretory capacity. With age, there are also a reduced number of beta-cells because of increased cell death. db-db mice will be studied at different stages in their natural progression to diabetes to fully characterise the secretory dysfunction and the changes in beta-cell phenotype over the time-course of diabetes development. The use of laser capture microdissection will allow us to study selectively the actual beta-cells without contamination from the other cells of the pancreas. The mice will also be treated with an agent that lowers blood glucose levels without affecting lipids to test the influence of hyperglycaemia itself in the development of beta-cell dysfunction. We will also test if the changes observed in the mice are regulated independently by high glucose levels in cell culture systems. The role of one candidate protein called ID-1 will be investigated as a potential link between hyperglycaemia and the development of beta-cell dysfunction.

在澳大利亚，超过7%的人口患有2型糖尿病。这种流行病是一个主要的健康问题。大多数超重的人不会患上糖尿病，因为他们分泌胰岛素的胰岛β细胞足以抵消过度分泌的影响。正是这种所谓的β细胞代偿的失败，才是糖尿病发展的根本。我们认为，在易感个体中，肥胖和胰岛素抵抗导致的血糖水平逐渐上升会导致β细胞衰竭和显性糖尿病。该项目将在与人类相似的肥胖和2型糖尿病的时间依赖进展的小鼠模型中，研究导致β细胞衰竭的机制。C57BL-KSJ db-db小鼠从胰岛素过度分泌、肥胖和胰岛素抵抗的糖尿病前期进展到糖尿病状态，特征是出现高血糖和高血脂水平以及胰岛素分泌能力丧失。随着年龄的增长，由于细胞死亡增加，β细胞的数量也会减少。DB-db小鼠将在其自然发展为糖尿病的不同阶段进行研究，以全面描述糖尿病发展过程中分泌功能障碍和β细胞表型的变化。激光捕获显微解剖的使用将使我们能够有选择地研究实际的β细胞，而不会受到胰腺其他细胞的污染。这些小鼠还将接受一种在不影响血脂的情况下降低血糖水平的药物治疗，以测试高血糖本身在β细胞功能障碍发展中的影响。我们还将测试在小鼠中观察到的变化是否独立于细胞培养系统中的高葡萄糖水平调节。一种名为ID-1的候选蛋白的作用将被作为高血糖和β细胞功能障碍发展的潜在联系进行调查。