Role of TLR4 on insulin resistance in humans

描述(申请人提供)：2型糖尿病(T2 DM)是美国人口发病率和死亡率的主要原因。因此，迫切需要新的更好的方法来预防和治疗T2 DM。胰岛素抵抗是T2 DM发病机制中最早和最显著的异常之一。然而，T2 DM胰岛素抵抗的分子基础尚不完全清楚。Toll样受体(TLR4)是一种细胞表面受体，通过激活一系列促炎事件而产生免疫反应。TLR4在胰岛素靶细胞(心肌细胞、肝细胞、脂肪细胞)和炎性细胞(单核/巨噬细胞)上表达。这种受体被细菌来源的脂多糖(LPS)和饱和游离脂肪酸(FFA)激活。包括我们在内的不同研究小组的研究表明，TLR4在胰岛素抵抗受试者的肌肉和炎症细胞中的表达增加。多项研究还表明，肥胖和2型糖尿病患者血浆中两种TLR4配体FFA和LPS的浓度升高。此外，来自细胞培养和动物研究的新证据表明，TLR4及其下游通路[MAPKs和核因子κB]可能在胰岛素抵抗和T2 DM的发病机制中发挥重要作用。尽管有相当多的数据将TLR4与胰岛素抵抗联系在一起，但尚不清楚TLR4是否直接参与了肥胖和T2 DM患者的胰岛素抵抗的发病机制。在这项研究中，我们将在体内使用一种特异性的TLR4抑制剂，目的是(I)确定TLR4信号在人类胰岛素抵抗和T2 DM发病机制中所起的作用；(Ii)阐明TLR4介导人类胰岛素抵抗的机制/S。我们提出了两个目的来检验以下假设：(1)用E5564药物抑制TLR4将防止瘦小的正常糖耐量受试者的脂质诱导的胰岛素抵抗；(2)用E5564药物抑制TLR4将减少胰岛素抵抗(肥胖的非糖尿病和肥胖的T2 DM)受试者的炎症和改善糖代谢。这项研究的结果将促进我们对人类胰岛素抵抗病理生理学的理解，如果阳性，将验证TLR4作为T2 DM预防和治疗的可行靶点。

DESCRIPTION (provided by applicant): Type 2 diabetes mellitus (T2DM) is a major cause of morbidity and mortality among the U.S. population. Therefore, new and better ways to prevent and treat T2DM are urgently needed. Insulin resistance is one of the earliest and most significant abnormalities in the pathogenesis of T2DM. However, the molecular basis for the insulin resistance of T2DM is not fully understood. Toll-like receptor (TLR) 4 is a cell surface receptor that generates immune responses by activating a cascade of pro-inflammatory events. TLR4 is expressed on insulin-target (myocytes, hepatocytes, adipocytes) and inflammatory (monocytes/macrophages) cells. This receptor is activated by bacteria-derived lipopolysaccharide (LPS) and by saturated free fatty acids (FFA). Studies from various groups, including ours, have shown that TLR4 expression is elevated in muscle and inflammatory cells from insulin resistant subjects. Several studies also have demonstrated that the plasma concentration of two TLR4 ligands, FFA and LPS, is increased in obese and T2DM subjects. Moreover, emerging evidence from cell culture and animal studies suggest that TLR4 and downstream pathways [MAPKs and nuclear factor (NF)κB] could play an important role in the pathogenesis of insulin resistance and T2DM. Despite the considerable body of data linking TLR4 with insulin resistance, it is not known whether TLR4 is directly involved in the pathogenesis of insulin resistance in obese and T2DM human subjects. In this study, we will utilize a specific TLR4 inhibitor in vivo with the goals to (i) determine the role that TLR4 signalng plays in the pathogenesis of insulin resistance and T2DM in humans; and (ii) elucidate the mechanism/s by which TLR4 mediates insulin resistance in human subjects. We propose two Aims to test the following hypotheses: (1) Pharmacologic inhibition of TLR4 with E5564 will prevent lipid-induced insulin resistance in lean normal glucose-tolerant subjects; and (2) Pharmacologic inhibition of TLR4 with E5564 will reduce inflammation and improve glucose metabolism in insulin resistant (obese nondiabetic and obese T2DM) subjects. The results from this study will advance our understanding about the pathophysiology of insulin resistance in human subjects, and, if positive, will validate TLR4 as a viable target for T2DM prevention and treatment.