Creatine Supplementation as an Adjunct to Exercise in Type 2 Diabetes: Effects on Muscle Metabolism and Glycemic Control – A Literature-Based Review
DOI:
https://doi.org/10.12775/QS.2026.57.72536Keywords
creatine, glucose metabolism, skeletal muscle, exercise, type 2 diabetes, supplementationAbstract
Introduction and aim of the study. This study aimed to evaluate the role of creatine supplementation, particularly in combination with physical activity, in the management of type 2 diabetes mellitus, with emphasis on muscle metabolism and glycemic control.
Research materials and methods: A literature-based review was conducted using major scientific databases, including PubMed, Scopus, and Web of Science. The analysis included randomized controlled trials, systematic reviews, and mechanistic studies investigating creatine supplementation and its metabolic effects in diabetic and non-diabetic populations.
Basic results: Creatine plays a central role in cellular energy metabolism through the phosphocreatine system. Evidence suggests that supplementation may enhance glucose uptake via increased GLUT-4 translocation, improve insulin sensitivity, and support skeletal muscle function. When combined with exercise, creatine may exert synergistic effects on glycemic control. However, available clinical evidence remains limited and heterogeneous.
Conclusions: Creatine supplementation may be a promising adjunct strategy in the management of type 2 diabetes, particularly when combined with regular physical activity. Further high-quality clinical trials are required to establish clear clinical recommendations.
References
1. Kalyani RR, Neumiller JJ, Maruthur NM, Wexler DJ. Diagnosis and Treatment of Type 2 Diabetes in Adults: A Review. JAMA. 2025;334(11):984–1002. 10.1001/jama.2025.5956:
https://doi.org/10.1001/jama.2025.5956
2. Ahmad E, Lim S, Lamptey R, Webb DR, Davies MJ. Type 2 diabetes. Lancet. 2022;400(10365):1803–20. 10.1016/S0140-6736(22)01655-5:
https://doi.org/10.1016/S0140-6736(22)01655-5
3. Collaborators GBDD. Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the Global Burden of Disease Study 2021. Lancet. 2023;402(10397):203–34. 10.1016/S0140-6736(23)01301-6:
https://doi.org/10.1016/S0140-6736(23)01301-6
4. Hwang J, Thurmond DC. Exocytosis Proteins: Typical and Atypical Mechanisms of Action in Skeletal Muscle. Front Endocrinol (Lausanne). 2022;13:915509. 10.3389/fendo.2022.915509:
https://doi.org/10.3389/fendo.2022.915509
5. Richter EA, Bilan PJ, Klip A. A comprehensive view of muscle glucose uptake: regulation by insulin, contractile activity, and exercise. Physiol Rev. 2025;105(3):1867–945. 10.1152/physrev.00033.2024:
https://doi.org/10.1152/physrev.00033.2024
6. Zierath JR, Krook A, Wallberg-Henriksson H. Insulin action in skeletal muscle from patients with NIDDM. Mol Cell Biochem. 1998;182(1-2):153–60.
7. Shepherd PR, Kahn BB. Glucose transporters and insulin action--implications for insulin resistance and diabetes mellitus. N Engl J Med. 1999;341(4):248–57. 10.1056/NEJM199907223410406:
https://doi.org/10.1056/NEJM199907223410406
8. Shulman GI. Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N Engl J Med. 2014;371(12):1131–41. 10.1056/NEJMra1011035:
https://doi.org/10.1056/NEJMra1011035
9. Samuel VT, Petersen KF, Shulman GI. Lipid-induced insulin resistance: unravelling the mechanism. Lancet. 2010;375(9733):2267–77. 10.1016/S0140-6736(10)60408-4:
https://doi.org/10.1016/S0140-6736(10)60408-4
10. Richter EA, Hargreaves M. Exercise, GLUT4, and skeletal muscle glucose uptake. Physiol Rev. 2013;93(3):993–1017. 10.1152/physrev.00038.2012:
https://doi.org/10.1152/physrev.00038.2012
11. Kjobsted R, Munk-Hansen N, Birk JB, Foretz M, Viollet B, Bjornholm M, et al. Enhanced Muscle Insulin Sensitivity After Contraction/Exercise Is Mediated by AMPK. Diabetes. 2017;66(3):598–612. 10.2337/db16-0530:
https://doi.org/10.2337/db16-0530
12. Kjobsted R, Roll JLW, Jorgensen NO, Birk JB, Foretz M, Viollet B, et al. AMPK and TBC1D1 Regulate Muscle Glucose Uptake After, but Not During, Exercise and Contraction. Diabetes. 2019;68(7):1427–40. 10.2337/db19-0050:
https://doi.org/10.2337/db19-0050
13. Cartee GD. Roles of TBC1D1 and TBC1D4 in insulin- and exercise-stimulated glucose transport of skeletal muscle. Diabetologia. 2015;58(1):19–30. 10.1007/s00125-014-3395-5:
https://doi.org/10.1007/s00125-014-3395-5
14. Holloszy JO. Regulation of mitochondrial biogenesis and GLUT4 expression by exercise. Compr Physiol. 2011;1(2):921–40. 10.1002/cphy.c100052:
https://doi.org/10.1002/cphy.c100052
15. Sharer JD, Bodamer O, Longo N, Tortorelli S, Wamelink MM, Young S. Laboratory diagnosis of creatine deficiency syndromes: a technical standard and guideline of the American College of Medical Genetics and Genomics. Genet Med. 2017;19(2):256–63. 10.1038/gim.2016.203:
https://doi.org/10.1038/gim.2016.203
16. Wallimann T, Tokarska-Schlattner M, Schlattner U. The creatine kinase system and pleiotropic effects of creatine. Amino Acids. 2011;40(5):1271–96. 10.1007/s00726-011-0877-3:
https://doi.org/10.1007/s00726-011-0877-3
17. 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. 10.1007/s00726-016-2277-1:
https://doi.org/10.1007/s00726-016-2277-1
18. Ju JS, Smith JL, Oppelt PJ, Fisher JS. Creatine feeding increases GLUT4 expression in rat skeletal muscle. Am J Physiol Endocrinol Metab. 2005;288(2):E347–52. 10.1152/ajpendo.00238.2004:
https://doi.org/10.1152/ajpendo.00238.2004
19. Su Y. Three-dimensional network of creatine metabolism: From intracellular energy shuttle to systemic metabolic regulatory switch. Mol Metab. 2025;100:102228. 10.1016/j.molmet.2025.102228:
https://doi.org/10.1016/j.molmet.2025.102228
20. Sahlin K, Harris RC. The creatine kinase reaction: a simple reaction with functional complexity. Amino Acids. 2011;40(5):1363–7. 10.1007/s00726-011-0856-8:
https://doi.org/10.1007/s00726-011-0856-8
21. Barclay CJ. Energy demand and supply in human skeletal muscle. J Muscle Res Cell Motil. 2017;38(2):143–55. 10.1007/s10974-017-9467-7:
https://doi.org/10.1007/s10974-017-9467-7
22. Schlattner U, Klaus A, Ramirez Rios S, Guzun R, Kay L, Tokarska-Schlattner M. Cellular compartmentation of energy metabolism: creatine kinase microcompartments and recruitment of B-type creatine kinase to specific subcellular sites. Amino Acids. 2016;48(8):1751–74. 10.1007/s00726-016-2267-3:
https://doi.org/10.1007/s00726-016-2267-3
23. 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. J Int Soc Sports Nutr. 2017;14:18. 10.1186/s12970-017-0173-z:
https://doi.org/10.1186/s12970-017-0173-z
24. Casey A, Greenhaff PL. Does dietary creatine supplementation play a role in skeletal muscle metabolism and performance? Am J Clin Nutr. 2000;72(2 Suppl):607S–17S. 10.1093/ajcn/72.2.607S:
https://doi.org/10.1093/ajcn/72.2.607S
25. Terjung RL, Clarkson P, Eichner ER, Greenhaff PL, Hespel PJ, Israel RG, et al. American College of Sports Medicine roundtable. The physiological and health effects of oral creatine supplementation. Med Sci Sports Exerc. 2000;32(3):706–17. 10.1097/00005768-200003000-00024:
https://doi.org/10.1097/00005768-200003000-00024
26. Candow DG, Ostojic SM, Chilibeck PD, Longobardi I, Gualano B, Tarnopolsky MA, et al. Creatine monohydrate supplementation for older adults and clinical populations. J Int Soc Sports Nutr. 2025;22(sup1):2534130. 10.1080/15502783.2025.2534130:
https://doi.org/10.1080/15502783.2025.2534130
27. Musi N, Yu H, Goodyear LJ. AMP-activated protein kinase regulation and action in skeletal muscle during exercise. Biochem Soc Trans. 2003;31(Pt 1):191–5. 10.1042/bst0310191:
https://doi.org/10.1042/bst0310191
28. Winder WW. Energy-sensing and signaling by AMP-activated protein kinase in skeletal muscle. J Appl Physiol (1985). 2001;91(3):1017–28. 10.1152/jappl.2001.91.3.1017:
https://doi.org/10.1152/jappl.2001.91.3.1017
29. Ponticos M, Lu QL, Morgan JE, Hardie DG, Partridge TA, Carling D. Dual regulation of the AMP-activated protein kinase provides a novel mechanism for the control of creatine kinase in skeletal muscle. EMBO J. 1998;17(6):1688–99. 10.1093/emboj/17.6.1688:
https://doi.org/10.1093/emboj/17.6.1688
30. Taylor EB, Ellingson WJ, Lamb JD, Chesser DG, Compton CL, Winder WW. Evidence against regulation of AMP-activated protein kinase and LKB1/STRAD/MO25 activity by creatine phosphate. Am J Physiol Endocrinol Metab. 2006;290(4):E661–9. 10.1152/ajpendo.00313.2005:
https://doi.org/10.1152/ajpendo.00313.2005
31. Ceddia RB, Sweeney G. Creatine supplementation increases glucose oxidation and AMPK phosphorylation and reduces lactate production in L6 rat skeletal muscle cells. J Physiol. 2004;555(Pt 2):409–21. 10.1113/jphysiol.2003.056291:
https://doi.org/10.1113/jphysiol.2003.056291
32. Eijnde BO, Derave W, Wojtaszewski JF, Richter EA, Hespel P. AMP kinase expression and activity in human skeletal muscle: effects of immobilization, retraining, and creatine supplementation. J Appl Physiol (1985). 2005;98(4):1228–33. 10.1152/japplphysiol.00665.2004:
https://doi.org/10.1152/japplphysiol.00665.2004
33. 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. 10.1007/s00726-012-1246-6:
https://doi.org/10.1007/s00726-012-1246-6
34. Morino K, Petersen KF, Shulman GI. Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes. 2006;55 Suppl 2(Suppl 2):S9–S15. 10.2337/db06-S002:
https://doi.org/10.2337/db06-S002
35. Roszczyc-Owsiejczuk K, Zabielski P. Sphingolipids as a Culprit of Mitochondrial Dysfunction in Insulin Resistance and Type 2 Diabetes. Front Endocrinol (Lausanne). 2021;12:635175. 10.3389/fendo.2021.635175:
https://doi.org/10.3389/fendo.2021.635175
36. Befroy DE, Petersen KF, Dufour S, Mason GF, de Graaf RA, Rothman DL, et al. Impaired mitochondrial substrate oxidation in muscle of insulin-resistant offspring of type 2 diabetic patients. Diabetes. 2007;56(5):1376–81. 10.2337/db06-0783:
https://doi.org/10.2337/db06-0783
37. Yonamine CY, Alves-Wagner AB, Esteves JV, Okamoto MM, Correa-Giannella ML, Giannella-Neto D, et al. Diabetes induces tri-methylation at lysine 9 of histone 3 at Slc2a4 gene in skeletal muscle: A new target to improve glycemic control. Mol Cell Endocrinol. 2019;481:26–34. 10.1016/j.mce.2018.11.006:
https://doi.org/10.1016/j.mce.2018.11.006
38. Mora S, Pessin JE. The MEF2A isoform is required for striated muscle-specific expression of the insulin-responsive GLUT4 glucose transporter. J Biol Chem. 2000;275(21):16323–8. 10.1074/jbc.M910259199:
https://doi.org/10.1074/jbc.M910259199
39. McGee SL, Hargreaves M. Exercise and myocyte enhancer factor 2 regulation in human skeletal muscle. Diabetes. 2004;53(5):1208–14. 10.2337/diabetes.53.5.1208:
https://doi.org/10.2337/diabetes.53.5.1208
40. Op 't Eijnde B, Urso B, Richter EA, Greenhaff PL, Hespel P. Effect of oral creatine supplementation on human muscle GLUT4 protein content after immobilization. Diabetes. 2001;50(1):18–23. 10.2337/diabetes.50.1.18:
https://doi.org/10.2337/diabetes.50.1.18
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. J Appl Physiol (1985). 2003;94(5):1910–6. 10.1152/japplphysiol.00977.2002:
https://doi.org/10.1152/japplphysiol.00977.2002
42. Gualano B, V DESP, Roschel H, Artioli GG, Neves M, Jr., De Sa Pinto AL, et al. Creatine in type 2 diabetes: a randomized, double-blind, placebo-controlled trial. Med Sci Sports Exerc. 2011;43(5):770–8. 10.1249/MSS.0b013e3181fcee7d:
https://doi.org/10.1249/MSS.0b013e3181fcee7d
43. van Loon LJ, Murphy R, Oosterlaar AM, Cameron-Smith D, Hargreaves M, Wagenmakers AJ, et al. Creatine supplementation increases glycogen storage but not GLUT-4 expression in human skeletal muscle. Clin Sci (Lond). 2004;106(1):99–106. 10.1042/CS20030116:
https://doi.org/10.1042/CS20030116
44. Rooney K, Bryson J, Phuyal J, Denyer G, Caterson I, Thompson C. Creatine supplementation alters insulin secretion and glucose homeostasis in vivo. Metabolism. 2002;51(4):518–22. 10.1053/meta.2002.31330:
https://doi.org/10.1053/meta.2002.31330
45. Rocic B, Lovrencic MV, Poje M, Ashcroft SJ. Effect of creatine on the pancreatic beta-cell. Exp Clin Endocrinol Diabetes. 2007;115(1):29–32. 10.1055/s-2007-949591:
https://doi.org/10.1055/s-2007-949591
46. Rizo-Roca D, Guimaraes D, Pendergrast LA, Di Leo N, Chibalin AV, Maqdasy S, et al. Decreased mitochondrial creatine kinase 2 impairs skeletal muscle mitochondrial function independently of insulin in type 2 diabetes. Sci Transl Med. 2024;16(768):eado3022. 10.1126/scitranslmed.ado3022:
https://doi.org/10.1126/scitranslmed.ado3022
47. Mancini de Sousa M, Nakata MTK, Baldini CES, de Oliveira-Sales EB, Boim MA, Martimbianco ALC, et al. Creatine Supplementation in Type 2 Diabetic Patients: A Systematic Review of Randomized Clinical Trials. Curr Diabetes Rev. 2022;18(3):e120721194709. 10.2174/1573399817666210712151737:
https://doi.org/10.2174/1573399817666210712151737
48. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258):405–12. 10.1136/bmj.321.7258.405:
https://doi.org/10.1136/bmj.321.7258.405
49. Gualano B, Novaes RB, Artioli GG, Freire TO, Coelho DF, Scagliusi FB, et al. Effects of creatine supplementation on glucose tolerance and insulin sensitivity in sedentary healthy males undergoing aerobic training. Amino Acids. 2008;34(2):245–50. 10.1007/s00726-007-0508-1:
https://doi.org/10.1007/s00726-007-0508-1
50. Newman JE, Hargreaves M, Garnham A, Snow RJ. Effect of creatine ingestion on glucose tolerance and insulin sensitivity in men. Med Sci Sports Exerc. 2003;35(1):69–74. 10.1097/00005768-200301000-00012:
https://doi.org/10.1097/00005768-200301000-00012
51. Rooney KB, Bryson JM, Digney AL, Rae CD, Thompson CH. Creatine supplementation affects glucose homeostasis but not insulin secretion in humans. Ann Nutr Metab. 2003;47(1):11–5. 10.1159/000068908:
https://doi.org/10.1159/000068908
52. Gualano B, de Salles Painelli V, Roschel H, Lugaresi R, Dorea E, Artioli GG, et al. Creatine supplementation does not impair kidney function in type 2 diabetic patients: a randomized, double-blind, placebo-controlled, clinical trial. Eur J Appl Physiol. 2011;111(5):749–56. 10.1007/s00421-010-1676-3:
https://doi.org/10.1007/s00421-010-1676-3
53. Naeini EK, Eskandari M, Mortazavi M, Gholaminejad A, Karevan N. Effect of creatine supplementation on kidney function: a systematic review and meta-analysis. BMC Nephrol. 2025;26(1):622. 10.1186/s12882-025-04558-6:
https://doi.org/10.1186/s12882-025-04558-6
54. Tsiaras A, Loufopoulos G, Theodoridis X, Liakopoulos V, Poulia KA, Chourdakis M. The effect of creatine supplementation on kidney function: a systematic review and meta-analysis of randomized controlled trials. J Ren Nutr. 2026. 10.1053/j.jrn.2026.04.010:
https://doi.org/10.1053/j.jrn.2026.04.010
55. de Souza ESA, Pertille A, Reis Barbosa CG, Aparecida de Oliveira Silva J, de Jesus DV, Ribeiro A, et al. Effects of Creatine Supplementation on Renal Function: A Systematic Review and Meta-Analysis. J Ren Nutr. 2019;29(6):480–9. 10.1053/j.jrn.2019.05.004:
https://doi.org/10.1053/j.jrn.2019.05.004
56. Kim HJ, Kim CK, Carpentier A, Poortmans JR. Studies on the safety of creatine supplementation. Amino Acids. 2011;40(5):1409–18. 10.1007/s00726-011-0878-2:
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Patryk Marek Modelewski, Jakub Białożyt, Weronika Wagner, Anna Dębniak, Patryk Twardy, Maciej Gutarowicz, Kaja Nieradka, Krystyna Klahs, Michał Armatys, Maciej Muraszko-Kuźma

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Stats
Number of views and downloads: 38
Number of citations: 0