The effect of aerobic training on serum levels of Growth differentiation factor-15 and insulin resistance in elderly women with metabolic syndrome

Authors

Abstract

Background and Objective: Aerobic training plays an important role in the improvement of cardiovascular-metabolic disorders associated with aging and metabolic syndrome; however, the role of this type of training on growth differentiation factor-15 (GDF-15) as a new biomarker for predicting cardiac disorders is not understood. Therefore, the purpose of the present study was to investigate the effect of aerobic training on serum levels of GDF-15 and insulin resistance index in elderly women with metabolic syndrome.
Materials and Method: 24 elderly women with metabolic syndrome (age: 65.37±4.08, weight: 88.98±6.56 kg, BMI: 34.14±1.47) were randomly divided into two groups of aerobic training (n=12) and control group (n=12). The aerobic training protocol was administered for 12 weeks, three sessions per week at an intensity of 65-50% of maximum heart rate. Serum samples were collected in pre-test and post-test for ELISA using insulin, glucose and GDF-15.
Results: Results of data analysis showed that aerobic training resulted in a significant decrease in serum GDF-15 compared to control group (P˂0.05). Also, aerobic training was associated with a significant decrease in serum glucose and insulin resistance (P˂0.05), while it had no effect on serum insulin (P˃0.05).
Conclusion: It seems that aerobic training has an effective role in reducing serum GDF-15, which may be due to the improvement of metabolic parameters and consequently a reduction in the need for GDF-15 compensation.

Keywords


1. Expert Panel on Detection E. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). The Journal of the American Medical Association 2001 16;285(19):2486-97. 2. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. The Journal of the American Medical Association 2002;287(3):356-9. 3. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults. JAMA: the journal of the American Medical Association 2002;287(3):356-9. 4. Xiao R-P, Tomhave ED, Wang D-J, Ji X, Boluyt MO, Cheng H, et al. Age-associated reductions in cardiac beta1-and beta2-adrenergic responses without changes in inhibitory G proteins or receptor kinases. The Journal of Clinical Investigation 1998;101(6):1273-82. 5. Ritchie S, Connell J. The link between abdominal obesity, metabolic syndrome and cardiovascular disease. Nutrition, Metabolism and Cardiovascular Diseases 2007;17(4):319-26. 6. Wang CCL, Hess CN, Hiatt WR, Goldfine AB. Clinical update: cardiovascular disease in diabetes mellitus: atherosclerotic cardiovascular disease and heart failure in type 2 diabetes mellitus–mechanisms, management, and clinical considerations. Circulation 2016;133(24):2459-502. 7. Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. New England Journal of Medicine 2004;350(7):664-71. 8. Hsu L-A, Wu S, Juang J-MJ, Chiang F-T, Teng M-S, Lin J-F, et al. Growth Differentiation Factor 15 May Predict Mortality of Peripheral and Coronary Artery Diseases and Correlate with Their Risk Factors. Mediators of Inflammation 2017;20. 17:9398401 9. Kempf T, Eden M, Strelau J, Naguib M, Willenbockel C, Tongers J, et al. The transforming growth factor-beta superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury. Circulation Research 2006;98(3):351-6. 10. Ago T, Sadoshima J. GDF15, a cardioprotective TGF-beta superfamily protein. Circulation Research 2006;98(3): 294-7. 11. Xu J, Kimball TR, Lorenz JN, Brown DA, Bauskin AR, Klevitsky R, et al. GDF15/MIC-1 functions as a protective and antihypertrophic factor released from the myocardium in association with SMAD protein activation. C Circulation Research 2006;98(3):342-50. 12. Bonaca MP, Morrow DA, Braunwald E, Cannon CP, Jiang S, Breher S, et al. Growth differentiation factor-15 and risk of recurrent events in patients stabilized after acute coronary syndrome: observations from PROVE IT-TIMI 22. Arteriosclerosis, Thrombosis, and Vascular Biology 2011;31(1):203-10. 13. Khan SQ, Ng K, Dhillon O, Kelly D, Quinn P, Squire IB, et al. Growth differentiation factor-15 as a prognostic marker in patients with acute myocardial infarction. The European Heart Journal 2009;30(9):1057-65. 14. Schopfer DW, Ku IA, Regan M, Whooley MA. Growth differentiation factor 15 and cardiovascular events in patients with stable ischemic heart disease (The Heart and Soul Study). The European Heart Journal 2014;167(2):186-92.e1. 15. Fujita Y, Taniguchi Y, Shinkai S, Tanaka M, Ito M. Secreted growth differentiation factor 15 as a potential biomarker for mitochondrial dysfunctions in aging and age‐related disorders. Geriatrics & gerontology international 2016;16 Suppl 1:17-29. 16. Lind L, Wallentin L, Kempf T, Tapken H, Quint A, Lindahl B, et al. Growth-differentiation factor-15 is an independent marker of cardiovascular dysfunction and disease in the elderly: results from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) Study. European Heart Journal 2009;30(19):2346-53. 17. Colberg SR, Sigal RJ, Fernhall B, Regensteiner JG, Blissmer BJ, Rubin RR, et al. Exercise and type 2 diabetes: the American College of Sports Medicine and the American Diabetes Association: joint position statement. Diabetes Care 2010;33(12):e147-e67. 18. Association AD. Standards of medical care in diabetes—2014. Diabetes care 2014;37(Supplement 1):S14-S80. 19. Araki A, Ito H. Diabetes mellitus and geriatric syndromes. Geriatrics & Gerontology International 2009;9(2):105-14. 20. Chodzko-Zajko WJ, Proctor DN, Singh MAF, Minson CT, Nigg CR, Salem GJ, et al. Exercise and physical activity for older adults. Medicine & Science In Sports & Exercise 2009;41(7):1510-1530. 21. Vissers D, Hens W, Taeymans J, Baeyens J-P, Poortmans J, Van Gaal L. The effect of exercise on visceral adipose tissue in overweight adults: a systematic review and meta-analysis. PloS one. 2013;8(2):e56415. 22. Pattyn N, Cornelissen VA, Eshghi SRT, Vanhees L. The effect of exercise on the cardiovascular risk factors constituting the metabolic syndrome. Sports Medicine. 2013;43(2):121-33. 23. Pescatello LS, Blanchard BE, Van Heest JL, Maresh CM, Gordish-Dressman H, Thompson PD. The metabolic syndrome and the immediate antihypertensive effects of aerobic exercise: a randomized control design. BMC cardiovascular disorders. 2008;8(1):12. 24. Stefanyk LE, Dyck DJ. The interaction between adipokines, diet and exercise on muscle insulin sensitivity. Current Opinion in Clinical Nutrition & Metabolic Care. 2010;13(3):255-9. 25. El-Kader SMA, Al-Jiffri OH, Al-Shreef FM. Aerobic exercises alleviate symptoms of fatigue related to inflammatory cytokines in obese patients with type 2 diabetes. African Health Sciences 2015;15(4):1142-8. 26. El-Kader SA, Gari A, El-Den AS. Impact of moderate versus mild aerobic exercise training on inflammatory cytokines in obese type 2 diabetic patients: a randomized clinical trial. African Health Sciences 2013;13(4):857-63. 27. Galliera E, Lombardi G, Marazzi MG, Grasso D, Vianello E, Pozzoni R, et al. Acute exercise in elite rugby players increases the circulating level of the cardiovascular biomarker GDF-15. Scandinavian Journal of Clinical and Laboratory Investigation 2014;74(6):492-9. 28. Munk PS, Valborgland T, Butt N, Larsen AI. Response of growth differentiation factor-15 to percutaneous coronary intervention and regular exercise training. Scandinavian Cardiovascular Journal 2011;45(1):27-32. 29. Farinha JB, Steckling FM, Stefanello ST, Cardoso MS, Nunes LS, Barcelos RP, et al. Response of oxidative stress and inflammatory biomarkers to a 12-week aerobic exercise training in women with metabolic syndrome. Sports Medicine - Open 2015;1(1):19. 30. Cummings DM HS, Kolasa KM, Olsson J, Collier D. Insulin resistance status: Predicting weight response in overweight children. rchives of Pediatrics and Adolescent Medicine 2008;162(8):764-8. 31. Kleinert M, Clemmensen C, Sjoberg KA, Carl CS, Jeppesen JF, Wojtaszewski JFP, et al. Exercise increases circulating GDF15 in humans. Molecular Metabolism 2018;9:187-91. 32. Tchou I, Margeli A, Tsironi M, Skenderi K, Barnet M, Kanaka-Gantenbein C, et al. Growth-differentiation factor-15, endoglin and N-terminal pro-brain natriuretic peptide induction in athletes participating in an ultramarathon foot race. Biomarkers: Biochemical Indicators of Exposure, Response, and Susceptibility to Chemicals 2009;14(6):418-22. 33. Munk PS, Valborgland T, Butt N, Larsen AI. Response of growth differentiation factor-15 to percutaneous coronary intervention and regular exercise training. Scandinavian Cardiovascular Journal 2011;45(1):27-32. 34. Zhang H, Fealy CE, Kirwan JP. Exercise training promotes a GDF15-associated reduction in fat mass in older adults with obesity. American Journal of Physiology-Endocrinology and Metabolism 2019; 316(5):E829-E836. 35. Dostálová I, Roubíček T, Bártlová M, Mráz M, Lacinová Z, Haluzíková D, et al. Increased serum concentrations of macrophage inhibitory cytokine-1 in patients with obesity and type 2 diabetes mellitus: the influence of very low calorie diet. European Journal of Endocrinology 2009;161(3):397-404. 36. Vila G, Riedl M, Anderwald C, Resl M, Handisurya A, Clodi M, et al. The relationship between insulin resistance and the cardiovascular biomarker growth differentiation factor-15 in obese patients. Clinical Chemistry. 2011;57(2):309-16. 37. Sugulle M, Dechend R, Herse F, Weedon-Fekjaer MS, Johnsen GM, Brosnihan KB, et al. Circulating and placental growth-differentiation factor 15 in preeclampsia and in pregnancy complicated by diabetes mellitus. Hypertension 2009;54(1):106-12. 38. Kempf T, Guba-Quint A, Torgerson J, Magnone MC, Haefliger C, Bobadilla M, et al. Growth differentiation factor 15 predicts future insulin resistance and impaired glucose control in obese nondiabetic individuals: results from the XENDOS trial. European Journal of Endocrinology 2012;167(5):671-8. 39. Bao X, Borné Y, Muhammad IF, Nilsson J, Lind L, Melander O, et al. Growth differentiation factor 15 is positively associated with incidence of diabetes mellitus: the Malmö Diet and Cancer–Cardiovascular Cohort. Diabetologia 2019;62(1):78-86. 40. Ding Q, Mracek T, Gonzalez-Muniesa P, Kos K, Wilding J, Trayhurn P, et al. Identification of macrophage inhibitory cytokine-1 in adipose tissue and its secretion as an adipokine by human adipocytes. Endocrinology 2008;150(4):1688-96. 41. Mullican SE, Lin-Schmidt X, Chin C-N, Chavez JA, Furman JL, Armstrong AA, et al. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nature medicine 2017;23(10):1150. 42. Johnen H, Lin S, Kuffner T, Brown DA, Tsai VW-W, Bauskin AR, et al. Tumor-induced anorexia and weight loss are mediated by the TGF-β superfamily cytokine MIC-1. Nature Medicine 2007;13(11):1333. 43. Bonaterra GA, Zügel S, Thogersen J, Walter SA, Haberkorn U, Strelau J, et al. Growth differentiation factor‐15 deficiency inhibits atherosclerosis progression by regulating interleukin‐6–dependent inflammatory response to vascular injury. Journal of the American Heart Association 2012;1(6): e002550. 44. Tsai VW-W, Macia L, Johnen H, Kuffner T, Manadhar R, Jørgensen SB, et al. TGF-b superfamily cytokine MIC-1/GDF15 is a physiological appetite and body weight regulator. PloS One 2013;8(2):e55174. 45. Johnen H, Kuffner T, Brown DA, Wu BJ, Stocker R, Breit SN. Increased expression of the TGF-b superfamily cytokine MIC-1/GDF15 protects ApoE−/− mice from the development of atherosclerosis. Cardiovascular Pathology 2012;21(6):499-505. 46. Yalcin MM, Altinova AE, Akturk M, Gulbahar O, Arslan E, Ors Sendogan D, et al. GDF-15 and hepcidin levels in nonanemic patients with impaired glucose tolerance. Journal of Diabetes Research 2016;2016. 47. Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH, et al. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. The Lancet 1996;348(9021): 159-61. 48. Walton RG, Finlin BS, Mula J, Long DE, Zhu B, Fry CS, et al. Insulin‐resistant subjects have normal angiogenic response to aerobic exercise training in skeletal muscle, but not in adipose tissue. Physiological Reports 2015;3(6):e12415. 49. Motahari-Tabari N, Ahmad Shirvani M, Shirzad-E-Ahoodashty M, Yousefi-Abdolmaleki E, Teimourzadeh M. The effect of 8 weeks aerobic exercise on insulin resistance in type 2 diabetes: a randomized clinical trial. Global Journal of Health Science 2014;7(1):115-21. 50. Le S, Mao L, Lu D, Yang Y, Tan X, Wiklund P, et al. Effect of aerobic exercise on insulin resistance and central adiposity disappeared after the discontinuation of intervention in overweight women. Journal of Sport and Health Science 2016;5(2):166-70. 51. Bruno E, Roveda E, Vitale J, Montaruli A, Berrino F, Villarini A, et al. Effect of aerobic exercise intervention on markers of insulin resistance in breast cancer women. European Journal of Cancer Care 2018;27(2):e12617. 52. Azali Alamdari K, Ghorbanian B. Effect of aerobic training on serum adiponectin and ctrp-3 in males with metabolic syndrome. Iranian Journal of Endocrinology and Metabolism 2017;18(5):368-77. 53. Musa DI, Adeniran SA, Dikko A, Sayers SP. The effect of a high-intensity interval training program on high-density lipoprotein cholesterol in young men. The Journal of Strength & Conditioning Research. 2009; 23(2):587-92. 54. Moholdt TT, Amundsen BH, Rustad LA, Wahba A, Løvø KT, Gullikstad LR, et al. Aerobic interval training versus continuous moderate exercise after coronary artery bypass surgery: a randomized study of cardiovascular effects and quality of life. American Heart Journal 2009;158(6):1031-7. 55. Swift DL, Houmard JA, Slentz CA, Kraus WE. Effects of aerobic training with and without weight loss on insulin sensitivity and lipids. PloS One 2018;13(5):e0196637. 56. Schjerve IE, Tyldum GA, Tjønna AE, Stølen T, Loennechen JP, Hansen HE, et al. Both aerobic endurance and strength training programmes improve cardiovascular health in obese adults. Clinical Science 2008;115(9):283-93. 57. Thomas T, Adeniran S, Iltis P, Aquiar C, Albers J. Effects of interval and continuous running on HDL-cholesterol, apoproteins A-1 and B, and LCAT. Canadian Journal of Applied Sport Sciences 1985;10(1):52-9. 58. Teixeira-Lemos E, Nunes S, Teixeira F, Reis F. Regular physical exercise training assists in preventing type 2 diabetes development: focus on its antioxidant and anti-inflammatory properties. Cardiovascular Diabetology 2011;10(1):12. 59. Turcotte LP, Fisher JS. Skeletal muscle insulin resistance: roles of fatty acid metabolism and exercise. Physical Therapy 2008;88(11):1279-96. 60. Motahari-Tabari N, Shirvani MA, Shirzad-e-Ahoodashty M, Yousefi-Abdolmaleki E, Teimourzadeh M. The effect of 8 weeks aerobic exercise on insulin resistance in type 2 diabetes: a randomized clinical trial. Glob J Health Science 2015;7(1):115.