Leucine supplementation in rats induced a delay in muscle IR/PI3K signaling pathway associated with overall impaired glucose tolerance

• Published in: The Journal of nutritional biochemistry Vol. 22; no. 3; pp. 219 - 226
• Main Authors: Balage, Michèle, Dupont, Joëlle, Mothe-Satney, Isabelle, Tesseraud, Sophie, Mosoni, Laurent, Dardevet, Dominique
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.03.2011; New York, NY: Elsevier Science; Elsevier
• Subjects: Adipose Tissue - metabolism; Animals; Biological and medical sciences; Dietary Supplements; Feeding. Feeding behavior; Fundamental and applied biological sciences. Psychology; Glucose - metabolism; Glucose Intolerance - chemically induced; Glucose Intolerance - metabolism; Glucose tolerance; Glucose Tolerance Test; Insulin; Insulin - blood; Insulin - metabolism; Insulin Receptor Substrate Proteins - metabolism; Insulin Resistance; Leucine; Leucine - pharmacology; Life Sciences; Linear Models; Male; Muscle, Skeletal - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Rat; Rats; Rats, Wistar; Receptor, Insulin - metabolism; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Signal Transduction; Signaling; Sirolimus - pharmacology; TOR Serine-Threonine Kinases - metabolism; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Glucose tolerance; Signaling; Leucine; Rat; Insulin; Endocrinopathy; Pancreatic hormone; Rodentia; Tolerance; Glucose; Striated muscle; Signal transduction; Vertebrata; Mammalia; Animal; Supplementation; Impaired glucose tolerance; leucine; insuline; signalisation; glucose; RAT
• ISSN: 0955-2863; 1873-4847
• DOI: 10.1016/j.jnutbio.2010.02.001

Although activation of the mammalian target of rapamycin complex/p70 S6 kinase (S6K1) pathway by leucine is efficient to stimulate muscle protein synthesis, it can also exert inhibition on the early steps of insulin signaling leading to insulin resistance. We investigated the impact of 5-week leucine supplementation on insulin signaling and sensitivity in 4-month old rats fed a 15% protein diet supplemented (LEU) or not (C) with 4.5% leucine. An oral glucose tolerance test was performed in each rat at the end of the supplementation and glucose transport was measured in vitro using isolated epitrochlearis muscles incubated with 2-deoxy- d-[ 3H]-glucose under increasing insulin concentrations. Insulin signaling was assessed on gastrocnemius at the postabsorptive state or 30 and 60 min after gavage with a nutrient bolus. Tyrosine phosphorylation of IRβ, IRS1 and PI3 kinase activity were reduced in LEU group 30 min after feeding (−36%, −36% and −38% respectively, P<.05) whereas S6K1, S6rp and 4EBP1 phosphorylations were similar. Overall glucose tolerance was reduced in leucine-supplemented rats and was associated with accumulation of perirenal adipose tissue (+27%, P<.05). Conversely, in vitro insulin-response of muscle glucose transport tended to be improved in leucine-supplemented rats. In conclusion, dietary leucine supplementation in adult rats induced a delay in the postprandial stimulation in the early steps of muscle insulin signaling without muscle resistance on insulin-induced glucose uptake. However, it resulted in overall glucose intolerance linked to increased local adiposity. Further investigations are necessary to clearly define the beneficial and/or deleterious effects of chronic dietary leucine supplementation in healthy subjects.