Novel insulin-sensitizing NASH/diabetes drugs.

肥胖与一些慢性和进行性疾病以及肥胖的风险增加有关- 相关的代谢性疾病构成了重大的公共卫生负担。更大的可能性 患上胰岛素抵抗和糖尿病可能是最常见的肥胖风险。在……里面 此外，肥胖还与肝实质中脂质的积聚有关(肝脏脂肪变性或 非酒精性脂肪肝(NAFLD))。术语NAFLD包括肝脏脂肪变性( 肝细胞胞浆中性脂质堆积)和更严重的非酒精性 脂肪性肝炎(NASH)(与脂肪变性损害相关的肝脏炎症和纤维化)。一个重要的 NAFLD和NASH患者的比例将进展为肝硬化和肝功能衰竭，并面临更高的风险 发展为肝细胞癌。NASH目前是一种没有得到批准的治疗方法的疾病 构成了一个重大的未得到满足的医疗需求。重要的是，炎症、胰岛素抵抗和糖尿病 铅与NASH的发展密切相关，因此针对这些作用途径的药物是铅 治疗这种疾病的候选人。这一应用旨在测试新的胰岛素增敏剂的疗效。 通过一种新的机制来改善胰岛素作用，同时减少副作用的药物。我们将研究一个 治疗胰岛素的新型原型化合物(MSDC-5514)及其载体(MSDC-5445) 抵抗和纳什。在第一阶段，我们将确定这些化合物是否可以改善胰岛素敏感性 并验证磷脂酶D_1(PLD_1)信号是其分子靶点的假设。在第二阶段，我们会 在NASH小鼠模型上检测MSDC-5514和MSDC-5445的肝脏作用并验证PLD1 在这个模型中遗传的。在这些研究中获得的发现将定义机制并提供证据 支持未来临床试验以测试这些药物对糖尿病患者疗效的概念证据 以及其他与肥胖相关的心脏代谢性疾病，这些疾病有可能造福数百万美国人。

Obesity is associated with an increased risk of a number of chronic and progressive diseases and obesity- related metabolic diseases constitute a significant public health burden. The increased likelihood of developing insulin resistance and diabetes is probably the most commonly recognized risk of being obese. In addition, obesity is also associated with accumulation of lipid in the liver parenchyma (hepatic steatosis or nonalcoholic fatty liver disease (NAFLD)). The term, NAFLD, encompasses both hepatic steatosis (the accumulation of neutral lipid within the cytosol of hepatocytes) and the more severe nonalcoholic steatohepatitis (NASH) (hepatic inflammation and fibrosis associated with steatotic lesions). A significant proportion of NAFLD and NASH patients will progress to cirrhosis and liver failure and are at increased risk for developing hepatocellular carcinoma. NASH is currently a disease without an approved treatment and constitutes a significant unmet medical need. Importantly, inflammation, insulin resistance, and diabetes are tightly linked to development of NASH and thus drugs that target these contributing pathways are lead candidates for treating the disease. This application is designed to test the efficacy of new insulin-sensitizing agents that act via a novel mechanism to improve insulin action while reducing side effects. We will study a novel prototype compound (MSDC-5514) and its backup (MSDC-5445) for efficacy at treating insulin resistance and NASH. In Phase I, we will determine whether these compounds improve insulin sensitivity and test the hypothesis that phospholipase D 1 (PLD1) signaling is their molecular target. In Phase II, we will examine the hepatic effects of MSDC-5514 and MSDC-5445 in a mouse model of NASH and validate PLD1 genetically in this model. Findings obtained in these studies will define mechanisms and provide proof-of- concept evidence supporting future clinical trials to test the efficacy of these drugs in patients with diabetes and other obesity-related cardiometabolic diseases that have the potential to benefit millions of Americans.