The Role of Sorcs1 and Sortilin in Diabetes Susceptibility

 描述(申请人提供)：我们正处于一场史无前例的肥胖症流行之中，这导致了2型糖尿病(T2D)的流行。肥胖导致胰岛素抵抗，导致胰腺细胞对胰岛素的需求增加。遗传因素在决定？细胞是否有能力对增加的胰岛素需求作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，糖尿病会导致并可能反映？细胞损伤的某些方面(发育、增殖、生存 或胰岛素分泌)。我们定位克隆了Sorcs1，这是一个与肥胖诱导的T2D有关的基因。SORCS1与人类的T2D和糖尿病并发症有关。我们获得了Sorcs1基因敲除(KO)小鼠，当它们肥胖时，它们会患上糖尿病。肥胖的Sorcs1KO小鼠的胰腺细胞存在严重的胰岛素颗粒缺陷，这是由于翻译后胰岛素降解的急剧增加。我们已经证明了山梨素，一种与 众所周知，Sorcs1可以将蛋白质靶向溶酶体进行降解，并与胰岛素结合。Sorcs1的前结构域也与山梨素结合并抑制其活性。我们的初步研究表明 与过表达Sorcs1的细胞相比，山梨素在？细胞中的过表达降低了细胞中的胰岛素含量。我们假设Sorcs1抑制了sortilin促进胰岛素降解的能力。拟议的研究将阐明Sorcs1和sortilin在决定胰岛素在细胞内的命运中的作用。我们已经在人类山梨素(SORT1)中发现了两个编码SNPs；一个与胰岛素水平降低有关，另一个与胆固醇升高有关。我们将描述SORT1中这些SNP的特征，以了解它们与这些不同表型的关联。我们将评估小鼠Sorcs1中与胰岛素减少相关的一个等位基因变异。我们提议的研究将阐明一个新确定的分支点，该分支点决定胰岛素是被包装在胰岛素颗粒中，还是被转移到降解中。我们将描述与人类和小鼠的胰岛素减少相关的Sortilin和Sorcs1的突变。我们工作的洞察力可能为开发新的治疗方法提供线索，旨在保护胰岛细胞的胰岛素储备。

 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.