Identification and characterisation of a gene causing insulin hypersecretion in a mouse model of diabetes susceptibility

糖尿病易感性小鼠模型中导致胰岛素分泌过多的基因的鉴定和表征

• 批准号: nhmrc : 400269
• 负责人: A/Pr Sofianos Andrikopoulos
• 金额: $ 28.69万
• 依托单位: The University of Melbourne
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2006
• 资助国家: 澳大利亚
• 起止时间: 2006-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/identification-characterisation-gene-diabetes-susceptibility/76600
• 关键词: Identification; characterisation; gene; causing; insulin

Diabetes is a disorder primarily characterised by the inability to produce and secrete the pancreatic hormone insulin, which regulates plasma sugar levels. This results in increased sugar levels which cause diabetic complications such as retinopathy and nephropathy. The inability to produce and secrete insulin is due to both defects in function as well as a reduction in pancreatic beta cells. Paradoxically it has been shown that some patients who are at risk of develping diabetes actually secrete more insulin than normal. Furthermore it has been suggested that this increase in insulin secretion actually may be associated with the decreased production and secretion of insulin characteristic of diabetes. The DBA-2 mouse is a model of reduced insulin production and secretion when exposed to high sugar levels or diabetes. However we have shown that in the normal non-stressed state DBA-2 mice actually secrete more insulin than normal and that this occurs from a very early age, suggesting that this trait is inherited. We have subsequently performed genetic studies and have identified a segment of DNA containing 10 genes associated with increased insulin secretion in DBA-2 mice. The level of one of these genes we have called Hip1 is increased 5-fold in DBA-2 mice, providing a candidate gene for increased insulin secretion in this model of diabetes susceptibility. However, whether Hip1 is also responsible for reduced insulin production and secretion in the DBA-2 mouse is not known. Therefore the overall hypothesis of this project is that the gene Hip1 which is associated with increased insulin secretion is also responsible for reduced insulin production and secretion when DBA-2 mice are exposed to high sugar or obesity. Determining why Hip1 is increased and whether it results in diabetes in DBA-2 mice may provide a reasonable candidate for the development of therapeutic interventions which may prevent the progression of diabetes in some patients.

糖尿病是一种疾病，其主要特征是无法产生和分泌调节血糖水平的胰腺激素胰岛素。这会导致血糖水平升高，从而导致糖尿病并发症，如视网膜病变和肾病。不能产生和分泌胰岛素是由于功能缺陷和胰腺细胞减少。矛盾的是，一些有患糖尿病风险的患者实际上分泌的胰岛素比正常人多。此外，有研究表明，胰岛素分泌的增加实际上可能与糖尿病特征胰岛素的产生和分泌减少有关。DBA-2小鼠是暴露于高糖水平或糖尿病时胰岛素产生和分泌减少的模型。然而，我们已经证明，在正常的非应激状态下，DBA-2小鼠实际上比正常状态分泌更多的胰岛素，而且这种情况从很小的时候就发生了，这表明这种特征是遗传的。我们随后进行了遗传研究，并在DBA-2小鼠中确定了一个包含10个基因的DNA片段，这些基因与胰岛素分泌增加有关。其中一种被我们称为Hip1的基因水平在DBA-2小鼠中增加了5倍，这为糖尿病易感性模型中胰岛素分泌增加提供了一个候选基因。然而，在DBA-2小鼠中，Hip1是否也会导致胰岛素的产生和分泌减少尚不清楚。因此，本项目的总体假设是，当DBA-2小鼠暴露于高糖或肥胖时，与胰岛素分泌增加相关的Hip1基因也负责胰岛素的产生和分泌减少。确定Hip1增加的原因以及它是否会导致DBA-2小鼠的糖尿病，可能为开发治疗干预措施提供合理的候选者，这些干预措施可能会阻止某些患者的糖尿病进展。