Lipid Metabolism Links Nutrient-Exercise Timing to Insulin Sensitivity in Men Classified as Overweight or Obese

Robert M Edinburgh, Helen E Bradley, Nurul-Fadhilah Abdullah, Scott L Robinson, Oliver J Chrzanowski-Smith, Jean-Philippe Walhin, Sophie Joanisse, Konstantinos N Manolopoulos, Andrew Philp, Aaron Hengist, Adrian Chabowski, Frances M Brodsky, Francoise Koumanov, James A Betts, Dylan Thompson, Gareth A Wallis, Javier T Gonzalez, Robert M Edinburgh, Helen E Bradley, Nurul-Fadhilah Abdullah, Scott L Robinson, Oliver J Chrzanowski-Smith, Jean-Philippe Walhin, Sophie Joanisse, Konstantinos N Manolopoulos, Andrew Philp, Aaron Hengist, Adrian Chabowski, Frances M Brodsky, Francoise Koumanov, James A Betts, Dylan Thompson, Gareth A Wallis, Javier T Gonzalez

Abstract

Context: Pre-exercise nutrient availability alters acute metabolic responses to exercise, which could modulate training responsiveness.

Objective: To assess acute and chronic effects of exercise performed before versus after nutrient ingestion on whole-body and intramuscular lipid utilization and postprandial glucose metabolism.

Design: (1) Acute, randomized, crossover design (Acute Study); (2) 6-week, randomized, controlled design (Training Study).

Setting: General community.

Participants: Men with overweight/obesity (mean ± standard deviation, body mass index: 30.2 ± 3.5 kg⋅m-2 for Acute Study, 30.9 ± 4.5 kg⋅m-2 for Training Study).

Interventions: Moderate-intensity cycling performed before versus after mixed-macronutrient breakfast (Acute Study) or carbohydrate (Training Study) ingestion.

Results: Acute Study-exercise before versus after breakfast consumption increased net intramuscular lipid utilization in type I (net change: -3.44 ± 2.63% versus 1.44 ± 4.18% area lipid staining, P < 0.01) and type II fibers (-1.89 ± 2.48% versus 1.83 ± 1.92% area lipid staining, P < 0.05). Training Study-postprandial glycemia was not differentially affected by 6 weeks of exercise training performed before versus after carbohydrate intake (P > 0.05). However, postprandial insulinemia was reduced with exercise training performed before but not after carbohydrate ingestion (P = 0.03). This resulted in increased oral glucose insulin sensitivity (25 ± 38 vs -21 ± 32 mL⋅min-1⋅m-2; P = 0.01), associated with increased lipid utilization during exercise (r = 0.50, P = 0.02). Regular exercise before nutrient provision also augmented remodeling of skeletal muscle phospholipids and protein content of the glucose transport protein GLUT4 (P < 0.05).

Conclusions: Experiments investigating exercise training and metabolic health should consider nutrient-exercise timing, and exercise performed before versus after nutrient intake (ie, in the fasted state) may exert beneficial effects on lipid utilization and reduce postprandial insulinemia.

Trial registration: ClinicalTrials.gov NCT02744183 NCT02397304.

© Endocrine Society 2019.

Figures

Figure 1.
Figure 1.
Protocol schematic for the Training Study.
Figure 2.
Figure 2.
Plasma glucose (A), serum insulin (B), plasma glycerol (C), and plasma NEFA (D) concentrations and whole-body carbohydrate (E) and lipid (F) utilization rates. Muscle was sampled pre-exercise and immediately postexercise (vastus lateralis) to assess mixed-muscle glycogen (G) and fiber-type specific intramuscular lipid (IMTG) utilization (H & I). Panel J shows representative images from IMTG staining where IMTG (stained green) in combination with dystrophin (to identify the cell border and stained red) is shown from skeletal muscle samples of a representative participant for the carbohydrate-exercise and exercise-carbohydrate trials. White I shows type 1 fibers, and all other fibers are assumed to be type II. Yellow bars are scale (50 μm). All data are presented as means ± 95% confidence interval. For panels A–F, n = 12 men classified as overweight or obese; for panels G, H, and I, n = 9. The difference between PRE versus POST exercise is designated by a; and the difference between BREAKFAST-EXERCISE versus EXERCISE-BREAKFAST is designated by b. (P < 0.05).
Figure 3.
Figure 3.
Skeletal muscle mRNA expression responses to a single bout of exercise before versus after nutrient provision (in the form of breakfast) in overweight men (n = 8). Muscle was sample pre-exercise and at 3 hours postexercise (vastus lateralis) to assess the intramuscular gene expression responses to exercise. The difference between EXERCISE-BREAKFAST vs BREAKFAST-EXERCISE. (P < 0.05).
Figure 4.
Figure 4.
Whole-body rates of lipid utilization (A), carbohydrate utilization (B), the respiratory exchange ratio (C), and energy expenditure (D) during every exercise session in a 6-week training intervention with exercise performed after (CARBOHYDRATE-EXERCISE) or before carbohydrate intake (EXERCISE-CARBOHYDRATE). All data are presented as means ± 95% confidence interval. For control, n = 9; for carbohydrate-exercise, n = 12; and for exercise-carbohydrate, n = 9 men classified as overweight or obese.
Figure 5.
Figure 5.
The change in the plasma glucose area under the curve (AUC; A), the change in the plasma insulin AUC (B), the change in the oral glucose insulin sensitivity index (OGIS; C), and the change in the postprandial plasma C-peptide: insulin ratio (D) in response to a 6-week training intervention with exercise performed after (CARBOHYDRATE-EXERCISE) or before carbohydrate intake (EXERCISE-CARBOHYDRATE). Panels E and F display Pearson correlations between changes in the OGIS index and cumulative lipid utilization and energy expenditure throughout the exercise training intervention, respectively. All data are presented as means ± 95% confidence interval. For control, n = 9; for carbohydrate-exercise, n = 12; and for exercise-carbohydrate, n = 9 men classified as overweight or obese. The shaded grey area represents the 95% confidence bands for the regression line. The difference between CONTROL versus EXERCISE-CARBOHYDRATE is designated by a. The difference between CARBOHYDRATE-EXERCISE versus EXERCISE-CARBOHYDRATE is designated by b (P < 0.05).
Figure 6.
Figure 6.
Body mass (A), the waist-to-hip ratio (B), peak fat utilization rates during an incremental exercise test (C), and (D) whole-body oxidative capacity (VO2peak) at baseline, week 3, and week 6 of an intervention in control (no-exercise), carbohydrate-exercise, and exercise-carbohydrate groups. All data are presented as means ± 95% confidence interval. For control, n = 9; for carbohydrate-exercise, n = 12; and for exercise-carbohydrate, n = 9 men classified as overweight or obese. The difference between CONTROL versus CARBOHYDRATE-EXERCISE is designated by a. The difference between CONTROL versus EXERCISE-CARBOHYDRATE is designated by b (P < 0.05).
Figure 7.
Figure 7.
A Pearson correlation between postprandial insulinemia with the change in the proportion of saturated fatty acids in skeletal muscle phospholipids. All data are presented as means ± 95% confidence interval. For control, n = 6; for carbohydrate-exercise, n = 9; and for exercise-carbohydrate, n = 5 men classified as overweight or obese. The shaded area represents the 95% confidence bands for the regression line.
Figure 8.
Figure 8.
Pre- to postintervention changes in the levels of energy-sensing proteins and proteins involved in insulin-sensitive GLUT4 trafficking in skeletal muscle (A and B). Representative immunoblots are shown (C) for each protein (including those reported in text but not shown in this figure) from the same representative participant as well as the loading controls used. All data are presented as means ± 95% confidence interval, and the dotted horizontal line represents the baseline (pre-intervention) values. For control, n = 6; for carbohydrate-exercise, n = 9; and for exercise-carbohydrate, n = 5 men classified as overweight or obese. The difference between CONTROL versus EXERCISE-CARBOHYDRATE is designated by a; the difference between CARBOHYDRATE-EXERCISE versus EXERCISE-CARBOHYDRATE is designated by b; and the difference between CONTROL versus CARBOHYDRATE-EXERCISE is designated by c (P < 0.05).

References

    1. DeFronzo RA, Gunnarsson R, Björkman O, Olsson M, Wahren J. Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. J Clin Invest. 1985;76(1):149–155.
    1. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37(12):1595–1607.
    1. Tricò D, Natali A, Arslanian S, Mari A, Ferrannini E. Identification, pathophysiology, and clinical implications of primary insulin hypersecretion in nondiabetic adults and adolescents. JCI Insight. 2018;3(24):e124912.
    1. Must A, Spadano J, Coakley EH, Field AE, Colditz G, Dietz WH. The disease burden associated with overweight and obesity. JAMA. 1999;282(16):1523–1529.
    1. McLaughlin T, Lamendola C, Liu A, Abbasi F. Preferential fat deposition in subcutaneous versus visceral depots is associated with insulin sensitivity. J Clin Endocrinol Metab. 2011;96(11):E1756–E1760.
    1. Borghouts LB, Keizer HA. Exercise and insulin sensitivity: a review. Int J Sports Med. 2000;21(1):1–12.
    1. Sylow L, Richter EA. Current advances in our understanding of exercise as medicine in metabolic disease. Curr Opin Physiol. 2019;12:12–19.
    1. Lund S, Pryor PR, Ostergaard S, Schmitz O, Pedersen O, Holman GD. Evidence against protein kinase B as a mediator of contraction-induced glucose transport and GLUT4 translocation in rat skeletal muscle. FEBS Lett. 1998;425(3):472–474.
    1. Geiger PC, Han DH, Wright DC, Holloszy JO. How muscle insulin sensitivity is regulated: testing of a hypothesis. Am J Physiol Endocrinol Metab. 2006;291(6):E1258–E1263.
    1. Hansen PA, Wang W, Marshall BA, Holloszy JO, Mueckler M. Dissociation of GLUT4 translocation and insulin-stimulated glucose transport in transgenic mice overexpressing GLUT1 in skeletal muscle. J Biol Chem. 1998;273(29):18173–18179.
    1. Holloszy JO, Coyle EF. Adaptations of skeletal muscle to endurance exercise and their metabolic consequences. J Appl Physiol Respir Environ Exerc Physiol. 1984;56(4):831–838.
    1. O’Gorman DJ, Karlsson HK, McQuaid S, et al. . Exercise training increases insulin-stimulated glucose disposal and GLUT4 (SLC2A4) protein content in patients with type 2 diabetes. Diabetologia. 2006;49(12):2983–2992.
    1. Andersson A, Sjödin A, Olsson R, Vessby B. Effects of physical exercise on phospholipid fatty acid composition in skeletal muscle. Am J Physiol. 1998;274(3):E432–E438.
    1. Helge JW, Dela F. Effect of training on muscle triacylglycerol and structural lipids: a relation to insulin sensitivity? Diabetes. 2003;52(8):1881–1887.
    1. de Lannoy L, Clarke J, Stotz PJ, Ross R. Effects of intensity and amount of exercise on measures of insulin and glucose: analysis of inter-individual variability. PLoS One. 2017;12(5):e0177095.
    1. Atkinson G, Batterham AM. True and false interindividual differences in the physiological response to an intervention. Exp Physiol. 2015;100(6):577–588.
    1. Chen YC, Travers RL, Walhin JP, et al. . Feeding influences adipose tissue responses to exercise in overweight men. Am J Physiol Endocrinol Metab. 2017;313(1):E84–E93.
    1. Edinburgh RM, Hengist A, Smith HA, et al. . Preexercise breakfast ingestion versus extended overnight fasting increases postprandial glucose flux after exercise in healthy men. Am J Physiol Endocrinol Metab. 2018;315(5):E1062–E1074.
    1. Gonzalez JT, Veasey RC, Rumbold PL, Stevenson EJ. Breakfast and exercise contingently affect postprandial metabolism and energy balance in physically active males. Br J Nutr. 2013;110(4):721–732.
    1. Wallis GA, Gonzalez JT. Is exercise best served on an empty stomach? Proc Nutr Soc. 2019;78(1):110–117.
    1. De Bock K, Richter EA, Russell AP, et al. . Exercise in the fasted state facilitates fibre type-specific intramyocellular lipid breakdown and stimulates glycogen resynthesis in humans. J Physiol. 2005;564(Pt 2):649–660.
    1. Cluberton LJ, McGee SL, Murphy RM, Hargreaves M. Effect of carbohydrate ingestion on exercise-induced alterations in metabolic gene expression. J Appl Physiol (1985). 2005;99(4):1359–1363.
    1. Civitarese AE, Hesselink MK, Russell AP, Ravussin E, Schrauwen P. Glucose ingestion during exercise blunts exercise-induced gene expression of skeletal muscle fat oxidative genes. Am J Physiol Endocrinol Metab. 2005;289(6):E1023–E1029.
    1. Stocks B, Dent JR, Ogden HB, Zemp M, Philp A. Postexercise skeletal muscle signaling responses to moderate- to high-intensity steady-state exercise in the fed or fasted state. Am J Physiol Endocrinol Metab. 2019;316(2):E230–E238.
    1. Van Proeyen K, Szlufcik K, Nielens H, et al. . Training in the fasted state improves glucose tolerance during fat-rich diet. J Physiol. 2010;588(Pt 21):4289–4302.
    1. Burke LM, Hawley JA. Swifter, higher, stronger: what’s on the menu? Science. 2018;362(6416):781–787.
    1. Gonzalez JT, Richardson JD, Chowdhury EA, et al. . Molecular adaptations of adipose tissue to 6 weeks of morning fasting vs. daily breakfast consumption in lean and obese adults. J Physiol. 2018;596(4):609–622.
    1. Farah NM, Gill JM. Effects of exercise before or after meal ingestion on fat balance and postprandial metabolism in overweight men. Br J Nutr. 2013;109(12):2297–2307.
    1. Gillen JB, Percival ME, Ludzki A, Tarnopolsky MA, Gibala MJ. Interval training in the fed or fasted state improves body composition and muscle oxidative capacity in overweight women. Obesity (Silver Spring). 2013;21(11):2249–2255.
    1. Food and Agriculture Organization. Human energy requirements. Report of a Joint FAO/WHO/UNU Expert Consultation; 17–24 October 2001; Rome. . Accessed 3 April 2019.
    1. Borg GA. Perceived exertion: a note on “history” and methods. Med Sci Sports. 1973;5(2):90–93.
    1. Brouns F, Bjorck I, Frayn KN, et al. . Glycaemic index methodology. Nutr Res Rev. 2005;18(1):145–171.
    1. Gonzalez JT, Fuchs CJ, Smith FE, et al. . Ingestion of glucose or sucrose prevents liver but not muscle glycogen depletion during prolonged endurance-type exercise in trained cyclists. Am J Physiol Endocrinol Metab. 2015;309(12):E1032–E1039.
    1. Fletcher G, Eves FF, Glover EI, et al. . Dietary intake is independently associated with the maximal capacity for fat oxidation during exercise. Am J Clin Nutr. 2017;105(4):864–872.
    1. Edinburgh RM, Hengist A, Smith HA, et al. . Prior exercise alters the difference between arterialised and venous glycaemia: implications for blood sampling procedures. Br J Nutr. 2017;117(10):1414–1421.
    1. Edinburgh R, Bradley H, Abdullah N, et al. . Dataset for “Lipid metabolism links nutrient-exercise timing to insulin sensitivity in overweight men”. University of Bath Research Data Archive; 10.15125/BATH-00672 Accessed 27 September 2019.
    1. Compher C, Frankenfield D, Keim N, Roth-Yousey L; Evidence Analysis Working Group Best practice methods to apply to measurement of resting metabolic rate in adults: a systematic review. J Am Diet Assoc. 2006;106(6):881–903.
    1. Frayn KN. Calculation of substrate oxidation rates in vivo from gaseous exchange. J Appl Physiol Respir Environ Exerc Physiol. 1983;55(2):628–634.
    1. Jeukendrup AE, Wallis GA. Measurement of substrate oxidation during exercise by means of gas exchange measurements. Int J Sports Med. 2005;26 Suppl 1:S28–S37.
    1. Thompson D, Batterham AM, Bock S, Robson C, Stokes K. Assessment of low-to-moderate intensity physical activity thermogenesis in young adults using synchronized heart rate and accelerometry with branched-equation modeling. J Nutr. 2006;136(4):1037–1042.
    1. Villars C, Bergouignan A, Dugas J, et al. . Validity of combining heart rate and uniaxial acceleration to measure free-living physical activity energy expenditure in young men. J Appl Physiol (1985). 2012;113(11):1763–1771.
    1. Brage S, Westgate K, Franks PW, et al. . Estimation of free-living energy expenditure by heart rate and movement sensing: a doubly-labelled water study. PLoS One. 2015;10(9):e0137206.
    1. Mari A, Pacini G, Brazzale AR, Ahrén B. Comparative evaluation of simple insulin sensitivity methods based on the oral glucose tolerance test. Diabetologia. 2005;48(4):748–751.
    1. Perry CG, Lally J, Holloway GP, Heigenhauser GJ, Bonen A, Spriet LL. Repeated transient mRNA bursts precede increases in transcriptional and mitochondrial proteins during training in human skeletal muscle. J Physiol. 2010;588(Pt 23):4795–4810.
    1. Ehrenborg E, Krook A. Regulation of skeletal muscle physiology and metabolism by peroxisome proliferator-activated receptor delta. Pharmacol Rev. 2009;61(3):373–393.
    1. Russell AP, Hesselink MK, Lo SK, Schrauwen P. Regulation of metabolic transcriptional co-activators and transcription factors with acute exercise. Faseb J. 2005;19(8):986–988.
    1. Polonsky KS, Rubenstein AH. C-peptide as a measure of the secretion and hepatic extraction of insulin. Pitfalls and limitations. Diabetes. 1984;33(5):486–494.
    1. Mari A, Pacini G, Murphy E, Ludvik B, Nolan JJ. A model-based method for assessing insulin sensitivity from the oral glucose tolerance test. Diabetes Care. 2001;24(3):539–548.
    1. Brinkmann C, Weh-Gray O, Brixius K, Bloch W, Predel HG, Kreutz T. Effects of exercising before breakfast on the health of T2DM patients—a randomized controlled trial. Scand J Med Sci Sport. 2019;29(12):1930–1936.
    1. Bergman BC, Brooks GA. Respiratory gas-exchange ratios during graded exercise in fed and fasted trained and untrained men. J Appl Physiol (1985). 1999;86(2):479–487.
    1. Vessby B, Tengblad S, Lithell H. Insulin sensitivity is related to the fatty acid composition of serum lipids and skeletal muscle phospholipids in 70-year-old men. Diabetologia. 1994;37(10):1044–1050.
    1. Helge JW, Wu BJ, Willer M, Daugaard JR, Storlien LH, Kiens B. Training affects muscle phospholipid fatty acid composition in humans. J Appl Physiol (1985). 2001;90(2):670–677.
    1. Bergouignan A, Trudel G, Simon C, et al. . Physical inactivity differentially alters dietary oleate and palmitate trafficking. Diabetes. 2009;58(2):367–376.
    1. Lefai E, Blanc S, Momken I, et al. . Exercise training improves fat metabolism independent of total energy expenditure in sedentary overweight men, but does not restore lean metabolic phenotype. Int J Obes (Lond). 2017;41(12):1728–1736.
    1. Handschin C, Spiegelman BM. Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism. Endocr Rev. 2006;27(7):728–735.
    1. Wu Z, Puigserver P, Andersson U, et al. . Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell. 1999;98(1):115–124.
    1. Ojuka EO, Jones TE, Nolte LA, et al. . Regulation of GLUT4 biogenesis in muscle: evidence for involvement of AMPK and Ca(2+). Am J Physiol Endocrinol Metab. 2002;282(5):E1008–E1013.
    1. Frøsig C, Jørgensen SB, Hardie DG Richter EA, Wojtaszewski JF. 5′-AMP-activated protein kinase activity and protein expression are regulated by endurance training in human skeletal muscle. Am J Physiol Endocrinol Metab. 2004;286(3):411–417.
    1. Friedrichsen M, Mortensen B, Pehmøller C, Birk JB, Wojtaszewski JF. Exercise-induced AMPK activity in skeletal muscle: role in glucose uptake and insulin sensitivity. Mol Cell Endocrinol. 2013;366(2):204–214.
    1. Richter EA, Hargreaves M. Exercise, GLUT4, and skeletal muscle glucose uptake. Physiol Rev. 2013;93(3):993–1017.
    1. Leturque A, Loizeau M, Vaulont S, Salminen M, Girard J. Improvement of insulin action in diabetic transgenic mice selectively overexpressing GLUT4 in skeletal muscle. Diabetes. 1996;45(1):23–27.
    1. Watt MJ, Holmes AG, Pinnamaneni SK, et al. . Regulation of HSL serine phosphorylation in skeletal muscle and adipose tissue. Am J Physiol Endocrinol Metab. 2006;290(3):E500–E508.
    1. Wojtaszewski JF, Birk JB, Frøsig C, Holten M, Pilegaard H, Dela F. 5’AMP activated protein kinase expression in human skeletal muscle: effects of strength training and type 2 diabetes. J Physiol. 2005;564(Pt 2):563–573.
    1. Hansen PA, Nolte LA, Chen MM, Holloszy JO. Increased GLUT-4 translocation mediates enhanced insulin sensitivity of muscle glucose transport after exercise. J Appl Physiol (1985). 1998;85(4):1218–1222.
    1. Fisher JS, Gao J, Han DH, Holloszy JO, Nolte LA. Activation of AMP kinase enhances sensitivity of muscle glucose transport to insulin. Am J Physiol Endocrinol Metab. 2002;282(1):E18–E23.
    1. Vassilopoulos S, Esk C, Hoshino S, et al. . A role for the CHC22 clathrin heavy-chain isoform in human glucose metabolism. Science. 2009;324(5931):1192–1196.
    1. Fumagalli M, Camus SM, Diekmann Y, et al. . Genetic diversity of CHC22 clathrin impacts its function in glucose metabolism. eLife. 2019;8:e41517.
    1. Dannhauser PN, Camus SM, Sakamoto K, et al. . CHC22 and CHC17 clathrins have distinct biochemical properties and display differential regulation and function. J Biol Chem. 2017;292(51):20834–20844.
    1. Weijers RN. Lipid composition of cell membranes and its relevance in type 2 diabetes mellitus. Curr Diabetes Rev. 2012;8(5):390–400.
    1. Apostolopoulou M, Strassburger K, Herder C, et al. . Metabolic flexibility and oxidative capacity independently associate with insulin sensitivity in individuals with newly diagnosed type 2 diabetes. Diabetologia. 2016;59(10):2203–2207.
    1. Chowdhury EA, Richardson JD, Holman GD, Tsintzas K, Thompson D, Betts JA. The causal role of breakfast in energy balance and health: a randomized controlled trial in obese adults. Am J Clin Nutr. 2016;103(3):747–756.

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj