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European Journal of Applied Physiology

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01-06-2015 | Original Article

Acute systemic insulin intolerance does not alter the response of the Akt/GSK-3 pathway to environmental hypoxia in human skeletal muscle

Authors: Gommaar D’Hulst, Lykke Sylow, Peter Hespel, Louise Deldicque

Published in: European Journal of Applied Physiology | Issue 6/2015

Abstract

Purpose

To investigate how acute environmental hypoxia regulates blood glucose and downstream intramuscular insulin signaling after a meal in healthy humans.

Methods

Fifteen subjects were exposed for 4 h to normoxia (NOR) or to normobaric hypoxia (HYP, F_iO₂ = 0.11) in a randomized order 40 min after consumption of a high glycemic meal. A muscle biopsy from m. vastus lateralis and a blood sample were taken before (T0), after 1 h (T60) and 4 h (T240) in NOR or HYP and blood glucose levels were measured before exposure and every 30 min.

Results

In HYP, blood glucose was reduced 100 min (110.1 ± 5.4 in NOR vs 89.5 ± 4.7 mg dl⁻¹ in HYP) and 130 min (98.7 ± 3.8 in NOR vs 85.6 ± 4.9 mg dl⁻¹ in HYP) after completion of a meal, which resulted in an 83 % lower AUC in HYP compared to NOR (p = 0.006). This coincided with 40 % lower GLUT4 protein in the cytosolic fraction (p = 0.013) and a tendency to increase in the crude membrane fraction (p = 0.070) in HYP compared to NOR. At T240, blood glucose concentration was similar between HYP and NOR, whereas plasma insulin as well as phosphorylation of muscle Akt and GSK-3 was ~2-fold higher in HYP compared to NOR (p < 0.05). In contrast, Rac1 protein was less abundant in the membrane fraction in HYP compared to NOR (p = 0.003), reflecting lower activation.

Conclusion

Acute environmental hypoxia initially reduced blood glucose response to a meal, possibly via an increase in GLUT4 abundance at the sarcolemmal membrane. Later on, whole body insulin intolerance developed independently of defects in conventional insulin signaling in skeletal muscle.

Alvarez-Tejado M, Naranjo-Suarez S, Jimenez C, Carrera AC, Landazuri MO, del PL (2001) Hypoxia induces the activation of the phosphatidylinositol 3-kinase/Akt cell survival pathway in PC12 cells: protective role in apoptosis. J Biol Chem 276:22368–22374CrossRefPubMed

Brozinick JT Jr, Reynolds TH, Dean D, Cartee G, Cushman SW (1999) 1-[N, O-bis-(5-isoquinolinesulphonyl)-N-methyl-L-tyrosyl]-4- phenylpiperazine (KN-62), an inhibitor of calcium-dependent camodulin protein kinase II, inhibits both insulin- and hypoxia-stimulated glucose transport in skeletal muscle. Biochem J 339(Pt 3):533–540CrossRefPubMedCentralPubMed

Bustelo XR, Sauzeau V, Berenjeno IM (2007) GTP-binding proteins of the Rho/Rac family: regulation, effectors and functions in vivo. BioEssays 29:356–370CrossRefPubMedCentralPubMed

Cartee GD, Douen AG, Ramlal T, Klip A, Holloszy JO (1991) Stimulation of glucose transport in skeletal muscle by hypoxia. J Appl Physiol 70:1593–1600PubMed

Castillo O, Woolcott OO, Gonzales E, Tello V, Tello L, Villarreal C, Mendez N, Damas L, Florentini E (2007) Residents at high altitude show a lower glucose profile than sea-level residents throughout 12-hour blood continuous monitoring. High Alt Med Biol 8:307–311CrossRefPubMed

Catalucci D, Latronico MV, Ceci M, Rusconi F, Young HS, Gallo P, Santonastasi M, Bellacosa A, Brown JH, Condorelli G (2009) Akt increases sarcoplasmic reticulum Ca2 + cycling by direct phosphorylation of phospholamban at Thr17. J Biol Chem 284:28180–28187CrossRefPubMedCentralPubMed

Chiu TT, Jensen TE, Sylow L, Richter EA, Klip A (2011) Rac1 signalling towards GLUT4/glucose uptake in skeletal muscle. Cell Signal 23:1546–1554CrossRefPubMed

DeFronzo RA, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP (1981) The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes 30:1000–1007CrossRefPubMed

D’Hulst G, Jamart C, Van TR, Hespel P, Francaux M, Deldicque L (2013) Effect of acute environmental hypoxia on protein metabolism in human skeletal muscle. Acta Physiol (Oxf) 208:251–264CrossRef

Dongiovanni P, Valenti L, Ludovica FA, Gatti S, Cairo G, Fargion S (2008) Iron depletion by deferoxamine up-regulates glucose uptake and insulin signaling in hepatoma cells and in rat liver. Am J Pathol 172:738–747CrossRefPubMedCentralPubMed

Du J, Xu R, Hu Z, Tian Y, Zhu Y, Gu L, Zhou L (2011) PI3 K and ERK-induced Rac1 activation mediates hypoxia-induced HIF-1alpha expression in MCF-7 breast cancer cells. PLoS One 6:e25213CrossRefPubMedCentralPubMed

Emerling BM, Weinberg F, Snyder C, Burgess Z, Mutlu GM, Viollet B, Budinger GR, Chandel NS (2009) Hypoxic activation of AMPK is dependent on mitochondrial ROS but independent of an increase in AMP/ATP ratio. Free Radic Biol Med 46:1386–1391CrossRefPubMedCentralPubMed

Favier FB, Costes F, Defour A, Bonnefoy R, Lefai E, Bauge S, Peinnequin A, Benoit H, Freyssenet D (2010) Downregulation of Akt/mammalian target of rapamycin pathway in skeletal muscle is associated with increased REDD1 expression in response to chronic hypoxia. Am J Physiol Regul Integr Comp Physiol 298:R1659–R1666CrossRefPubMed

Freckmann G, Baumstark A, Jendrike N, Zschornack E, Kocher S, Tshiananga J, Heister F, Haug C (2010) System accuracy evaluation of 27 blood glucose monitoring systems according to DIN EN ISO 15197. Diabetes Technol Ther 12:221–231CrossRefPubMed

Gamboa JL, Garcia-Cazarin ML, Andrade FH (2011) Chronic hypoxia increases insulin-stimulated glucose uptake in mouse soleus muscle. Am J Physiol Regul Integr Comp Physiol 300:R85–R91CrossRefPubMedCentralPubMed

Gkourogianni A, Kosteria I, Telonis AG, Margeli A, Mantzou E, Konsta M, Loutradis D, Mastorakos G, Papassotiriou I, Klapa MI, Kanaka-Gantenbein C, Chrousos GP (2014) Plasma metabolomic profiling suggests early indications for predisposition to latent insulin resistance in children conceived by ICSI. PLoS One 9:e94001CrossRefPubMedCentralPubMed

Gualano B, DE Salles PV, Roschel H, Artioli GG, Neves M Jr, De Sa Pinto AL, da Silva ME, Cunha MR, Otaduy MC, Leite CC, Ferreira JC, Pereira RM, Brum PC, Bonfa E, Lancha AH Jr (2011) Creatine in type 2 diabetes: a randomized, double-blind, placebo-controlled trial. Med Sci Sports Exerc 43:770–778CrossRefPubMed

Hayashi T, Hirshman MF, Fujii N, Habinowski SA, Witters LA, Goodyear LJ (2000) Metabolic stress and altered glucose transport: activation of AMP-activated protein kinase as a unifying coupling mechanism. Diabetes 49:527–531CrossRefPubMed

Kelly KR, Williamson DL, Fealy CE, Kriz DA, Krishnan RK, Huang H, Ahn J, Loomis JL, Kirwan JP (2010) Acute altitude-induced hypoxia suppresses plasma glucose and leptin in healthy humans. Metabolism 59:200–205CrossRefPubMedCentralPubMed

Larsen JJ, Hansen JM, Olsen NV, Galbo H, Dela F (1997) The effect of altitude hypoxia on glucose homeostasis in men. J Physiol 504(Pt 1):241–249CrossRefPubMedCentralPubMed

Lecoultre V, Peterson CM, Covington JD, Ebenezer PJ, Frost EA, Schwarz JM, Ravussin E (2013) Ten nights of moderate hypoxia improves insulin sensitivity in obese humans. Diabetes Care 36:e197–e198CrossRefPubMedCentralPubMed

Marquez JL, Rubinstein S, Fattor JA, Shah O, Hoffman AR, Friedlander AL (2013) Cyclic hypobaric hypoxia improves markers of glucose metabolism in middle-aged men. High Alt Med Biol 14:263–272CrossRefPubMed

Masschelein E, Van Thienen R, D’Hulst G, Hespel P, Thomis M, Deldicque L (2014) Acute environmental hypoxia induces LC3 lipidation in a genotype-dependent manner. FASEB J 28:1022–1034CrossRefPubMed

Mattagajasingh SN, Yang XP, Irani K, Mattagajasingh I, Becker LC (2012) Activation of Stat3 in endothelial cells following hypoxia-reoxygenation is mediated by Rac1 and protein Kinase C. Biochim Biophys Acta 1823:997–1006CrossRefPubMedCentralPubMed

Mollen KP, McCloskey CA, Tanaka H, Prince JM, Levy RM, Zuckerbraun BS, Billiar TR (2007) Hypoxia activates c-Jun N-terminal kinase via Rac1-dependent reactive oxygen species production in hepatocytes. Shock 28:270–277CrossRefPubMed

Mu J, Brozinick JT Jr, Valladares O, Bucan M, Birnbaum MJ (2001) A role for AMP-activated protein kinase in contraction- and hypoxia-regulated glucose transport in skeletal muscle. Mol Cell 7:1085–1094CrossRefPubMed

Nielsen JN, Wojtaszewski JF (2004) Regulation of glycogen synthase activity and phosphorylation by exercise. Proc Nutr Soc 63:233–237CrossRefPubMed

Oltmanns KM, Gehring H, Rudolf S, Schultes B, Rook S, Schweiger U, Born J, Fehm HL, Peters A (2004) Hypoxia causes glucose intolerance in humans. Am J Respir Crit Care Med 169:1231–1237CrossRefPubMed

Osei K, Falko JM, O’Dorisio TM, Adam DR (1984) Decreased serum C-peptide/insulin molar ratios after oral glucose ingestion in hyperthyroid patients. Diabetes Care 7:471–475CrossRefPubMed

Ostman E, Granfeldt Y, Persson L, Bjorck I (2005) Vinegar supplementation lowers glucose and insulin responses and increases satiety after a bread meal in healthy subjects. Eur J Clin Nutr 59:983–988CrossRefPubMed

Peltonen GL, Scalzo RL, Schweder MM, Larson DG, Luckasen GJ, Irwin D, Hamilton KL, Schroeder T, Bell C (2012) Sympathetic inhibition attenuates hypoxia induced insulin resistance in healthy adult humans. J Physiol 590:2801–2809CrossRefPubMedCentralPubMed

Radu M, Semenova G, Kosoff R, Chernoff J (2014) PAK signalling during the development and progression of cancer. Nat Rev Cancer 14:13–25CrossRefPubMedCentralPubMed

Reaven GM (1979) Effects of differences in amount and kind of dietary carbohydrate on plasma glucose and insulin responses in man. Am J Clin Nutr 32:2568–2578PubMed

Regazzetti C, Peraldi P, Gremeaux T, Najem-Lendom R, Ben-Sahra I, Cormont M, Bost F, Le Marchand-Brustel Y, Tanti JF, Giorgetti-Peraldi S (2009) Hypoxia decreases insulin signaling pathways in adipocytes. Diabetes 58:95–103CrossRefPubMedCentralPubMed

Richter EA, Hargreaves M (2013) Exercise, GLUT4, and Skeletal Muscle Glucose Uptake. Physiol Rev 93:993–1017CrossRefPubMed

Roberts AC, Reeves JT, Butterfield GE, Mazzeo RS, Sutton JR, Wolfel EE, Brooks GA (1996) Altitude and beta-blockade augment glucose utilization during submaximal exercise. J Appl Physiol 80(2):605–615PubMed

Sakagami H, Makino Y, Mizumoto K, Isoe T, Takeda Y, Watanabe J, Fujita Y, Takiyama Y, Abiko A, Haneda M (2014) Loss of HIF-1alpha impairs GLUT4 translocation and glucose uptake by the skeletal muscle cells. Am J Physiol Endocrinol Metab 306:E1065–E1076CrossRefPubMed

Sandstrom ME, Zhang SJ, Bruton J, Silva JP, Reid MB, Westerblad H, Katz A (2006) Role of reactive oxygen species in contraction-mediated glucose transport in mouse skeletal muscle. J Physiol 575:251–262CrossRefPubMedCentralPubMed

Satoh T (2014) Rho GTPases in insulin-stimulated glucose uptake. Small GTPases 5:e28102CrossRefPubMedCentralPubMed

Sigal RJ, Kenny GP, Wasserman DH, Castaneda-Sceppa C, White RD (2006) Physical activity/exercise and type 2 diabetes: a consensus statement from the American Diabetes Association. Diabetes Care 29:1433–1438CrossRefPubMed

Singh B, Saxena A (2010) Surrogate markers of insulin resistance: a review. World J Diabetes 1:36–47CrossRefPubMedCentralPubMed

Sylow L, Jensen TE, Kleinert M, Mouatt JR, Maarbjerg SJ, Jeppesen J, Prats C, Chiu TT, Boguslavsky S, Klip A, Schjerling P, Richter EA (2013a) Rac1 is a novel regulator of contraction-stimulated glucose uptake in skeletal muscle. Diabetes 62:1139–1151CrossRefPubMedCentralPubMed

Sylow L, Jensen TE, Kleinert M, Hojlund K, Kiens B, Wojtaszewski J, Prats C, Schjerling P, Richter EA (2013b) Rac1 signaling is required for insulin-stimulated glucose uptake and is dysregulated in insulin-resistant murine and human skeletal muscle. Diabetes 62:1865–1875CrossRefPubMedCentralPubMed

Sylow L, Kleinert M, Pehmoller C, Prats C, Chiu TT, Klip A, Richter EA, Jensen TE (2014) Akt and Rac1 signaling are jointly required for insulin-stimulated glucose uptake in skeletal muscle and downregulated in insulin resistance. Cell Signal 26:323–331CrossRefPubMed

Taniguchi CM, Finger EC, Krieg AJ, Wu C, Diep AN, LaGory EL, Wei K, McGinnis LM, Yuan J, Kuo CJ, Giaccia AJ (2013) Cross-talk between hypoxia and insulin signaling through Phd3 regulates hepatic glucose and lipid metabolism and ameliorates diabetes. Nat Med 19:1325–1330CrossRefPubMedCentralPubMed

Treebak JT, Pehmoller C, Kristensen JM, Kjobsted R, Birk JB, Schjerling P, Richter EA, Goodyear LJ, Wojtaszewski JF (2014) Acute exercise and physiological insulin induce distinct phosphorylation signatures on TBC1D1 and TBC1D4 proteins in human skeletal muscle. J Physiol 592:351–375CrossRefPubMedCentralPubMed

Van Thienen R, D’Hulst G, Deldicque L, Hespel P (2014) Biochemical artifacts in experiments involving repeated biopsies in the same muscle. Physiol Rep 2:e00286CrossRefPubMedCentralPubMed

Vittone L, Mundina-Weilenmann C, Mattiazzi A (2008) Phospholamban phosphorylation by CaMKII under pathophysiological conditions. Front Biosci 13:5988–6005CrossRefPubMed

Wojtaszewski JF, Laustsen JL, Derave W, Richter EA (1998) Hypoxia and contractions do not utilize the same signaling mechanism in stimulating skeletal muscle glucose transport. Biochim Biophys Acta 1380:396–404CrossRefPubMed

Wolever TM, Bolognesi C (1996) Prediction of glucose and insulin responses of normal subjects after consuming mixed meals varying in energy, protein, fat, carbohydrate and glycemic index. J Nutr 126:2807–2812PubMed

Wright DC, Geiger PC, Holloszy JO, Han DH (2005) Contraction- and hypoxia-stimulated glucose transport is mediated by a Ca2 + -dependent mechanism in slow-twitch rat soleus muscle. Am J Physiol Endocrinol Metab 288:E1062–E1066CrossRefPubMed

Title: Acute systemic insulin intolerance does not alter the response of the Akt/GSK-3 pathway to environmental hypoxia in human skeletal muscle
Authors: Gommaar D’Hulst
Lykke Sylow
Peter Hespel
Louise Deldicque
Publication date: 01-06-2015
Publisher: Springer Berlin Heidelberg
Published in: European Journal of Applied Physiology / Issue 6/2015
Print ISSN: 1439-6319
Electronic ISSN: 1439-6327
DOI: https://doi.org/10.1007/s00421-015-3103-2

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Springer Medicine

Acute systemic insulin intolerance does not alter the response of the Akt/GSK-3 pathway to environmental hypoxia in human skeletal muscle

Abstract

Purpose

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

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