Dual peroxisome proliferator-activated receptor α/δ agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects.
Diabetes Care
; 36(10): 2923-30, 2013 Oct.
Article
em En
| MEDLINE
| ID: mdl-23715754
ABSTRACT
OBJECTIVE:
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. RESEARCH DESIGN ANDMETHODS:
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.RESULTS:
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.CONCLUSIONS:
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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Base de dados:
MEDLINE
Assunto principal:
Propionatos
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Músculo Esquelético
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Chalconas
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PPAR alfa
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PPAR delta
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Fígado
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Obesidade
Tipo de estudo:
Clinical_trials
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Diagnostic_studies
Limite:
Adult
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article