Effect of training and creatine supplementation interaction on insulin resistance and glucose tolerance in obese male rats

Document Type : original article


1 Faculty of Sport Sciences, Bu Ali Sina University, Hamedan, Iran

2 Master of Sports Physiology, Faculty of Sports Sciences, Bu Ali Sina University, Hamedan, Iran


Purpose: The present study was undertaken to explore the effects of exercise training and creatine supplementation interaction on insulin resistance and glucose tolerance in obese male rats.
Methods: 50 male Wistar rats (weigh; 160 ± 15 g) were randomly divided into five groups. Control, High-fat Diet, High-Fat Diet plus creatine supplementation, High-Fat Diet plus exercise training and High-Fat Diet plus Creatine plus exercise training. Training program was 12 weeks swimming and each week its duration increased. At the end, rats underwent the glucose tolerance test (OGTT) and the blood samples for analyzing TG, HDL and insulin collected. Moreover, for determining of PGC-1α expression the SOL muscle dissected. 
Results: Obesity resulted in increased insulin resistance level and it also reduced glucose tolerance and insulin efficiency; creatine supplementation alone did not affect these changes. Training reduced insulin resistance and also elevated glucose tolerance and insulin efficiency in high-fat fed rats and creatine supplementation combined with training had additive effect on these variables. High-fat diet reduced PGC-1α protein level and training elevated it. Creatine supplementation alone or combined with training did not change the expression of this protein (P < 0.05).
Conclusion: For the first time, this study shows that combined creatine supplementation with training resulted in improved glycemic control and insulin efficiency and it also reduced the insulin resistance of obese rats.


  1. Rahmani A, Sayehmiri K, Asadollahi K, Sarokhani D, Islami F, Sarokhani MJAMI. Investigation of the prevalence of obesity in Iran: a systematic review and meta-analysis study. 2015:596-607.
  2. Rice Bradley BH. Dietary Fat and Risk for Type 2 Diabetes: a Review of Recent Research. Curr Nutr Rep. 2018;7(4):214-26.
  3. Acosta-Montano P, Garcia-Gonzalez V. Effects of Dietary Fatty Acids in Pancreatic Beta Cell Metabolism, Implications in Homeostasis. Nutrients. 2018;10(4).
  4. Pi-Sunyer FX. The medical risks of obesity. Obesity surgery. 2002;12 Suppl 1:6s-11s.
  5. Dassonvalle J, Díaz-Castro F, Donoso-Barraza C, Sepúlveda C, Pino-de la Fuente F, Pino P, et al. Moderate Aerobic Exercise Training Prevents the Augmented Hepatic Glucocorticoid Response Induced by High-Fat Diet in Mice. International journal of molecular sciences. 2020;21(20).
  6. Thyfault JP, Bergouignan A. Exercise and metabolic health: beyond skeletal muscle. Diabetologia. 2020;63(8):1464-74.
  7. Kazeminasab F, Marandi SM, Ghaedi K, Safaeinejad Z, Esfarjani F, Nasr-Esfahani MHJAp, nutrition,, et al. A comparative study on the effects of high-fat diet and endurance training on the PGC-1α-FNDC5/irisin pathway in obese and nonobese male C57BL/6 mice. 2018;43(7):651-62.
  8. Lira VA, Benton CR, Yan Z, Bonen AJAJoP-E, Metabolism. PGC-1α regulation by exercise training and its influences on muscle function and insulin sensitivity. 2010;299(2):E145-E61.
  9. Harris RC, Söderlund K, Hultman E. Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clinical science (London, England : 1979). 1992;83(3):367-74.
  10. Kreider RB, Kalman DS, Antonio J, Ziegenfuss TN, Wildman R, Collins R, et al. International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine. Journal of the International Society of Sports Nutrition. 2017;14:18.
  11. Pinto CL, Botelho PB, Pimentel GD, Campos-Ferraz PL, Mota JF. Creatine supplementation and glycemic control: a systematic review. Amino Acids. 2016;48(9):2103-29.
  12. Pinto CL, Botelho PB, Carneiro JA, Mota JFJJoc, sarcopenia, muscle. Impact of creatine supplementation in combination with resistance training on lean mass in the elderly. 2016;7(4):413-21.
  13. Vaisy M, Szlufcik K, De Bock K, Eijnde BO, Van Proeyen K, Verbeke K, et al. Exercise-induced, but not creatine-induced, decrease in intramyocellular lipid content improves insulin sensitivity in rats. 2011;22(12):1178-85.
  14. Nagy C, Einwallner EJJ. Study of in vivo glucose metabolism in high-fat diet-fed mice using oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). 2018(131):e56672.
  15. Koh J-H, Hancock CR, Han D-H, Holloszy JO, Nair KS, Dasari SJAJoP-E, et al. AMPK and PPARβ positive feedback loop regulates endurance exercise training-mediated GLUT4 expression in skeletal muscle. 2019;316(5):E931-E9.
  16. Lowry OH, Rosebrough NJ, Farr AL, Randall RJJJobc. Protein measurement with the Folin phenol reagent. 1951;193:265-75.
  17. Wallace TM, Levy JC, Matthews DRJDc. Use and abuse of HOMA modeling. 2004;27(6):1487-95.
  18. Sakaguchi K, Takeda K, Maeda M, Ogawa W, Sato T, Okada S, et al. Glucose area under the curve during oral glucose tolerance test as an index of glucose intolerance. 2016;7(1):53-8.
  19. Ismail HM, Xu P, Libman IM, Becker DJ, Marks JB, Skyler JS, et al. The shape of the glucose concentration curve during an oral glucose tolerance test predicts risk for type 1 diabetes. 2018;61(1):84-92.
  20. Lee MOJAjop-lc. Determination of the surface area of the white rat with its application to the expression of metabolic results. 1929;89(1):24-33.
  21. Hariri N, Thibault LJNrr. High-fat diet-induced obesity in animal models. 2010;23(2):270-99.
  22. Qatanani M, Lazar MAJG, development. Mechanisms of obesity-associated insulin resistance: many choices on the menu. 2007;21(12):1443-55.
  23. Roberts CK, Hevener AL, Barnard RJ. Metabolic syndrome and insulin resistance: underlying causes and modification by exercise training. Compr Physiol. 2013;3(1):1-58.
  24. Liang H, Ward WFJAipe. PGC-1α: a key regulator of energy metabolism. 2006.
  25. Łukaszuk B, Kurek K, Mikłosz A, Żendzian-Piotrowska M, Chabowski AJCP, Biochemistry. The role of PGC-1α in the development of insulin resistance in skeletal muscle-revisited. 2015;37(6):2288-96.
  26. Bournat JC, Brown CWJCoie, diabetes,, obesity. Mitochondrial dysfunction in obesity. 2010;17(5):446.
  27. Storlien L, Baur L, Kriketos A, Pan D, Cooney G, Jenkins A, et al. Dietary fats and insulin action. 1996;39(6):621-31.
  28. Honors MA, Hargrave SL, Kinzig KP. Glucose tolerance in response to a high-fat diet is improved by a high-protein diet. Obesity (Silver Spring, Md). 2012;20(9):1859-65.
  29. Buettner R, Schölmerich J, Bollheimer LC. High-fat diets: modeling the metabolic disorders of human obesity in rodents. Obesity (Silver Spring, Md). 2007;15(4):798-808.
  30. Lin J, Handschin C, Spiegelman BM. Metabolic control through the PGC-1 family of transcription coactivators. Cell metabolism. 2005;1(6):361-70.
  31. Handschin C, Spiegelman BM. Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism. Endocrine reviews. 2006;27(7):728-35.
  32. Koves TR, Li P, An J, Akimoto T, Slentz D, Ilkayeva O, et al. Peroxisome proliferator-activated receptor-gamma co-activator 1alpha-mediated metabolic remodeling of skeletal myocytes mimics exercise training and reverses lipid-induced mitochondrial inefficiency. The Journal of biological chemistry. 2005;280(39):33588-98.
  33. Michael LF, Wu Z, Cheatham RB, Puigserver P, Adelmant G, Lehman JJ, et al. Restoration of insulin-sensitive glucose transporter (GLUT4) gene expression in muscle cells by the transcriptional coactivator PGC-1. Proceedings of the National Academy of Sciences of the United States of America. 2001;98(7):3820-5.
  34. Stefani GP, Nunes RB, Dornelles AZ, Alves JP, Piva MO, Domenico MD, et al. Effects of creatine supplementation associated with resistance training on oxidative stress in different tissues of rats. Journal of the International Society of Sports Nutrition. 2014;11(1):11.
  35. Volek JS, Duncan ND, Mazzetti SA, Staron RS, Putukian M, Gomez A, et al. Performance and muscle fiber adaptations to creatine supplementation and heavy resistance training. 1999;31(8):1147-56.
  36. Li N, Fu J, Koonen DP, Kuivenhoven JA, Snieder H, Hofker MHJA. Are hypertriglyceridemia and low HDL causal factors in the development of insulin resistance? 2014;233(1):130-8.
  37. Rahimi RJTJoS, Research C. Creatine supplementation decreases oxidative DNA damage and lipid peroxidation induced by a single bout of resistance exercise. 2011;25(12):3448-55.
  38. Ingram KH, Hill H, Moellering DR, Hill BG, Lara-Castro C, Newcomer B, et al. Skeletal muscle lipid peroxidation and insulin resistance in humans. 2012;97(7):E1182-E6.
  39. Ferretti R, Moura EG, Dos Santos VC, Caldeira EJ, Conte M, Matsumura CY, et al. High-fat diet suppresses the positive effect of creatine supplementation on skeletal muscle function by reducing protein expression of IGF-PI3K-AKT-mTOR pathway. PLoS One. 2018;13(10):e0199728.
  40. Dolan E, Artioli GG, Pereira RMR, Gualano B. Muscular Atrophy and Sarcopenia in the Elderly: Is There a Role for Creatine Supplementation? Biomolecules. 2019;9(11).
  41. Derave W, Eijnde BO, Verbessem P, Ramaekers M, Van Leemputte M, Richter EA, et al. Combined creatine and protein supplementation in conjunction with resistance training promotes muscle GLUT-4 content and glucose tolerance in humans. Journal of applied physiology (Bethesda, Md : 1985). 2003;94(5):1910-6.
  42. Alves CR, Ferreira JC, de Siqueira-Filho MA, Carvalho CR, Lancha AH, Jr., Gualano B. Creatine-induced glucose uptake in type 2 diabetes: a role for AMPK-alpha? Amino Acids. 2012;43(4):1803-7.
  • Receive Date: 22 December 2020
  • Revise Date: 22 May 2021
  • Accept Date: 24 May 2021
  • First Publish Date: 05 December 2021
  • Publish Date: 21 March 2022