title: Protein Ingestion Induces Muscle Insulin Resistance Independent of Leucine-Mediated mTOR Activation.
abstract: Increased plasma branched-chain amino acid concentrations are associated with insulin resistance, and intravenous amino acid infusion blunts insulin-mediated glucose disposal. We tested the hypothesis that protein ingestion impairs insulin-mediated glucose disposal by leucine-mediated mTOR signaling, which can inhibit AKT. We measured glucose disposal and muscle p-mTOR(Ser2448), p-AKT(Ser473), and p-AKT(Thr308) in 22 women during a hyperinsulinemic-euglycemic clamp procedure with and without concomitant ingestion of whey protein (0.6 g/kg fat-free mass; n = 11) or leucine that matched the amount given with whey protein (n = 11). Both whey protein and leucine ingestion raised plasma leucine concentration by approximately twofold and muscle p-mTOR(Ser2448) by ∼30% above the values observed in the control (no amino acid ingestion) studies; p-AKT(Ser473) and p-AKT(Thr308) were not affected by whey protein or leucine ingestion. Whey protein ingestion decreased insulin-mediated glucose disposal (median 38.8 [quartiles 30.8, 61.8] vs. 51.9 [41.0, 77.3] µmol glucose/µU insulin · mL(-1) · min(-1); P < 0.01), whereas ingestion of leucine did not (52.3 [43.3, 65.4] vs. 52.3 [43.9, 73.2]). These results indicate that 1) protein ingestion causes insulin resistance and could be an important regulator of postprandial glucose homeostasis and 2) the insulin-desensitizing effect of protein ingestion is not due to inhibition of AKT by leucine-mediated mTOR signaling.
authors.affiliation: Department of Medicine and Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO.
authors.forename: Gordon I
authors.initials: GI
authors.lastname: Smith
authors.affiliation: Department of Medicine and Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO.
authors.forename: Jun
authors.initials: J
authors.lastname: Yoshino
authors.affiliation: Department of Medicine and Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Stromsdorfer
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Klein
authors.affiliation: Department of Medicine and Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO.
authors.forename: Faidon
authors.initials: F
authors.lastname: Magkos
authors.affiliation: Department of Medicine and Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO.
authors.forename: Dominic N
authors.initials: DN
authors.lastname: Reeds
authors.affiliation: Department of Medicine and Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO.
authors.forename: Samuel
authors.initials: S
authors.lastname: Klein
authors.affiliation: Department of Medicine and Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO mittendb@wustl.edu.
authors.forename: Bettina
authors.initials: B
authors.lastname: Mittendorfer
mesh_terms: D000368:Aged; D000596:Amino Acids / Q000097:blood / Q000378:metabolism; D001786:Blood Glucose; D004044:Dietary Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D007930:Leucine / Q000378:metabolism*; D008875:Middle Aged; D008894:Milk Proteins / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000502:physiology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000067816:Whey Proteins
chemical_list: D000596:Amino Acids; D001786:Blood Glucose; D004044:Dietary Proteins; D007328:Insulin; D008894:Milk Proteins; D000067816:Whey Proteins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D007930:Leucine