Dual peroxisome proliferator-activated receptor α/δ agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects.
Dual peroxisome proliferator-activated receptor α/δ agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects.
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DOI：
10.2337/dc12-2012
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发表时间：
2013-10
期刊：
影响因子：
16.2
通讯作者：
Laville M
中科院分区：
文献类型：
--
作者：
Cariou B;Hanf R;Lambert-Porcheron S;Zaïr Y;Sauvinet V;Noël B;Flet L;Vidal H;Staels B;Laville M
开发新的胰岛素增敏剂是治疗2型糖尿病的一个未满足的需求。我们研究了GFT 505（一种双重过氧化物酶体增殖物激活受体（PPAR）-α/δ激动剂）对外周和肝脏胰岛素敏感性的影响。在一项随机交叉研究中，将22例腹部肥胖胰岛素抵抗男性（胰岛素抵抗的稳态模型评估>3）随机分配至随后的8周GFT 505（80 mg/天）或安慰剂治疗期，随后使用葡萄糖示踪剂进行两步高胰岛素-正常血糖胰岛素钳夹试验，以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。GFT 505改善了外周胰岛素敏感性，第二个胰岛素输注期的GIR增加了21%（P = 0.048）。GFT 505还增强了肝脏胰岛素敏感性，在首次胰岛素输注期EGP的胰岛素抑制增加44%（P = 0.006）。GFT 505给药后，胰岛素抑制的血浆游离脂肪酸浓度显著降低（0.21 ± 0.07 vs. 0.27 ± 0.11 mmol/L; P = 0.006）。在骨骼肌中未诱导PPARα和PPARδ靶基因，表明GFT 505具有肝脏靶向作用。GFT 505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）。GFT 505无安全性问题或任何PPARγ活化迹象。双重PPARα/δ激动剂GFT 505是一种肝脏靶向胰岛素增敏剂，是治疗2型糖尿病和非酒精性脂肪肝的有前景的候选药物。
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.
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影响因子：
5.3
作者：
Rizza, Stefano;Cardellini, Marina;Federici, Massimo
通讯作者：
Federici, Massimo
影响因子：
8.2
作者：
Bajaj, M.;Suraamornkul, S.;DeFronzo, R. A.
通讯作者：
DeFronzo, R. A.
DOI：
10.1056/nejmoa1001282
发表时间：
2010-04-29
期刊：
The New England journal of medicine
影响因子：
--
作者：
ACCORD Study Group;Ginsberg HN;Elam MB;Lovato LC;Crouse JR 3rd;Leiter LA;Linz P;Friedewald WT;Buse JB;Gerstein HC;Probstfield J;Grimm RH;Ismail-Beigi F;Bigger JT;Goff DC Jr;Cushman WC;Simons-Morton DG;Byington RP
通讯作者：
Byington RP
影响因子：
29.4
作者：
Ratziu, Vlad;Giral, Philippe;Poynard, Thierry
通讯作者：
Poynard, Thierry
影响因子：
24
作者：
Naoumova, Rossi P.;Kindler, Heiko;Camici, Paolo G.
通讯作者：
Camici, Paolo G.