Genetic Modifers of Diabetes

2型糖尿病的遗传基础已被证明是复杂的。考虑到参与调节葡萄糖代谢的大量组织：肝脏、肌肉、脂肪、内分泌胰腺、肠道和大脑，这并不令人惊讶。许多影响胰岛β细胞功能和肝脏碳水化合物代谢的基因(所有已知的MODY基因)的改变会导致碳水化合物不耐受和高血糖。脂肪细胞的突变可能导致糖尿病易感性，如瘦素缺乏症或糖尿病抵抗，就像Perilipin缺乏症一样。因此，功能突变的丧失既可以提供糖尿病的易感性，也可以提供对糖尿病的保护。关于这一点，还有更多的有待发现 调节碳水化合物新陈代谢的基因组和胞体之间的复杂关系。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上产生并鉴定了一种新的LEPR缺失小鼠的糖尿病表型 紧张。FVB品系的肥胖LEPR缺陷小鼠会出现持续性高血糖和伴随的高胰岛素血症，这是由于大量的胰岛β细胞团扩张所致。FVB小鼠的β细胞对糖毒性的这种明显的抵抗力是由小鼠5号染色体上的一个主要基因座控制的基因决定的，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来分离和鉴定在β细胞中赋予糖毒性抗性或敏感性的遗传变异。我们有三个具体目标： 1.确定调节胰岛β细胞对高血糖反应的主要基因座(MODB1)。 2.在亚厘米分辨率下定义MODB1的临界遗传间隔。 3.确定控制β细胞反应的modb1基因和序列变体 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.