Corresponding author: Bertrand Cariou,
Diabetes Care. 2013 Oct;36(10):2923-30. doi: 10.2337/dc12-2012. Epub 2013 May 28.
The development of new insulin sensitizers is an unmet need for the treatment of type 2 diabetes. We investigated the effect of GFT505, a dual peroxisome proliferator-activated receptor (PPAR)-α/δ agonist, on peripheral and hepatic insulin sensitivity.
Twenty-two abdominally obese insulin-resistant males (homeostasis model assessment of insulin resistance>3) were randomly assigned in a randomized crossover study to subsequent 8-week treatment periods with GFT505 (80 mg/day) or placebo, followed by a two-step hyperinsulinemic-euglycemic insulin clamp with a glucose tracer to calculate endogenous glucose production (EGP). The primary end point was the improvement in glucose infusion rate (GIR). Gene expression analysis was performed on skeletal muscle biopsy specimens.
GFT505 improved peripheral insulin sensitivity, with a 21% (P=0.048) increase of the GIR at the second insulin infusion period. GFT505 also enhanced hepatic insulin sensitivity, with a 44% (P=0.006) increase of insulin suppression of EGP at the first insulin infusion period. Insulin-suppressed plasma free fatty acid concentrations were significantly reduced on GFT505 treatment (0.21±0.07 vs. 0.27±0.11 mmol/L; P=0.006). Neither PPARα nor PPARδ target genes were induced in skeletal muscle, suggesting a liver-targeted action of GFT505. GFT505 significantly reduced fasting plasma triglycerides (-21%; P=0.003) and LDL cholesterol (-13%; P=0.0006), as well as liver enzyme concentrations (γ-glutamyltranspeptidase: -30.4%, P=0.003; alanine aminotransferase: -20.5%, P=0.004). There was no safety concern or any indication of PPARγ activation with GFT505.
The dual PPARα/δ agonist GFT505 is a liver-targeted insulin-sensitizer that is a promising drug candidate for the treatment of type 2 diabetes and nonalcoholic fatty liver disease.
开发新型胰岛素增敏剂是治疗 2 型糖尿病的未满足需求。我们研究了双重过氧化物酶体增殖物激活受体（PPAR）-α/δ激动剂 GFT505 对周围和肝脏胰岛素敏感性的影响。
22 名腹部肥胖的胰岛素抵抗男性（稳态模型评估的胰岛素抵抗>3）被随机分配到一项随机交叉研究中，随后分别接受 8 周的 GFT505（80mg/天）或安慰剂治疗，随后进行两步高胰岛素-正常血糖钳夹试验，并用葡萄糖示踪剂计算内源性葡萄糖生成（EGP）。主要终点是葡萄糖输注率（GIR）的改善。对骨骼肌活检标本进行基因表达分析。
GFT505 改善了外周胰岛素敏感性，第二次胰岛素输注期间 GIR 增加了 21%（P=0.048）。GFT505 还增强了肝脏胰岛素敏感性，第一次胰岛素输注期间胰岛素抑制 EGP 的作用增加了 44%（P=0.006）。GFT505 治疗时，胰岛素抑制的血浆游离脂肪酸浓度显著降低（0.21±0.07 与 0.27±0.11mmol/L；P=0.006）。骨骼肌中既没有诱导 PPARα 也没有诱导 PPARδ 靶基因，这表明 GFT505 具有肝脏靶向作用。GFT505 显著降低空腹血浆甘油三酯（-21%；P=0.003）和 LDL 胆固醇（-13%；P=0.0006），以及肝酶浓度（γ-谷氨酰转肽酶：-30.4%，P=0.003；丙氨酸氨基转移酶：-20.5%，P=0.004）。GFT505 没有安全性问题，也没有表明其激活了 PPARγ。
双重过氧化物酶体增殖物激活受体（PPAR）-α/δ 激动剂 GFT505 是一种肝脏靶向胰岛素增敏剂，有望成为治疗 2 型糖尿病和非酒精性脂肪性肝病的候选药物。
