Exercise and metabolic health: beyond skeletal muscle


Regular exercise is a formidable regulator of insulin sensitivity and overall systemic metabolism through both acute events driven by each exercise bout and through chronic adaptations. As a result, regular exercise significantly reduces the risks for chronic metabolic disease states, including type 2 diabetes and non-alcoholic fatty liver disease. Many of the metabolic health benefits of exercise depend on skeletal muscle adaptations; however, there is plenty of evidence that exercise exerts many of its metabolic benefit through the liver, adipose tissue, vasculature and pancreas. This review will highlight how exercise reduces metabolic disease risk by activating metabolic changes in non-skeletal-muscle tissues. We provide an overview of exercise-induced adaptations within each tissue and discuss emerging work on the exercise-induced integration of inter-tissue communication by a variety of signalling molecules, hormones and cytokines collectively named ‘exerkines’. Overall, the evidence clearly indicates that exercise is a robust modulator of metabolism and a powerful protective agent against metabolic disease, and this is likely to be because it robustly improves metabolic function in multiple organs.

Graphical abstract

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3



Atrial natriuretic peptide




Fibroblast growth factor 21


Lipoprotein lipase


Non-alcoholic fatty liver disease


  1. 1.

    Donnelly JE, Blair SN, Jakicic JM, Manore MM, Rankin JW, Smith BK (2009) American College of Sports Medicine Position Stand. Appropriate physical activity intervention strategies for weight loss and prevention of weight regain for adults. Med Sci Sports Exerc 41(2):459–471. https://doi.org/10.1249/MSS.0b013e3181949333

    Article  PubMed  Google Scholar 

  2. 2.

    Hashida R, Kawaguchi T, Bekki M et al (2017) Aerobic vs. resistance exercise in non-alcoholic fatty liver disease: a systematic review. J Hepatol 66(1):142–152. https://doi.org/10.1016/j.jhep.2016.08.023

    Article  PubMed  Google Scholar 

  3. 3.

    Katzmarzyk PT (2010) Physical activity, sedentary behavior, and health: paradigm paralysis or paradigm shift? Diabetes 59(11):2717–2725. https://doi.org/10.2337/db10-0822

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Hodson L, Karpe F (2019) Hyperinsulinemia: does it tip the balance toward intrahepatic fat accumulation? Endocr Connect 8(10):R157–R168. https://doi.org/10.1530/EC-19-0350

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Meex RCR, Blaak EE, van Loon LJC (2019) Lipotoxicity plays a key role in the development of both insulin resistance and muscle atrophy in patients with type 2 diabetes. Obes Rev 20(9):1205–1217. https://doi.org/10.1111/obr.12862

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Smith GI, Shankaran M, Yoshino M et al (2019) Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease. J Clin Invest 130(3):1453–1460. https://doi.org/10.1172/JCI134165

    Article  Google Scholar 

  7. 7.

    Goodpaster BH, Sparks LM (2017) Metabolic flexibility in health and disease. Cell Metab 25(5):1027–1036. https://doi.org/10.1016/j.cmet.2017.04.015

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Petersen MC, Shulman GI (2018) Mechanisms of insulin action and insulin resistance. Physiol Rev 98(4):2133–2223. https://doi.org/10.1152/physrev.00063.2017

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Iozzo P (2009) Viewpoints on the way to the consensus session: where does insulin resistance start? The adipose tissue. Diabetes Care 32(Suppl 2):S168–S173. https://doi.org/10.2337/dc09-S304

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Templeman NM, Skovso S, Page MM, Lim GE, Johnson JD (2017) A causal role for hyperinsulinemia in obesity. J Endocrinol 232(3):R173–R183. https://doi.org/10.1530/JOE-16-0449

    CAS  Article  Google Scholar 

  11. 11.

    Thyfault JP, Krogh-Madsen R (2011) Metabolic disruptions induced by reduced ambulatory activity in free-living humans. J Appl Physiol 111(4):1218–1224. https://doi.org/10.1152/japplphysiol.00478.2011

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Bergouignan A, Rudwill F, Simon C, Blanc S (2011) Physical inactivity as the culprit of metabolic inflexibility: evidence from bed-rest studies. J Appl Physiol 111(4):1201–1210. https://doi.org/10.1152/japplphysiol.00698.2011

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Laaksonen DE, Lindstrom J, Lakka TA et al (2005) Physical activity in the prevention of type 2 diabetes: the Finnish diabetes prevention study. Diabetes 54(1):158–165. https://doi.org/10.2337/diabetes.54.1.158

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Fretts AM, Howard BV, McKnight B et al (2012) Modest levels of physical activity are associated with a lower incidence of diabetes in a population with a high rate of obesity: the strong heart family study. Diabetes Care 35(8):1743–1745. https://doi.org/10.2337/dc11-2321

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Tudor-Locke C, Schuna JM Jr (2012) Steps to preventing type 2 diabetes: exercise, walk more, or sit less? Front Endocrinol (Lausanne) 3:142. https://doi.org/10.3389/fendo.2012.00142

    Article  Google Scholar 

  16. 16.

    Williams PT (2007) Changes in vigorous physical activity and incident diabetes in male runners. Diabetes Care 30(11):2838–2842. https://doi.org/10.2337/dc07-1189

    Article  PubMed  Google Scholar 

  17. 17.

    Wang Y, Lee DC, Brellenthin AG et al (2019) Leisure-time running reduces the risk of incident type 2 diabetes. Am J Med 132(10):1225–1232. https://doi.org/10.1016/j.amjmed.2019.04.035

    Article  PubMed  Google Scholar 

  18. 18.

    Lee DC, Sui X, Church TS, Lee IM, Blair SN (2009) Associations of cardiorespiratory fitness and obesity with risks of impaired fasting glucose and type 2 diabetes in men. Diabetes Care 32(2):257–262. https://doi.org/10.2337/dc08-1377

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Thyfault JP, Rector RS (2020) Exercise combats hepatic steatosis: potential mechanisms and clinical implications. Diabetes 69(4):517–524. https://doi.org/10.2337/dbi18-0043

    Article  PubMed  Google Scholar 

  20. 20.

    Church TS, Kuk JL, Ross R, Priest EL, Biltoft E, Blair SN (2006) Association of cardiorespiratory fitness, body mass index, and waist circumference to nonalcoholic fatty liver disease. Gastroenterology 130(7):2023–2030. https://doi.org/10.1053/j.gastro.2006.03.019

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Palve KS, Pahkala K, Suomela E et al (2017) Cardiorespiratory fitness and risk of fatty liver: the Young Finns Study. Med Sci Sports Exerc 49(9):1834–1841. https://doi.org/10.1249/MSS.0000000000001288

    Article  PubMed  Google Scholar 

  22. 22.

    Booth FW, Roberts CK, Thyfault JP, Ruegsegger GN, Toedebusch RG (2017) Role of inactivity in chronic diseases: evolutionary insight and pathophysiological mechanisms. Physiol Rev 97(4):1351–1402. https://doi.org/10.1152/physrev.00019.2016

    Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Deshmukh AS, Cox J, Jensen LJ, Meissner F, Mann M (2015) Secretome analysis of lipid-induced insulin resistance in skeletal muscle cells by a combined experimental and bioinformatics workflow. J Proteome Res 14(11):4885–4895. https://doi.org/10.1021/acs.jproteome.5b00720

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Meex RC, Hoy AJ, Morris A et al (2015) Fetuin B is a secreted hepatocyte factor linking steatosis to impaired glucose metabolism. Cell Metab 22(6):1078–1089. https://doi.org/10.1016/j.cmet.2015.09.023

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Crowe S, Wu LE, Economou C et al (2009) Pigment epithelium-derived factor contributes to insulin resistance in obesity. Cell Metab 10(1):40–47. https://doi.org/10.1016/j.cmet.2009.06.001

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Laurens C, Bergouignan A, Moro C (2020) Exercise-released myokines in the control of energy metabolism. Front Physiol 11:91. https://doi.org/10.3389/fphys.2020.00091

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Egan B, Zierath JR (2013) Exercise metabolism and the molecular regulation of skeletal muscle adaptation. Cell Metab 17(2):162–184. https://doi.org/10.1016/j.cmet.2012.12.012

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Bergouignan A, Latouche C, Heywood S et al (2016) Frequent interruptions of sedentary time modulates contraction- and insulin-stimulated glucose uptake pathways in muscle: ancillary analysis from randomized clinical trials. Sci Rep 6(1):32044. https://doi.org/10.1038/srep32044

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Thyfault JP (2008) Setting the stage: possible mechanisms by which acute contraction restores insulin sensitivity in muscle. Am J Physiol Regul Integr Comp Physiol 294(4):R1103–R1110. https://doi.org/10.1152/ajpregu.00542.2007

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Yan Z, Okutsu M, Akhtar YN, Lira VA (2011) Regulation of exercise-induced fiber type transformation, mitochondrial biogenesis, and angiogenesis in skeletal muscle. J Appl Physiol (1985) 110(1):264–274. https://doi.org/10.1152/japplphysiol.00993.2010

    CAS  Article  Google Scholar 

  31. 31.

    Kim Y, Triolo M, Hood DA (2017) Impact of aging and exercise on mitochondrial quality control in skeletal muscle. Oxidative Med Cell Longev 2017:3165396–3165316. https://doi.org/10.1155/2017/3165396

    CAS  Article  Google Scholar 

  32. 32.

    Parousis A, Carter HN, Tran C et al (2018) Contractile activity attenuates autophagy suppression and reverses mitochondrial defects in skeletal muscle cells. Autophagy 14(11):1886–1897. https://doi.org/10.1080/15548627.2018.1491488

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Lefai E, Blanc S, Momken I et al (2017) Exercise training improves fat metabolism independent of total energy expenditure in sedentary overweight men, but does not restore lean metabolic phenotype. Int J Obes 41(12):1728–1736. https://doi.org/10.1038/ijo.2017.151

    CAS  Article  Google Scholar 

  34. 34.

    Badin PM, Langin D, Moro C (2013) Dynamics of skeletal muscle lipid pools. Trends Endocrinol Metab 24(12):607–615. https://doi.org/10.1016/j.tem.2013.08.001

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Pedersen BK, Febbraio MA (2012) Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol 8(8):457–465. https://doi.org/10.1038/nrendo.2012.49

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Lee JH, Jun HS (2019) Role of myokines in regulating skeletal muscle mass and function. Front Physiol 10:42. https://doi.org/10.3389/fphys.2019.00042

    Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Piccirillo R (2019) Exercise-induced myokines with therapeutic potential for muscle wasting. Front Physiol 10:287. https://doi.org/10.3389/fphys.2019.00287

    Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Pedersen BK, Steensberg A, Fischer C et al (2003) Searching for the exercise factor: is IL-6 a candidate? J Muscle Res Cell Motil 24(2–3):113–119. https://doi.org/10.1023/A:1026070911202

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Suzuki K, Nakaji S, Yamada M, Totsuka M, Sato K, Sugawara K (2002) Systemic inflammatory response to exhaustive exercise. Cytokine kinetics. Exerc Immunol Rev 8:6–48

    PubMed  Google Scholar 

  40. 40.

    Keller C, Steensberg A, Pilegaard H et al (2001) Transcriptional activation of the IL-6 gene in human contracting skeletal muscle: influence of muscle glycogen content. FASEB J 15(14):2748–2750. https://doi.org/10.1096/fj.01-0507fje

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Febbraio MA, Steensberg A, Keller C et al (2003) Glucose ingestion attenuates interleukin-6 release from contracting skeletal muscle in humans. J Physiol 549(Pt 2):607–612. https://doi.org/10.1113/jphysiol.2003.042374

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Wolsk E, Mygind H, Grondahl TS, Pedersen BK, van Hall G (2010) IL-6 selectively stimulates fat metabolism in human skeletal muscle. Am J Physiol Endocrinol Metab 299(5):E832–E840. https://doi.org/10.1152/ajpendo.00328.2010

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Carey AL, Steinberg GR, Macaulay SL et al (2006) Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes 55(10):2688–2697. https://doi.org/10.2337/db05-1404

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Wasserman DH (2009) Four grams of glucose. Am J Physiol Endocrinol Metab 296(1):E11–E21. https://doi.org/10.1152/ajpendo.90563.2008

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Trefts E, Williams AS, Wasserman DH (2015) Exercise and the regulation of hepatic metabolism. Prog Mol Biol Transl Sci 135:203–225. https://doi.org/10.1016/bs.pmbts.2015.07.010

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Hu C, Hoene M, Plomgaard P et al (2019) Muscle-liver substrate fluxes in exercising humans and potential effects on hepatic metabolism. J Clin Endocrinol Metab 105(4):1196–1209. https://doi.org/10.1210/clinem/dgz266

    Article  PubMed Central  Google Scholar 

  47. 47.

    Rector RS, Thyfault JP, Morris RT et al (2008) Daily exercise increases hepatic fatty acid oxidation and prevents steatosis in Otsuka Long-Evans Tokushima Fatty rats. Am J Physiol Gastrointest Liver Physiol 294(3):G619–G626. https://doi.org/10.1152/ajpgi.00428.2007

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Linden MA, Fletcher JA, Morris EM et al (2015) Treating NAFLD in OLETF rats with vigorous-intensity interval exercise training. Med Sci Sports Exerc 47(3):556–567. https://doi.org/10.1249/MSS.0000000000000430

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Rector RS, Uptergrove GM, Morris EM et al (2011) Daily exercise vs. caloric restriction for prevention of nonalcoholic fatty liver disease in the OLETF rat model. Am J Physiol Gastrointest Liver Physiol 300(5):G874–G883. https://doi.org/10.1152/ajpgi.00510.2010

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Puchalska P, Crawford PA (2017) Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab 25(2):262–284. https://doi.org/10.1016/j.cmet.2016.12.022

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Karstoft K, Pedersen BK (2016) Skeletal muscle as a gene regulatory endocrine organ. Curr Opin Clin Nutr Metab Care 19(4):270–275. https://doi.org/10.1097/MCO.0000000000000283

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Seldin MM, Peterson JM, Byerly MS, Wei Z, Wong GW (2012) Myonectin (CTRP15), a novel myokine that links skeletal muscle to systemic lipid homeostasis. J Biol Chem 287(15):11968–11980. https://doi.org/10.1074/jbc.M111.336834

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Ingerslev B, Hansen JS, Hoffmann C et al (2017) Angiopoietin-like protein 4 is an exercise-induced hepatokine in humans, regulated by glucagon and cAMP. Mol Metab 6(10):1286–1295. https://doi.org/10.1016/j.molmet.2017.06.018

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Horowitz JF (2003) Fatty acid mobilization from adipose tissue during exercise. Trends Endocrinol Metab 14(8):386–392. https://doi.org/10.1016/S1043-2760(03)00143-7

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Lafontan M, Sengenes C, Galitzky J et al (2000) Recent developments on lipolysis regulation in humans and discovery of a new lipolytic pathway. Int J Obes Relat Metab Disord 24(Suppl 4):S47–S52. https://doi.org/10.1038/sj.ijo.0801505

    CAS  Article  PubMed  Google Scholar 

  56. 56.

    Stanford KI, Goodyear LJ (2016) Exercise regulation of adipose tissue. Adipocyte 5(2):153–162. https://doi.org/10.1080/21623945.2016.1191307

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Moro C, Pillard F, de Glisezinski I et al (2007) Sex differences in lipolysis-regulating mechanisms in overweight subjects: effect of exercise intensity. Obesity (Silver Spring) 15(9):2245–2255. https://doi.org/10.1038/oby.2007.267

    CAS  Article  Google Scholar 

  58. 58.

    Richterova B, Stich V, Moro C et al (2004) Effect of endurance training on adrenergic control of lipolysis in adipose tissue of obese women. J Clin Endocrinol Metab 89(3):1325–1331. https://doi.org/10.1210/jc.2003-031001

    CAS  Article  PubMed  Google Scholar 

  59. 59.

    Sutherland LN, Bomhof MR, Capozzi LC, Basaraba SA, Wright DC (2009) Exercise and adrenaline increase PGC-1α mRNA expression in rat adipose tissue. J Physiol 587(Pt 7):1607–1617. https://doi.org/10.1113/jphysiol.2008.165464

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Trevellin E, Scorzeto M, Olivieri M et al (2014) Exercise training induces mitochondrial biogenesis and glucose uptake in subcutaneous adipose tissue through eNOS-dependent mechanisms. Diabetes 63(8):2800–2811. https://doi.org/10.2337/db13-1234

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    Moro C, Pillard F, de Glisezinski I et al (2008) Exercise-induced lipid mobilization in subcutaneous adipose tissue is mainly related to natriuretic peptides in overweight men. Am J Physiol Endocrinol Metab 295(2):E505–E513. https://doi.org/10.1152/ajpendo.90227.2008

    CAS  Article  PubMed  Google Scholar 

  62. 62.

    Perreault L, Lavely JM, Kittelson JM, Horton TJ (2004) Gender differences in lipoprotein lipase activity after acute exercise. Obes Res 12(2):241–249. https://doi.org/10.1038/oby.2004.31

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Lithell H, Schele R, Vessby B, Jacobs I (1984) Lipoproteins, lipoprotein lipase, and glycogen after prolonged physical activity. J Appl Physiol Respir Environ Exerc Physiol 57(3):698–702. https://doi.org/10.1152/jappl.1984.57.3.698

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Malkova D, Evans RD, Frayn KN, Humphreys SM, Jones PR, Hardman AE (2000) Prior exercise and postprandial substrate extraction across the human leg. Am J Physiol Endocrinol Metab 279(5):E1020–E1028. https://doi.org/10.1152/ajpendo.2000.279.5.E1020

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Wilmore JH, Despres JP, Stanforth PR et al (1999) Alterations in body weight and composition consequent to 20 wk of endurance training: the HERITAGE Family Study. Am J Clin Nutr 70(3):346–352. https://doi.org/10.1093/ajcn/70.3.346

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    Mauriege P, Galitzky J, Berlan M, Lafontan M (1987) Heterogeneous distribution of beta and alpha-2 adrenoceptor binding sites in human fat cells from various fat deposits: functional consequences. Eur J Clin Investig 17(2):156–165. https://doi.org/10.1111/j.1365-2362.1987.tb02395.x

    CAS  Article  Google Scholar 

  67. 67.

    Ohkawara K, Tanaka S, Miyachi M, Ishikawa-Takata K, Tabata I (2007) A dose-response relation between aerobic exercise and visceral fat reduction: systematic review of clinical trials. Int J Obes 31(12):1786–1797. https://doi.org/10.1038/sj.ijo.0803683

    CAS  Article  Google Scholar 

  68. 68.

    Vieira VJ, Valentine RJ, Wilund KR, Antao N, Baynard T, Woods JA (2009) Effects of exercise and low-fat diet on adipose tissue inflammation and metabolic complications in obese mice. Am J Physiol Endocrinol Metab 296(5):E1164–E1171. https://doi.org/10.1152/ajpendo.00054.2009

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Fisher G, Hyatt TC, Hunter GR, Oster RA, Desmond RA, Gower BA (2011) Effect of diet with and without exercise training on markers of inflammation and fat distribution in overweight women. Obesity (Silver Spring) 19(6):1131–1136. https://doi.org/10.1038/oby.2010.310

    CAS  Article  Google Scholar 

  70. 70.

    Wedell-Neergaard AS, Lang Lehrskov L, Christensen RH et al (2019) Exercise-induced changes in visceral adipose tissue mass are regulated by il-6 signaling: a randomized controlled trial. Cell Metab 29(4):844–855 e843. https://doi.org/10.1016/j.cmet.2018.12.007

    CAS  Article  PubMed  Google Scholar 

  71. 71.

    Laurens C, Parmar A, Murphy E et al (2020) Growth and differentiation factor 15 is secreted by skeletal muscle during exercise and promotes lipolysis in humans. JCI Insight 5(6). https://doi.org/10.1172/jci.insight.131870

  72. 72.

    Takahashi H, Alves CRR, Stanford KI et al (2019) TGF-beta2 is an exercise-induced adipokine that regulates glucose and fatty acid metabolism. Nat Metab 1(2):291–303. https://doi.org/10.1038/s42255-018-0030-7

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Curran M, Drayson MT, Andrews RC et al (2020) The benefits of physical exercise for the health of the pancreatic beta-cell: a review of the evidence. Exp Physiol 105(4):579–589. https://doi.org/10.1113/EP088220

    Article  PubMed  Google Scholar 

  74. 74.

    Heath GW, Gavin JR 3rd, Hinderliter JM, Hagberg JM, Bloomfield SA, Holloszy JO (1983) Effects of exercise and lack of exercise on glucose tolerance and insulin sensitivity. J Appl Physiol 55(2):512–517. https://doi.org/10.1152/jappl.1983.55.2.512

    CAS  Article  PubMed  Google Scholar 

  75. 75.

    Kahn SE, Prigeon RL, McCulloch DK et al (1993) Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function. Diabetes 42(11):1663–1672. https://doi.org/10.2337/diab.42.11.1663

    CAS  Article  PubMed  Google Scholar 

  76. 76.

    Bergman RN, Phillips LS, Cobelli C (1981) Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose. J Clin Invest 68(6):1456–1467. https://doi.org/10.1172/JCI110398

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Solomon TP, Haus JM, Kelly KR, Rocco M, Kashyap SR, Kirwan JP (2010) Improved pancreatic beta-cell function in type 2 diabetic patients after lifestyle-induced weight loss is related to glucose-dependent insulinotropic polypeptide. Diabetes Care 33(7):1561–1566. https://doi.org/10.2337/dc09-2021

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Solomon TP, Malin SK, Karstoft K, Kashyap SR, Haus JM, Kirwan JP (2013) Pancreatic beta-cell function is a stronger predictor of changes in glycemic control after an aerobic exercise intervention than insulin sensitivity. J Clin Endocrinol Metab 98(10):4176–4186. https://doi.org/10.1210/jc.2013-2232

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Christensen CS, Christensen DP, Lundh M et al (2015) Skeletal muscle to pancreatic beta-cell cross-talk: the effect of humoral mediators liberated by muscle contraction and acute exercise on beta-cell apoptosis. J Clin Endocrinol Metab 100(10):E1289–E1298. https://doi.org/10.1210/jc.2014-4506

    CAS  Article  PubMed  Google Scholar 

  80. 80.

    Natalicchio A, Marrano N, Biondi G et al (2017) The myokine irisin is released in response to saturated fatty acids and promotes pancreatic beta-cell survival and insulin secretion. Diabetes 66(11):2849–2856. https://doi.org/10.2337/db17-0002

    CAS  Article  PubMed  Google Scholar 

  81. 81.

    Wagenmakers AJ, Strauss JA, Shepherd SO, Keske MA, Cocks M (2016) Increased muscle blood supply and transendothelial nutrient and insulin transport induced by food intake and exercise: effect of obesity and ageing. J Physiol 594(8):2207–2222. https://doi.org/10.1113/jphysiol.2014.284513

    CAS  Article  PubMed  Google Scholar 

  82. 82.

    Olver TD, Ferguson BS, Laughlin MH (2015) Molecular mechanisms for exercise training-induced changes in vascular structure and function: skeletal muscle, cardiac muscle, and the brain. Prog Mol Biol Transl Sci 135:227–257. https://doi.org/10.1016/bs.pmbts.2015.07.017

    CAS  Article  PubMed  Google Scholar 

  83. 83.

    Bergman RN (2003) Insulin action and distribution of tissue blood flow. J Clin Endocrinol Metab 88(10):4556–4558. https://doi.org/10.1210/jc.2003-031431

    CAS  Article  PubMed  Google Scholar 

  84. 84.

    Eringa EC, Stehouwer CD, Merlijn T, Westerhof N, Sipkema P (2002) Physiological concentrations of insulin induce endothelin-mediated vasoconstriction during inhibition of NOS or PI3-kinase in skeletal muscle arterioles. Cardiovasc Res 56(3):464–471. https://doi.org/10.1016/S0008-6363(02)00593-X

    CAS  Article  PubMed  Google Scholar 

  85. 85.

    Reynolds LJ, Credeur DP, Manrique C, Padilla J, Fadel PJ, Thyfault JP (2017) Obesity, type 2 diabetes, and impaired insulin-stimulated blood flow: role of skeletal muscle NO synthase and endothelin-1. J Appl Physiol (1985) 122(1):38–47. https://doi.org/10.1152/japplphysiol.00286.2016

    CAS  Article  Google Scholar 

  86. 86.

    Solomon TP, Haus JM, Li Y, Kirwan JP (2011) Progressive hyperglycemia across the glucose tolerance continuum in older obese adults is related to skeletal muscle capillarization and nitric oxide bioavailability. J Clin Endocrinol Metab 96(5):1377–1384. https://doi.org/10.1210/jc.2010-2069

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Frisbee JC (2005) Reduced nitric oxide bioavailability contributes to skeletal muscle microvessel rarefaction in the metabolic syndrome. Am J Physiol Regul Integr Comp Physiol 289(2):R307–R316. https://doi.org/10.1152/ajpregu.00114.2005

    CAS  Article  PubMed  Google Scholar 

  88. 88.

    Padilla J, Olver TD, Thyfault JP, Fadel PJ (2015) Role of habitual physical activity in modulating vascular actions of insulin. Exp Physiol 100(7):759–771. https://doi.org/10.1113/EP085107

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Sjoberg KA, Frosig C, Kjobsted R et al (2017) Exercise increases human skeletal muscle insulin sensitivity via coordinated increases in microvascular perfusion and molecular signaling. Diabetes 66(6):1501–1510. https://doi.org/10.2337/db16-1327

    CAS  Article  PubMed  Google Scholar 

  90. 90.

    McConell GK, Sjoberg KA, Ceutz F et al (2020) Insulin-induced membrane permeability to glucose in human muscles at rest and following exercise. J Physiol 598(2):303–315. https://doi.org/10.1113/JP278600

    CAS  Article  PubMed  Google Scholar 

  91. 91.

    Rapoport RM, Merkus D (2017) Endothelin-1 regulation of exercise-induced changes in flow: dynamic regulation of vascular tone. Front Pharmacol 8:517. https://doi.org/10.3389/fphar.2017.00517

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Hagberg CE, Falkevall A, Wang X et al (2010) Vascular endothelial growth factor B controls endothelial fatty acid uptake. Nature 464(7290):917–921. https://doi.org/10.1038/nature08945

    CAS  Article  PubMed  Google Scholar 

  93. 93.

    Martin JS, Padilla J, Jenkins NT et al (2012) Functional adaptations in the skeletal muscle microvasculature to endurance and interval sprint training in the type 2 diabetic OLETF rat. J Appl Physiol (1985) 113(8):1223–1232. https://doi.org/10.1152/japplphysiol.00823.2012

    Article  Google Scholar 

  94. 94.

    Mikus CR, Rector RS, Arce-Esquivel AA et al (2010) Daily physical activity enhances reactivity to insulin in skeletal muscle arterioles of hyperphagic Otsuka Long-Evans Tokushima Fatty rats. J Appl Physiol 109(4):1203–1210. https://doi.org/10.1152/japplphysiol.00064.2010

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  95. 95.

    DeVallance E, Branyan KW, Lemaster KC et al (2019) Exercise training prevents the perivascular adipose tissue-induced aortic dysfunction with metabolic syndrome. Redox Biol 26:101285. https://doi.org/10.1016/j.redox.2019.101285

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Authors’ relationships and activities

The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.


Work in JPT’s laboratories is supported by a VA-Merit Grant 1I01BX002567, NIH R01 KD121497 and R01 AR071263. Work by AB is supported by NIH R00 DK100465.

Author information




Both authors were responsible for drafting the article and revising it critically for important intellectual content. Both authors approved the version to be published.

Corresponding author

Correspondence to John P. Thyfault.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Slideset of figures

(PPTX 438 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Thyfault, J.P., Bergouignan, A. Exercise and metabolic health: beyond skeletal muscle. Diabetologia (2020). https://doi.org/10.1007/s00125-020-05177-6

Download citation


  • Adipose tissue
  • Endothelium
  • Exercise
  • Exerkines
  • Liver
  • Muscle
  • Pancreas
  • Review
  • Type 2 diabetes