Novel insulin-sensitizing NASH/diabetes drugs.

新型胰岛素增敏 NASH/糖尿病药物。

• 批准号: 10471836
• 负责人: Brian N Finck
• 金额: $ 49.75万
• 依托单位: BIOIO, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-17 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10471836
• 关键词: American; Antidiabetic Drugs; B-Lymphocytes; Biochemical; Biological Assay; Blood Glucose; Blood Preservation; CRISPR interference; Cardiometabolic Disease; Chronic Disease; Cirrhosis; Clinical Trials; Collaborations; Cytosol; Data; Development; Diabetes Mellitus; Diet; Disease; Drug Targeting; Drug usage; Excretory function; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Future; Glucose; Glucose Clamp; Hepatic; Hepatocyte; Homeostasis; In Vitro; Inflammation; Insulin; Insulin Resistance; Lesion; Link; Lipids; Liver Failure; Liver Fibrosis; Liver parenchyma; Mediating; Medical; Metabolic; Metabolic Diseases; Metformin; Modeling; Molecular; Molecular Analysis; Molecular Target; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Persons; Pharmaceutical Preparations; Phase; Phenotype; Phospholipase D; Phospholipases A; Primary carcinoma of the liver cells; Progressive Disease; Public Health; Refractory; Risk; Rodent; Signal Transduction; Sulfonylurea Compounds; Testing; Therapeutic; Therapeutic Effect; Thiazolidinediones; Tissues; Toxicology; Validation; Work; base; comorbidity; design; drug efficacy; efficacy testing; fatty liver disease; glucose production; improved; in vivo; inhibitor; insulin secretion; insulin sensitivity; insulin sensitizing drugs; intrahepatic; lead candidate; liver inflammation; liver injury; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; phospholipase D1; prototype; screening; side effect; stellate cell; urinary

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.

肥胖与许多慢性和进行性疾病以及肥胖的风险增加有关 相关的代谢疾病构成了重大的公共卫生负担。增加的可能性 出现胰岛素抵抗和糖尿病可能是最常见的肥胖风险。在 此外，肥胖还与肝实质中脂质的积累有关（肝脂肪变性或 非酒精性脂肪肝（NAFLD））。 NAFLD 这个术语涵盖了肝脂肪变性（ 肝细胞胞浆内中性脂质的积累）以及更严重的非酒精性 脂肪性肝炎 (NASH)（与脂肪病变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衰竭，并且风险增加 用于发展肝细胞癌。 NASH 目前是一种尚无批准治疗方法的疾病， 构成重大的未满足的医疗需求。重要的是，炎症、胰岛素抵抗和糖尿病是 与 NASH 的发展密切相关，因此针对这些影响途径的药物是领先的 治疗该疾病的候选人。该应用程序旨在测试新型胰岛素增敏剂的功效 通过一种新机制发挥作用，改善胰岛素作用，同时减少副作用的药物。我们将研究一个 具有治疗胰岛素功效的新型原型化合物 (MSDC-5514) 及其备用化合物 (MSDC-5445) 抵抗力和 NASH。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 并检验磷脂酶 D 1 (PLD1) 信号传导是其分子靶点的假设。在第二阶段，我们将 检查 MSDC-5514 和 MSDC-5445 对 NASH 小鼠模型的肝脏影响并验证 PLD1 在这个模型中遗传。这些研究中获得的结果将定义机制并提供证据- 支持未来临床试验的概念证据，以测试这些药物对糖尿病患者的疗效 以及其他与肥胖相关的心脏代谢疾病，这些疾病有可能使数百万美国人受益。

项目成果

Adipocyte lipin 1 is positively associated with metabolic health in humans and regulates systemic metabolism in mice.

脂肪细胞脂质 1 与人类的代谢健康呈正相关，并调节小鼠的全身代谢。

• DOI: 10.1101/2023.02.01.526676
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: LaPoint,Andrew;Singer,JasonM;Ferguson,Daniel;Shew,TrevorM;Renkemeyer,MKatie;Palacios,Hector;Field,Rachael;Shankaran,Mahalakshmi;Smith,GordonI;Yoshino,Jun;He,Mai;Patti,GaryJ;Hellerstein,MarcK;Klein,Samuel;Brestoff,Jonatha
• 通讯作者: Brestoff,Jonatha