Role of TLR4 on insulin resistance in humans

描述（由申请方提供）：2型糖尿病（T2 DM）是美国人群发病和死亡的主要原因。因此，迫切需要新的和更好的方法来预防和治疗T2 DM。胰岛素抵抗是2型糖尿病发病最早和最重要的异常之一。然而，T2 DM胰岛素抵抗的分子基础尚未完全了解。Toll样受体（TLR）4是一种细胞表面受体，通过激活促炎事件级联反应产生免疫应答。TLR 4在胰岛素靶细胞（肌细胞、肝细胞、脂肪细胞）和炎性细胞（单核细胞/巨噬细胞）上表达。该受体被细菌衍生的脂多糖（LPS）和饱和游离脂肪酸（FFA）激活。包括我们在内的多个研究小组的研究表明，在胰岛素抵抗受试者的肌肉和炎症细胞中，TLR 4的表达升高。几项研究还表明，两种TLR 4配体FFA和LPS的血浆浓度在肥胖和T2 DM受试者中增加。此外，来自细胞培养和动物研究的新证据表明，TLR 4及其下游通路[MAPKs和核因子（NF）？B]可能在胰岛素抵抗和2型糖尿病的发病中起重要作用。尽管有大量数据将TLR 4与胰岛素抵抗联系起来，但尚不清楚TLR 4是否直接参与肥胖和T2 DM人类受试者中胰岛素抵抗的发病机制。在本研究中，我们将在体内利用特异性TLR 4抑制剂，目的是（i）确定TLR 4信号传导在人类胰岛素抵抗和T2 DM发病机制中的作用;和（ii）阐明TLR 4介导人类受试者胰岛素抵抗的机制。我们提出了两个目的来检验以下假设：（1）E5564对TLR 4的药理学抑制将预防瘦正常葡萄糖耐受受试者中脂质诱导的胰岛素抵抗;（2）E5564对TLR 4的药理学抑制将减少胰岛素抵抗（肥胖非糖尿病和肥胖T2 DM）受试者中的炎症并改善葡萄糖代谢。这项研究的结果将促进我们对人类受试者胰岛素抵抗的病理生理学的理解，如果阳性，将验证TLR 4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)?B] 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.