Genetic Modifers of Diabetes

2型糖尿病的遗传基础已被证明是复杂的。这并不奇怪，因为有大量的组织参与调节葡萄糖代谢：肝脏，肌肉，脂肪，内分泌胰腺，肠道和大脑。影响胰腺β细胞功能和肝脏碳水化合物代谢的许多基因（所有已知的MODY基因）的改变可产生碳水化合物不耐受和高血糖症。脂肪细胞中的突变可以赋予糖尿病易感性，如瘦素缺乏症，或糖尿病抗性，如围脂蛋白缺乏症的情况。因此，功能缺失突变可以提供对糖尿病的易感性和保护。还有更多的东西有待发现， 基因组和调节碳水化合物代谢的索马之间的复杂关系。为此，我们利用瘦素受体（Lepr）缺乏的肥胖/糖尿病综合征的遗传修饰物的存在来鉴定新的糖尿病基因。 我们已经在FVB上产生并表征了LEPR缺失小鼠的新型糖尿病表型。 株FVB品系的肥胖LEPR缺陷小鼠由于大量胰腺β细胞群扩增而发展出持续性高血糖症和伴随的高胰岛素血症。FVB小鼠β细胞对葡萄糖毒性的这种明显抗性是由小鼠5号染色体上的一个主要基因座控制的遗传决定的性状，我们将提供证据支持这一说法。此外，我们将提供一种实验策略，以分离和鉴定赋予β细胞对葡萄糖毒性的抗性或易感性的遗传变异。我们有三个具体目标： 1.确定调节胰腺β细胞对高血糖反应的主要位点（Modbl）。 2.在亚厘摩分辨率下定义Modbl的临界遗传区间。 3.确定Modbl基因和控制β细胞对以下物质的反应的序列变体： 高血糖症

The genetic basis of type 2 diabetes mellitus has been shown to be complex. This is not surprising given the large number of tissues that are engaged in regulating glucose metabolism: liver, muscle, fat, endocrine pancreas, the gut, and the brain. Alterations in numerous genes that affect pancreatic beta cell function and hepatic carbohydrate metabolism (all of the known MODY genes) can produce carbohydrate intolerance and hyperglycemia. Mutations in adipocytes can confer diabetes susceptibility, such as leptin deficiency, or diabetes resistance, as is the case in perilipin deficiency. Thus, loss of function mutations can provide both susceptibility to and protection from diabetes. Much more remains to be discovered about the complex relationships between the genome and the soma that regulate carbohydrate metabolism. To this end, we have utilized the existence of genetic modifiers of the obesity/diabetes syndrome of leptin receptor (Lepr) deficiency to identify novel diabetes genes. We have generated and characterized a novel diabetes phenotype of LEPR-null mice on the FVB strain. Obese LEPR-deficient mice of the FVB strain develop persistent hyperglycemia and concomitant hyperinsulinemia due to massive pancreatic beta cell mass expansion. This apparent resistance of the FVB mouse's beta cell to glucotoxicity is a genetically determined trait controlled by one major locus on mouse Chromosome 5 and we will provide evidence in support of this statement. Moreover, we will provide an experimental strategy to isolate and identify the genetic variants that confer resistance or susceptibility to glucotoxicity in the beta cell. We have three specific aims: 1. Identify a major locus (Modbl) that regulates the pancreatic beta cell response to hyperglycemia. 2. Define a critical genetic interval for Modbl at subcentimorgan resolution. 3. Identify the Modbl gene and the sequence variants that control beta cell responses to hyperglycemia.