Dual Peroxisome Proliferator–Activated Receptor α/δ Agonist GFT505 Improves Hepatic and Peripheral Insulin Sensitivity in Abdominally Obese Subjects

Abstract

OBJECTIVEThe 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.RESEARCH DESIGN AND METHODSTwenty-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.RESULTSGFT505 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.CONCLUSIONSThe 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.

Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease

“…In phase II clinical trials, GFT505 treatment decreases plasma concentrations of ALT, cGT, and ALP, in MetS patients [9]. Considering its ability to improve peripheral insulin sensitivity and lower plasma FFA levels, likely via PPARd activation, in abdominally obese patients, as well as its TG lowering/HDL increasing activity in subjects with combined dyslipidemia, GFT505 is a promising drug candidate for the treatment of diseases linked to IR, such as T2DM and NASH [146,147].…”

Metabolic syndrome and nonalcoholic fatty liver disease: Is insulin resistance the link?

“…In addition to PPARg agonists, several studies have investigated the role of PPARa activation in NAFLD since it is involved in lipid and glucose metabolism (Auboeuf et al, 1997;Cariou et al, 2013;Fruchart, 2013;Shiri-Sverdlov et al, 2006). Recently, Pawlak et al, using a pharmacological approach, showed that activation of PPARa inhibited hepatic inflammation and the transition from steatosis toward NASH through a direct, anti-inflammatory mechanism independent of its lipid handling properties (Pawlak et al, 2014).…”

Targeting SREBPs for treatment of the metabolic syndrome

“…Examples include peroxisome proliferatoractivated receptor (PPAR) a,g or PPAR a,d dual agonists [26,27]. Potential targets for such a therapy are the SREBP transcription factors.…”