madman
Super Moderator
Abstract: Creatine is one of the most popular supplements worldwide, and it is frequently used by both athletic and non-athletic populations to improve power, strength, muscle mass, and performance. A growing body of evidence has been identified potential therapeutic effects of creatine in a wide variety of clinical conditions, such as cancer, muscle dystrophy, and neurodegenerative disorders. Evidence has suggested that creatine supplementation alone, and mainly in combination with exercise training, may improve glucose metabolism in healthy individuals and insulin-resistant individuals, such as in those with type 2 diabetes mellitus. Creatine itself may stimulate insulin secretion in vitro, improve muscle glycogen stores and ameliorate hyperglycemia in animals. In addition, exercise induces numerous metabolic benefits, including increases in insulin-independent muscle glucose uptake and insulin sensitivity. It has been speculated that creatine supplementation combined with exercise training could result in additional improvements in glucose metabolism when compared with each intervention separately. The possible mechanism underlying the effects of combined exercise and creatine supplementation is an enhanced glucose transport into the muscle cell by type 4 glucose transporter (GLUT-4) translocation to the sarcolemma. Although preliminary findings from small-scale trials involving patients with type 2 diabetes mellitus are promising, the efficacy of creatine for improving glycemic control is yet to be confirmed. In this review, we aim to explore the possible therapeutic role of creatine supplementation on glucose management and as a potential anti-diabetic intervention, summarizing the current knowledge and highlighting the research gaps.
1. Introduction
Type 2 diabetes mellitus (T2DM) is a major public health concern worldwide, imposing high health costs for public and private health systems. According to the Global Burden of Disease Study, diabetes incidence increased from 11.3 million in 1990 to 22.9 million in 2017, whilst prevalence increased from 211.2 million in 1990 to 476.0 million in 2017 [1]. In 2017, the International Diabetes Federation estimated that 451 million adults live with diabetes, and by 2045, this number could increase to 693 million if no preventive measures are adopted [2].
T2DM is a metabolic disorder characterized by sustained hyperglycemia resulting from impaired insulin production by pancreatic β cells, impaired insulin action (i.e., insulin resistance), or both [3]. Chronic hyperglycemia in diabetes is associated with several cardiometabolic disorders, such as hypertension, dyslipidemia, atherosclerosis, and visceral obesity. Moreover, T2DM is considered one of the top 10 causes of premature deaths from non-communicable diseases and is associated with increased mortality from infections, cardiovascular disease, stroke, chronic kidney disease, chronic liver disease, and cancer. In fact, all-cause mortality risk increases by 2- to 3-fold in individuals with diabetes [1].
T2DM can be managed with non-pharmacological treatment (i.e., weight reduction, dietary intervention, and physical activity) and/or pharmacological treatment [4]. There have been several dietary candidates to help control glycemia, so far with little or no clinical support from large, controlled trials. In the past two decades, creatine (α-methyl guanidine-acetic acid) supplementation has also been speculated as a dietary supplement potentially able to improve glucose control and insulin resistance.
Creatine is a naturally occurring amine, which is endogenously synthesized (~1 g·d −1 ) in the liver, kidneys, and pancreas from the amino acid glycine, methionine, and arginine. Creatine can also be exogenously obtained from food sources (~1–5 g·d −1 ), especially by the ingestion of beef, pork, chicken, and fish. In humans, creatine is found in its free (60 to 70%) and phosphorylated (30 to 40%) forms. Approximately 95% of the total bodily creatine store is found in skeletal muscle, with the remaining 5% being found in cells with rapid energy demands, such as cardiac myocytes, retina, neurons, and testicles. Creatine excretion occurs through its irreversible and non-enzymatic conversion to creatinine, which is then eliminated by the kidneys [5].
Creatine supplementation is a popular strategy to improve exercise performance in healthy individuals and athletes due to its efficacy of increasing muscle-free creatine and phosphorylcreatine contents [6]. Strong evidence indicates that creatine supplementation increases muscle strength, lean mass and improves performance in high-intensity, short-duration exercise [7]. Moreover, new applications for creatine have been proposed, as creatine seems to have potential therapeutic properties in a wide variety of clinical conditions, such as muscle disorders, neurodegenerative conditions and, metabolic dysfunctions, including insulin resistance and T2DM [8].
There is preliminary evidence showing that creatine supplementation could affect glucose metabolism. Studies have demonstrated that creatine ingestion combined with carbohydrate promotes greater total muscle glycogen accumulation in animals [9,10] and in humans [11]. Additionally, creatine supplementation along with carbohydrate promotes greater muscle creatine retention than creatine alone [12]. These effects may be partially explained by the fact that both muscle glucose and creatine uptake are influenced by insulin-dependent transporters. In vitro studies showed that creatine increases insulin secretion [13,14]; human studies, however, did not demonstrate the same effects [15,16]. In addition, creatine supplementation was shown to ameliorate hyperglycemia in transgenic Huntington mice and delay diabetes offset [17]. In humans, creatine supplementation associated with exercise training improved glycemia in sedentary [18] and T2DM adults [19]. Altogether, these findings provide the rationale for exploring the application of creatine as a potential anti-diabetic intervention. In this short, narrative review, we will describe the effects of creatine supplementation on glycemic control, summarizing the current knowledge and highlighting the research gaps.
2. Insulin resistance in the Context of the Interplay between Creatine and Glucose Metabolism
3. Effects of Creatine Supplementation Alone on Glycemic Control
4. Effects of Creatine Supplementation Combined with Exercise on Glycemic Control
5. Conclusions and Future Directions
Creatine supplementation has the potential to promote changes in glucose metabolism that may favor a healthier metabolic profile. This may be particularly true when exercise training is provided along with this supplement, as creatine seems to enhance the training adaptations.
Evidence supporting the role of creatine on glucose metabolism remains speculative. As discussed, pre-clinical data are difficult to interpret as creatine responses are highly dependent on the experimental model adopted. The few existing clinical trials are small-scale, short-term, and, therefore, exploratory. Despite the fact that a few of them have revealed promising benefits of creatine on glucose control, especially when exercise as co-prescribed, further large, longer-term, controlled trials involving T2DM with variable disease severity and under different pharmacological treatments are necessary to drawn firm conclusions on the efficacy and safety of creatine as an anti-diabetic intervention. It is equally important to develop new investigations aimed at unraveling the mechanisms by which creatine, aligned or not with training, could regulate glucose control, as basic research is indeed useful to better target potentially most benefited populations for testing creatine in the next clinical trials.
1. Introduction
Type 2 diabetes mellitus (T2DM) is a major public health concern worldwide, imposing high health costs for public and private health systems. According to the Global Burden of Disease Study, diabetes incidence increased from 11.3 million in 1990 to 22.9 million in 2017, whilst prevalence increased from 211.2 million in 1990 to 476.0 million in 2017 [1]. In 2017, the International Diabetes Federation estimated that 451 million adults live with diabetes, and by 2045, this number could increase to 693 million if no preventive measures are adopted [2].
T2DM is a metabolic disorder characterized by sustained hyperglycemia resulting from impaired insulin production by pancreatic β cells, impaired insulin action (i.e., insulin resistance), or both [3]. Chronic hyperglycemia in diabetes is associated with several cardiometabolic disorders, such as hypertension, dyslipidemia, atherosclerosis, and visceral obesity. Moreover, T2DM is considered one of the top 10 causes of premature deaths from non-communicable diseases and is associated with increased mortality from infections, cardiovascular disease, stroke, chronic kidney disease, chronic liver disease, and cancer. In fact, all-cause mortality risk increases by 2- to 3-fold in individuals with diabetes [1].
T2DM can be managed with non-pharmacological treatment (i.e., weight reduction, dietary intervention, and physical activity) and/or pharmacological treatment [4]. There have been several dietary candidates to help control glycemia, so far with little or no clinical support from large, controlled trials. In the past two decades, creatine (α-methyl guanidine-acetic acid) supplementation has also been speculated as a dietary supplement potentially able to improve glucose control and insulin resistance.
Creatine is a naturally occurring amine, which is endogenously synthesized (~1 g·d −1 ) in the liver, kidneys, and pancreas from the amino acid glycine, methionine, and arginine. Creatine can also be exogenously obtained from food sources (~1–5 g·d −1 ), especially by the ingestion of beef, pork, chicken, and fish. In humans, creatine is found in its free (60 to 70%) and phosphorylated (30 to 40%) forms. Approximately 95% of the total bodily creatine store is found in skeletal muscle, with the remaining 5% being found in cells with rapid energy demands, such as cardiac myocytes, retina, neurons, and testicles. Creatine excretion occurs through its irreversible and non-enzymatic conversion to creatinine, which is then eliminated by the kidneys [5].
Creatine supplementation is a popular strategy to improve exercise performance in healthy individuals and athletes due to its efficacy of increasing muscle-free creatine and phosphorylcreatine contents [6]. Strong evidence indicates that creatine supplementation increases muscle strength, lean mass and improves performance in high-intensity, short-duration exercise [7]. Moreover, new applications for creatine have been proposed, as creatine seems to have potential therapeutic properties in a wide variety of clinical conditions, such as muscle disorders, neurodegenerative conditions and, metabolic dysfunctions, including insulin resistance and T2DM [8].
There is preliminary evidence showing that creatine supplementation could affect glucose metabolism. Studies have demonstrated that creatine ingestion combined with carbohydrate promotes greater total muscle glycogen accumulation in animals [9,10] and in humans [11]. Additionally, creatine supplementation along with carbohydrate promotes greater muscle creatine retention than creatine alone [12]. These effects may be partially explained by the fact that both muscle glucose and creatine uptake are influenced by insulin-dependent transporters. In vitro studies showed that creatine increases insulin secretion [13,14]; human studies, however, did not demonstrate the same effects [15,16]. In addition, creatine supplementation was shown to ameliorate hyperglycemia in transgenic Huntington mice and delay diabetes offset [17]. In humans, creatine supplementation associated with exercise training improved glycemia in sedentary [18] and T2DM adults [19]. Altogether, these findings provide the rationale for exploring the application of creatine as a potential anti-diabetic intervention. In this short, narrative review, we will describe the effects of creatine supplementation on glycemic control, summarizing the current knowledge and highlighting the research gaps.
2. Insulin resistance in the Context of the Interplay between Creatine and Glucose Metabolism
3. Effects of Creatine Supplementation Alone on Glycemic Control
4. Effects of Creatine Supplementation Combined with Exercise on Glycemic Control
5. Conclusions and Future Directions
Creatine supplementation has the potential to promote changes in glucose metabolism that may favor a healthier metabolic profile. This may be particularly true when exercise training is provided along with this supplement, as creatine seems to enhance the training adaptations.
Evidence supporting the role of creatine on glucose metabolism remains speculative. As discussed, pre-clinical data are difficult to interpret as creatine responses are highly dependent on the experimental model adopted. The few existing clinical trials are small-scale, short-term, and, therefore, exploratory. Despite the fact that a few of them have revealed promising benefits of creatine on glucose control, especially when exercise as co-prescribed, further large, longer-term, controlled trials involving T2DM with variable disease severity and under different pharmacological treatments are necessary to drawn firm conclusions on the efficacy and safety of creatine as an anti-diabetic intervention. It is equally important to develop new investigations aimed at unraveling the mechanisms by which creatine, aligned or not with training, could regulate glucose control, as basic research is indeed useful to better target potentially most benefited populations for testing creatine in the next clinical trials.
