Author: LN. Luis Alberto Gómez Martín

Editorial staff: Prof. Jorge L. Petro, ND. Mayra Márquez & Prof. Jana Kočí, PhD

Type 2 diabetes (T2D) is a metabolic disorder characterized by sustained hyperglycemia resulting from impaired insulin secretion from pancreatic cells, impaired insulin action (i.e., peripheral insulin resistance), or both conditions. Chronic hyperglycemia in TD2 is associated with several cardiometabolic disorders, such as hypertension, dyslipidemia, atherosclerosis, and visceral obesity [1].

TD2 is a major public health problem worldwide because of high healthcare costs to public and private healthcare systems [1]. According to the Global Burden of Disease Study, the incidence of diabetes increased from 11.3 million in 1990 to 22.9 million in 2017, while the prevalence increased from 211.2 million in 1990 to 476.0 million in 2017 [2]. In 2017, the International Diabetes Federation estimated that 451 million adults are living with diabetes, and by 2045, this number could rise to 693 million if the necessary preventive measures are not taken [1,3].

The management of TD2 includes pharmacological and non-pharmacological treatments, the latter are lifestyle changes, intervention with diet and physical exercise (PE) [4,5]. The use of dietary supplements as part of the treatment of TD2 or its clinical outcomes has also been studied [6]. In this sense, over the past two decades, creatine (N-(aminoiminomethyl)-N-methyl-glycine) has also been proposed as a dietary supplement potentially capable of improving glycemic control (GC) and insulin resistance (IR) [1].

It is well known that creatine supplementation (SCr) is a popular strategy for improving physical performance in healthy individuals and athletes, due to its effectiveness in increasing creatine and phosphocreatine levels in skeletal muscle [1]. Robust evidence is available indicating that SCr increases muscle strength, lean mass, and improves performance in strength and high-intensity workouts [7-9]. Apart from sports performance, SCr also has an effect in the context of health and in the therapeutic management of several diseases (for more information, it is suggested to refer to Kreider & Stout [10]). Notably, its potential in the prevention and treatment of TD2 has been proposed [1,11,12].

Preclinical studies have shown the effect of SCr on clinical outcomes associated with TD2.   For example, it has been reported that SCr increased the total creatine content in the pancreas of rats [13]and also resulted in elevated insulin secretion in response to an oral glucose test. Along the same line, Op’t Eijnde et al. [14] observed that SCr in Goto-Kakizaki rats (an animal model of hereditary T2D) increased muscle creatine content and reduced insulinogenic index (i.e., a pancreatic beta cell function index). Therefore, it is proposed that SCr may improve insulin sensitivity at extrapancreatic sites. In humans, controlled clinical trials have shown that SCr, combined with a PE program, improves GC in patients with DT2 [11]. Furthermore, there are reports showing that it is safe for renal function in these types of patients [12]. On the other hand, a randomized, double-blind, placebo-controlled pilot trial, la SCr (5 g/day of creatine monohydrate, per 12 weeks) had no additional effects on markers of inflammation (e.g., chemoattractant protein of monocytes 1, interleukin-6) and IR in older adults [15].

According to Solis et al. [1], among the possible mechanisms involved in the effects of SCr to improve GC, are: increased insulin secretion from beta cells of the pancreas creatine-induced changes in osmoregulation; creatine-induced changes in osmoregulation; and creatine-induced enhancement of glucose uptake through an increase in glucose transporter content or translocation (i.e., GLUT-4). However, there are currently insufficient clinical data to support all these mechanisms.

Figure 1.  Possible creatine-related mechanisms on glycaemic control. Potential mechanisms underpinning creatine’s role in glucose metabolism involve: (1) increased insulin secretion by beta cells; (2) increased expression of genes related to osmosensitivity; (3) increased glucose uptake through the content and activity of the glucose transporter type 4 (GLUT-4); (4) creatine supplementation could enhance the known benefits of exercise on glucose transport/insulin sensitivity. Cr: creatine; CreaT: creatine transporter; IR, insulin receptor; GLUT-4: glucose transporter; PKBa/Akt1: RAC-alpha serine/threonine-protein kinase; AMPK: adenosine monophosphate-activated protein kinase. Taken from: Solis et al. (2021).

In conclusion, there have been promising effects of SCr on DT2-related markers, such as GC and insulin responsiveness in animals. On the other hand, human studies have shown a possible effect of SCr on GC, especially when combined with PE. However, further randomized controlled clinical trials are required to demonstrate whether there are independent or additive effects (i.e., with and without PE) of SCr on T2D, possible mechanisms of action, optimal doses, and interactions with drugs or supplements.

RECOMMENDED CONFERENCE

International Conference on Creatine in Health and Disease throughout the Lifetime
Don’t miss the world’s most important creatine conference!

REFERENCES

[1] Solis MY, Artioli GG, Gualano B. Potential of Creatine in Glucose Management and Diabetes. Nutrients. Feb 9 2021;13(2)doi:10.3390/nu13020570

[2] Lin X, Xu Y, Pan X, et al. Global, regional, and national burden and trend of diabetes in 195 countries and territories: an analysis from 1990 to 2025. Scientific reports. Sep 8 2020;10(1):14790. doi:10.1038/s41598-020-71908-9

[3] Cho NH, Shaw JE, Karuranga S, et al. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes research and clinical practice. Apr 2018;138:271-281. doi:10.1016/j.diabres.2018.02.023

[4] LeRoith D, Biessels GJ, Braithwaite SS, et al. Treatment of Diabetes in Older Adults: An Endocrine Society* Clinical Practice Guideline. The Journal of clinical endocrinology and metabolism. May 1 2019;104(5):1520-1574. doi:10.1210/jc.2019-00198

[5] Magkos F, Hjorth MF, Astrup A. Diet and exercise in the prevention and treatment of type 2 diabetes mellitus. Nature reviews Endocrinology. Oct 2020;16(10):545-555. doi:10.1038/s41574-020-0381-5

[6] Li X, Liu Y, Zheng Y, Wang P, Zhang Y. The Effect of Vitamin D Supplementation on Glycemic Control in Type 2 Diabetes Patients: A Systematic Review and Meta-Analysis. Nutrients. Mar 19 2018;10(3)doi:10.3390/nu10030375

[7] Bonilla DA, Kreider RB, Petro JL, et al. Creatine Enhances the Effects of Cluster-Set Resistance Training on Lower-Limb Body Composition and Strength in Resistance-Trained Men: A Pilot Study.  Nutrients. Jul 4 2021;13(7)doi:10.3390/nu13072303

[8]      Mielgo-Ayuso J, Calleja-Gonzalez J, Marqués-Jiménez D, Caballero-García A, Córdova A, Fernández-Lázaro D. Effects of Creatine Supplementation on Athletic Performance in Soccer Players: A Systematic Review and Meta-Analysis.  Nutrients. Mar 31 2019;11(4)doi:10.3390/nu11040757

[9] Kreider RB. Effects of creatine supplementation on performance and training adaptations. Molecular and cellular biochemistry. Feb 2003;244(1-2):89-94.

[10] Kreider RB, Stout JR. Creatine in Health and Disease. Nutrients. Jan 29 2021;13(2)doi:10.3390/nu13020447

[11] Gualano B, V DESP, Roschel H, et al. Creatine in type 2 diabetes: a randomized, double-blind, placebo-controlled trial.  Medicine and science in sports and exercise. May 2011;43(5):770-8. doi:10.1249/MSS.0b013e3181fcee7d

[12] Gualano B, de Salles Painelli V, Roschel H, et al. Creatine supplementation does not impair kidney function in type 2 diabetic patients: a randomized, double-blind, placebo-controlled, clinical trial.  European journal of applied physiology. May 2011;111(5):749-56. doi:10.1007/s00421-010-1676-3

[13] Rooney K, Bryson J, Phuyal J, Denyer G, Caterson I, Thompson C. Creatine supplementation alters insulin secretion and glucose homeostasis in vivo. Metabolism: clinical and experimental. Apr 2002;51(4):518-22. doi:10.1053/meta.2002.31330

[14] Op’t Eijnde B, Jijakli H, Hespel P, Malaisse WJ. Creatine supplementation increases soleus muscle creatine content and lowers the insulinogenic index in an animal model of inherited type 2 diabetes. International journal of molecular medicine. Jun 2006;17(6):1077-84.

[15] Oliveira CLP, Antunes BMM, Gomes AC, et al. Creatine supplementation does not promote additional effects on inflammation and insulin resistance in older adults: A pilot randomized, double-blind, placebo-controlled trial.  Clinical nutrition ESPEN. Aug 2020;38:94-98. doi:10.1016/j.clnesp.2020.05.024