PBI-4547 改善葡萄糖代谢和胰岛素抵抗，并减少肥胖和代谢综合征高脂饮食小鼠模型的肝损伤,Diabetes

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PBI-4547 改善葡萄糖代谢和胰岛素抵抗，并减少肥胖和代谢综合征高脂饮食小鼠模型的肝损伤
Diabetes ( IF 6.2 ) Pub Date : 2018-05-01 , DOI: 10.2337/db18-1858-p
MARTIN LEDUC ₁ , BRIGITTE GROUIX ₁ , MIKAËL TREMBLAY ₁ , LIETTE GERVAIS ₁ , FRANÇOIS SARRA-BOURNET ₁ , ALEXANDRA FELTON ₁ , JEAN-CHRISTOPHE SIMARD ₁ , FRANÇOIS A. LEBLOND ₁ , PIERRE LAURIN ₁ , LYNE GAGNON ₁

Affiliation

介绍和目标：肥胖及其导致的代谢紊乱是主要的健康威胁，也是包括非酒精性脂肪性肝病 (NAFLD) 在内的许多疾病的主要原因。PBI-4547 是一种新型的一流的口服活性抗糖尿病化合物，具有多效性，并已在不同的动物模型中显示可减少 NASH、糖尿病和肾纤维化。本研究的目的是研究 PBI-4547 在高脂肪饮食诱导的肥胖和代谢综合征小鼠模型中的作用。方法：给 C57BL/6 小鼠喂食标准或高脂肪饮食（HFD，Harlan，TD.06414）14 周。这些小鼠被分为三组 [正常食物、HFD + 载体和 HFD + PBI-4547（10 毫克/千克，每天口服一次）] 并再治疗 6 周。血糖、血清胰岛素水平、检查了血清甘油三酯和脂联素、肝脏组织学以及肝脏和白色脂肪组织 (WAT) 促炎/纤维化基因表达。结果：在口服葡萄糖耐量试验中，与 HFD 对照组相比，PBI-4547 增加了葡萄糖代谢。PBI-4547 改善了胰岛素抵抗（通过 HOMA-IR 测量）和 β 细胞功能（HOMA1-β）。PBI-4547 显着降低血清甘油三酯水平，而血清中的脂联素显着增加。组织学分析表明，PBI-4547 显着减少了肝脏脂肪变性和气球样变。为了进一步表征 PBI-4547 的活性，进行了促纤维化标志物的定量 RT-PCR 分析，证明 PBI-4547 降低了肝脏中的 CTGF 和 MMP2 基因表达以及 CTGF、MCP-1、MMP2 和 I 型胶原蛋白基因在 WAT 中的表达。结论：综上所述，这些结果表明 PBI-4547 具有作为治疗非酒精性脂肪肝、肥胖和相关代谢综合征的新疗法的潜力。披露 M. Leduc：员工；自己; Prometic Biosciences Inc.。股票/股东；自己; Prometic Life Sciences Inc. B. Grouix：员工；自己; Prometic Biosciences Inc.。股票/股东；自己; Prometic Life Sciences Inc. M. Tremblay：员工；自己; Prometic Biosciences Inc.。股票/股东；自己; Prometic Life Sciences Inc. L. Gervais：员工；自己; Prometic Biosciences Inc.。股票/股东；自己; Prometic Life Sciences Inc. F. Sarra-Bournet：员工；自己; Prometic Biosciences Inc.。股票/股东；自己; Prometic Life Sciences Inc. A. Felton：员工；自己; Prometic Biosciences Inc. 股票/股东；自己; Prometic Life Sciences Inc. J. Simard：员工；自己; Prometic Biosciences Inc.。股票/股东；自己; Prometic Life Sciences Inc. FA Leblond：员工；自己; Prometic Biosciences Inc.。股票/股东；自己; Prometic Life Sciences Inc. P. Laurin：员工；自己; Prometic Biosciences Inc.。股票/股东；自己; Prometic Life Sciences Inc.。董事会成员；自己; Prometic Life Sciences Inc. L. Gagnon：员工；自己; Prometic Biosciences Inc.。股票/股东；自己; Prometic Life Sciences Inc. 股票/股东；自己; Prometic Life Sciences Inc.。董事会成员；自己; Prometic Life Sciences Inc. L. Gagnon：员工；自己; Prometic Biosciences Inc.。股票/股东；自己; Prometic Life Sciences Inc. 股票/股东；自己; Prometic Life Sciences Inc.。董事会成员；自己; Prometic Life Sciences Inc. L. Gagnon：员工；自己; Prometic Biosciences Inc.。股票/股东；自己; Prometic Life Sciences Inc.

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PBI-4547 Improves Glucose Metabolism and Insulin Resistance, and Reduces Liver Damage in a High-Fat Diet Mouse Model of Obesity and Metabolic Syndrome

Introduction and Aims: Obesity and its resulting metabolic disturbances are major health threats and are the main cause of a host of diseases, including nonalcoholic fatty liver disease (NAFLD). PBI-4547 is a novel first-in-class orally active antidiabetic compound which displays pleiotropic activities and has been shown to reduce NASH, diabetes, and renal fibrosis in different animal models. The aim of this study was to investigate the effects of PBI-4547 in a mouse model of high-fat diet-induced obesity and metabolic syndrome. Methods: C57BL/6 mice were fed with either a standard or a high-fat diet (HFD, Harlan, TD.06414) for 14 weeks. These mice were divided in three groups [normal chow, HFD + vehicle, and HFD + PBI-4547 (10 mg/kg, oral once a day)] and treated for an additional 6 weeks. Blood glucose, serum insulin level, serum triglyceride and adiponectin, liver histology, as well as liver and white adipose tissue (WAT) pro-inflammatory/fibrotic gene expression were examined. Results: In an oral glucose tolerance test, PBI-4547 increased glucose metabolism compared to the HFD control group. Insulin resistance (measured by HOMA-IR) and β cell function (HOMA1-β) were improved by PBI-4547. Serum triglyceride level was significantly reduced by PBI-4547 while adiponectin in serum was significantly increased. Histological analysis showed a significant reduction of hepatic steatosis and ballooning by PBI-4547. To further characterize the activity of PBI-4547, quantitative RT-PCR analysis of pro-fibrotic markers was performed, demonstrating that PBI-4547 reduced CTGF and MMP2 gene expression in the liver as well as CTGF, MCP-1, MMP2 and collagen type I gene expression in the WAT. Conclusions: Taken together, these results suggest that PBI-4547 offers the potential as a novel therapy for nonalcoholic fatty liver disease, obesity and associated metabolic syndrome. Disclosure M. Leduc: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. B. Grouix: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. M. Tremblay: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. L. Gervais: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. F. Sarra-Bournet: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. A. Felton: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. J. Simard: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. F.A. Leblond: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. P. Laurin: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc.. Board Member; Self; Prometic Life Sciences Inc. L. Gagnon: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc..

更新日期：2018-05-01

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