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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.

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  • Authors+Show Affiliations

    ,

    Department of Medicine and Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO.

    ,

    Department of Medicine and Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO.

    ,

    Department of Medicine and Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO.

    ,

    Department of Radiology, Washington University School of Medicine, St. Louis, MO.

    ,

    Department of Medicine and Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO.

    ,

    Department of Medicine and Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO.

    ,

    Department of Medicine and Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO.

    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.

    Source

    Diabetes 64:5 2015 May pg 1555-63

    MeSH

    Aged
    Amino Acids
    Blood Glucose
    Dietary Proteins
    Female
    Glucose Clamp Technique
    Humans
    Insulin
    Insulin Resistance
    Leucine
    Middle Aged
    Milk Proteins
    Muscle, Skeletal
    Signal Transduction
    TOR Serine-Threonine Kinases
    Whey Proteins

    Pub Type(s)

    Journal Article
    Randomized Controlled Trial

    Language

    eng

    PubMed ID

    25475435

    Citation

    Smith, Gordon I., et al. "Protein Ingestion Induces Muscle Insulin Resistance Independent of Leucine-Mediated mTOR Activation." Diabetes, vol. 64, no. 5, 2015, pp. 1555-63.
    Smith GI, Yoshino J, Stromsdorfer KL, et al. Protein Ingestion Induces Muscle Insulin Resistance Independent of Leucine-Mediated mTOR Activation. Diabetes. 2015;64(5):1555-63.
    Smith, G. I., Yoshino, J., Stromsdorfer, K. L., Klein, S. J., Magkos, F., Reeds, D. N., ... Mittendorfer, B. (2015). Protein Ingestion Induces Muscle Insulin Resistance Independent of Leucine-Mediated mTOR Activation. Diabetes, 64(5), pp. 1555-63. doi:10.2337/db14-1279.
    Smith GI, et al. Protein Ingestion Induces Muscle Insulin Resistance Independent of Leucine-Mediated mTOR Activation. Diabetes. 2015;64(5):1555-63. PubMed PMID: 25475435.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Protein Ingestion Induces Muscle Insulin Resistance Independent of Leucine-Mediated mTOR Activation. AU - Smith,Gordon I, AU - Yoshino,Jun, AU - Stromsdorfer,Kelly L, AU - Klein,Seth J, AU - Magkos,Faidon, AU - Reeds,Dominic N, AU - Klein,Samuel, AU - Mittendorfer,Bettina, Y1 - 2014/12/04/ PY - 2014/08/19/received PY - 2014/11/24/accepted PY - 2014/12/6/entrez PY - 2014/12/6/pubmed PY - 2015/6/30/medline SP - 1555 EP - 63 JF - Diabetes JO - Diabetes VL - 64 IS - 5 N2 - 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. SN - 1939-327X UR - https://www.unboundmedicine.com/medline/citation/25475435/full_citation L2 - http://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&amp;pmid=25475435 DB - PRIME DP - Unbound Medicine ER -