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

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。无法产生和分泌胰岛素既是由于功能缺陷，也是由于胰岛β细胞减少。矛盾的是，研究表明，一些有患糖尿病风险的患者实际上比正常情况下分泌了更多的胰岛素。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有的胰岛素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小鼠实际上比正常情况下分泌更多的胰岛素，而且这种情况从很小的时候就发生了，这表明这一特征是遗传的。我们随后进行了遗传学研究，并确定了一段包含10个与DBA-2小鼠胰岛素分泌增加相关的基因的DNA片段。在DBA-2小鼠中，其中一个我们称为Hip1的基因的水平增加了5倍，为糖尿病易感性模型中胰岛素分泌增加提供了候选基因。然而，Hip1是否也是DBA-2小鼠胰岛素产生和分泌减少的原因尚不清楚。因此，该项目的总体假设是，当DBA-2小鼠暴露在高糖或肥胖环境中时，与胰岛素分泌增加相关的Hip1基因也是导致胰岛素产生和分泌减少的原因。确定为什么Hip1增加，以及它是否会导致DBA-2小鼠的糖尿病，可能会为开发可能防止某些患者糖尿病进展的治疗干预措施提供一个合理的候选方案。

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.