Pancreatic beta-cell dysfunction in diabetes

在澳大利亚，超过7%的人口患有2型糖尿病。这种流行病是一个重大的健康问题。大多数超重的人不会患糖尿病，因为他们分泌胰岛素的胰腺β细胞可以充分补偿分泌过多的胰岛素。这就是所谓的细胞补偿的失败，这是糖尿病发展的基础。我们认为，在易感个体中，由肥胖和胰岛素抵抗引起的血糖水平逐渐升高导致β细胞衰竭和明显的糖尿病。该项目将研究小鼠模型中β细胞衰竭的机制，该模型具有与人类相似的肥胖和2型糖尿病的时间依赖性进展。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发展到以高血糖和血脂水平和胰岛素分泌能力丧失为特征的糖尿病状态。随着年龄的增长，由于细胞死亡的增加，β细胞的数量也会减少。我们将对Db-db小鼠在其自然发展为糖尿病的不同阶段进行研究，以充分表征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药物治疗，这种药物可以在不影响血脂的情况下降低血糖水平，以测试高血糖本身对β细胞功能障碍的影响。我们还将测试在小鼠中观察到的变化是否由细胞培养系统中的高葡萄糖水平独立调节。一种被称为ID-1的候选蛋白的作用将被研究作为高血糖和β细胞功能障碍发展之间的潜在联系。

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.