The Role of Sorcs1 and Sortilin in Diabetes Susceptibility

 描述（由申请人提供）：我们正处于一个前所未有的肥胖流行病，这是导致2型糖尿病（T2 D）的流行病。肥胖引起胰岛素抵抗，导致胰腺β细胞对胰岛素的需求增加。遗传因素在决定胰岛细胞是否能够对增加的胰岛素需求做出反应方面起着关键作用。在这种胰岛素需求得不到满足的个体中，糖尿病的结果可能反映了β细胞损伤的某些方面（发育、增殖、存活 或胰岛素分泌）。我们定位克隆了Sorcs 1，这是一种导致肥胖诱导的T2 D的基因。SORCS 1与人类的T2 D和糖尿病并发症有关。我们获得了Sorcs 1敲除（KO）小鼠，当肥胖时，它们会患上糖尿病。来自肥胖Sorcs 1 KO小鼠的胰腺β细胞由于胰岛素翻译后降解的急剧增加而具有胰岛素颗粒的严重缺乏。我们已经证明，分拣蛋白，一种与 Sorcs 1与胰岛素结合，已知它将蛋白质靶向溶酶体进行降解。Sorcs 1的前结构域也与分拣蛋白结合并抑制其活性。我们的初步研究显示 与过表达Sorcs 1的胰岛β细胞相反，在胰岛β细胞中过表达分拣蛋白降低了细胞胰岛素含量。我们假设Sorcs 1抑制分拣蛋白促进胰岛素降解的能力。拟议的研究将阐明Sorcs 1和Sortilin在决定胰岛素的细胞内命运中的作用。我们已经确定了人类分拣蛋白（SORT 1）中的两个编码SNP;一个与胰岛素水平降低相关，另一个与胆固醇升高相关。我们将描述SORT 1中的这些SNP，以了解它们与这些不同表型的关联。我们将评估小鼠Sorcs 1中与胰岛素减少相关的等位基因变异。我们拟定的研究将阐明一个新发现的分支点，该点决定胰岛素是否包装在胰岛素颗粒中，或转向降解。我们将描述与人类和小鼠胰岛素减少相关的Sortilin和Sorcs 1突变。从我们的工作中获得的见解可能为开发旨在保护胰腺β细胞胰岛素储备的新治疗方法提供线索。

 DESCRIPTION (provided by applicant): We are in the midst of an unprecedented obesity epidemic, which is causing an epidemic of type 2 diabetes (T2D). Obesity causes insulin resistance, resulting in an increased demand for insulin from pancreatic ß-cells. Genetic factors play a critical role in determining whether or not the ß-cells are capable of responding to the increased demand for insulin. In individuals where this insulin demand is not met, diabetes results and likely reflects some aspect of ß-cell impairment (development, proliferation, survival or insulin secretion). We positionally cloned Sorcs1, a gene that contributes to obesity-induced T2D. SORCS1 is associated with T2D and diabetes complications in humans. We derived Sorcs1 knockout (KO) mice and when obese, they develop diabetes. Pancreatic ß-cells from obese Sorcs1 KO mice have a severe deficiency in insulin granules, due to a dramatic increase in the post-translational degradation of insulin. We have shown that Sortilin, a protein related to Sorcs1, which is known to target proteins to the lysosome for degradation, binds to insulin. The pro-domain of Sorcs1 also binds to Sortilin and inhibits its activity. Our preliminary studies show that overexpression of Sortilin in ß-cells, in contrast to ß-cells overexpressing Sorcs1, decreases cellular insulin content. We hypothesize that Sorcs1 inhibits the ability of Sortilin to promote insulin degradation. The proposed studies will elucidate the role of Sorcs1 and Sortilin in determining the intracellular fate of insulin. We have identified two coding SNPs in human Sortilin (SORT1); one associated with reduced insulin levels and the other with elevated cholesterol. We will characterize these SNPs in SORT1 to understand their association with these distinct phenotypes. We will evaluate an allelic variant in mouse Sorcs1 that is associated with reduced insulin. Our proposed studies will elucidate a newly identified branch point that determines whether insulin is packaged in insulin granules, or is diverted towards degradation. We will characterize mutations in Sortilin and Sorcs1 that are associated with decreased insulin in humans and in mice. Insights from our work may provide clues to the development of novel therapeutic approaches aimed at preserving the insulin reserve of pancreatic ß-cells.