Mechanisms of S6K1 Mediated Insulin Resistance

描述（由申请人提供）：肥胖导致胰岛素作用受损的分子机制尚不清楚。然而，最近的研究，特别是在缺乏胰岛素信号通路关键成分的小鼠中，已经开始为研究肥胖在2型糖尿病发展中的作用提供分子见解和潜在模型。在这里，我们提供了小鼠的初步数据，表明其中一种成分，核糖体蛋白S6激酶1 (S6K1)，在胰岛素诱导的与细胞生长相关的合成代谢反应中不仅起积极作用，而且起消极作用。这种负面作用在营养充足的条件下被揭示出来，并且很可能是通过胰岛素受体底物1 （IRS1）上特定残基的磷酸化介导的。已知这些位点的磷酸化抑制磷脂酰亚脂- 3oh激酶（PI3K）与IRS1的结合，减少葡萄糖摄取并导致胰岛素抵抗。然而，IRS1中磷酸化的位点不是S6K1磷酸化位点，而是由哺乳动物雷帕霉素靶蛋白（mTOR）调控的位点，mTOR是一种直接上游激酶，参与S6K1的磷酸化和激活。我们的假设是S6K1的营养激活通过促进IRS1的mTOR磷酸化来负性调节胰岛素作用，从而导致胰岛素抵抗。我们的研究计划是：(i)确定由mTOR介导的IRS1磷酸化位点，（ii）确定S6K1缺失减少mTOR对IRS1磷酸化的机制，以及（iii）测量S6K1在小鼠饮食诱导的胰岛素抵抗发展中的作用程度。考虑到营养饱足驱动S6K1激活，并与肥胖和胰岛素抵抗密切相关，确定S6K1在多大程度上促进这些病理是很重要的。肥胖已经成为一种世界性的流行病，不仅会导致2型糖尿病，也是癌症和心血管疾病死亡的主要原因。这种流行病的出现是由于食物摄入量的急剧增加，这是由于食物丰富、美味和便宜。人类是一个食腐动物，直到最近这一事实才突显了这一效应，以至于确保和保存食物的基因特征比那些抑制食物摄入的基因特征更占优势。因此，如果S6K1在这些疾病中起关键作用，那么S6K1的小分子抑制剂的开发可能有助于改善胰岛素抵抗患者的生活质量。

DESCRIPTION (provided by applicant): The molecular mechanisms by which obesity leads to impaired insulin action are not well understood. However, recent studies, particularly in mice deficient for key components of the insulin-signaling pathway, have begun to provide molecular insights and potential models to study the role of obesity in the development of type 2 diabetes. Here we provide preliminary data in the mouse, showing that one such component, ribosomal protein S6 kinase 1 (S6K1), plays not only a positive role in insulin-induced anabolic responses associated with cell growth, but also a negative role. This negative role is revealed under conditions of nutrient satiation and is most likely mediated through the phosphorylation of specific residues on insulin receptor substrate 1 (IRS1). Phosphorylation at these sites is known to dampen phosphatidylinositide-3OH kinase (PI3K) binding to IRS1, reduce glucose uptake and lead to insulin resistance. However, the sites of phosphorylated in IRS1 are not S6K1 phosphorylation sites, but sites regulated by the mammalian Target Of Rapamycin (mTOR) an immediate upstream kinase involved in the phosphorylation and activation of S6K1. Our hypothesis is that nutrient activation of S6K1 negatively regulates insulin action by promoting mTOR phosphorylation of IRS1, leading to insulin resistance. Our research plan is to (i) identify the IRS1 phosphorylation sites mediated by mTOR, (ii) determine the mechanism by which absence of S6K1 reduces IRS1 phosphorylation by mTOR, and (iii) measure the extent to which S6K1 contributes to the development of diet-induced insulin resistance in the mouse. Given that nutrient satiation drives S6K1 activation and is intimately associated with obesity and insulin resistance, it is important to determine the extent to which S6K1 contributes to these pathologies. Obesity has become a worldwide epidemic, not only leading to type 2 diabetes, but is also a major cause of cancer and cardiovascular deaths. This epidemic has arisen because of the dramatic rise in food intake, which is due to the fact that food is abundant, tasteful, and inexpensive. That man was a scavenger until recent times has accentuated this effect, such that genetic traits to secure and retain food have prevailed over those that suppressed food intake. Thus, if S6K1 is a critical player in these diseases the development of a small molecule inhibitor to S6K1 may act to improve the quality of life of those suffering from insulin resistance.