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From Brain to Glucose: Creatine’s Emerging Role as a Cellular Energy Master and Disease Prevention Tool

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dr. Karunia Valeriani Japar

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Introduction

Creatine, traditionally recognized as an ergogenic aid for athletic performance and muscle growth, has recently garnered attention for its nuanced roles in human metabolism beyond the skeletal muscle. Emerging research reveals that creatine is vital for cellular energy homeostasis, functioning as a rapid buffer and shuttle for adenosine triphosphate (ATP) within tissues that have high energy demands, including the brain and heart. This unique biochemical property positions creatine as a key mediator at the crossroads of neurocognitive function, recovery from physical stress, and metabolic health.

In brain health, creatin’s capacity to support mitochondrial integrity and neuronal resilience translates into promising effects on cognitive performance, fatigue resistance and neuroprotection, especially under conditions of sleep deprivation, aging, or metabolic stress. Meanwhile, creatine supplementation is increasingly investigated for its role in accelerating recovery from exercise-induced fatigue, enhancing tissue repair, and reducing inflammation, making it relevant for both athletes and individuals in clinical rehabilitation.

Importantly, creatine is now implicated in the regulation of glucose metabolism, with evidence suggesting it can improve insulins sensitivity, facilitate muscle glucose uptake, and potentially reduce metabolic risk in populations predisposed to insulin resistance or diabetes. As metabolic health and longevity become central to preventive medicine, understanding creatine’s multifaceted biological mechanisms and potential clinical applications is crucial. This article aims to synthesize current evidence on creatine’s role in brain function, recovery, and glucose control, and highlight its therapeutic potential in preventive health strategies.

Biochemistry of Creatine Metabolism

Endogenous Synthesis and Dietary Sources

Creatine is synthesized endogenously through a two-step enzymatic pathway involving the amino acids glycine, arginine, and methionine. The first step occurs primarily in the kidney, where L-arginine:  glycine amidinotransferase (AGAT) catalyses the reaction between arginine and glycine to produce guanidinoacetate. The second step takes place in the liver, where guanidinoacetate N-methyltransferase (GAMT) facilitates methylation of guanidinoacetate, using S-adenosylmethionine as the methyl donor, yielding creatine. Once synthesized, creatine is transported via the bloodstream to target tissues, predominantly skeletal muscle (about 95% of total body creatine), but also significant concentrations in the brain and heart. Dietary sources also contribute to creatine stores, with red meat, poultry, and fish being rich natural sources. Individuals consuming plant based diets typically have lower creatine stores, which may influence muscle and neurological energy metabolism [1,2,3,4,5] .

Phosphocreatine System and Cellular Energy Buffering

In highly metabolically active tissues, creatine functions as a vital energy buffer. Upon entering muscle or neural cells via the energy-dependent creatine transporter (CRT/SLC6A8), creatine is rapidly phosphorylated by creatine kinase (CK), producing phosphocreatine (PCr). The phosphocreatine system acts as a dynamic reservoir of high energy phosphate groups, permitting rapid regeneration of adenosine triphosphate (ATP) from adenosine diphosphate (ADP) during fluctuating or intense energy demands, such as explosive muscle contractions or rapid neuronal signalling. This buffering capacity underpins the cell’s ability to maintain energy homeostasis during acute metabolic stress and supports sustained performance and recovery. Disruptions in phosphocreatine metabolism, whether from genetic, dietary, or pathological origins, impair energy transfer and contribute to muscle weakness or neurological dysfunction [6,7,8].

Mitochondrial and Neuronal Energy Dynamics

The phosphocreatine shuttle is integral to efficient cellular energy transfer, linking mitochondrial ATP synthesis to peripheral cytosolic sites where energy is consumed, such as ion pumps and contractile proteins. In the mitochondria, mitochondrial creatine kinase (mtCK) catalyses the phosphorylation of creatine using newly generated ATP, forming PCr. The PCr then migrates to the cytosol, where cytosolic CK mediates the reverse reaction, yielding ATP for immediate cellular functions. This compartmentalization ensures both spatial and temporal buffering of ATP, particularly crucial in excitable tissues like the brain and myocardium, where rapid fluctuations in energy demand occur. In neurons, creatine and phosphocreatine not only support neurotransmission and synaptic plasticity but also contribute to neuroprotection, cognitive resilience, and adaptation to metabolic challenges such as hypoxia or oxidative stress. Deficiencies in creatine metabolism, via enzyme mutations or transporter defects can lead to neurodevelopmental and musculoskeletal symptoms, attesting to its physiological significance [9,10].

Creatine and Brain Health

Mechanisms Of Brain Energy Optimization

The brain, despite accounting for only approximately 2% of total body mass, consumes roughly 20% of the body’s total resting energy expenditure, making it one of the most metabolically demanding organs. This high energy requirement necessitates efficient systems for rapid adenosine triphosphate (ATP) regeneration to support fundamental neuronal processes including maintenance of ion gradients, neurotransmitter synthesis and release, and synaptic transmission. The phosphocreatine (PCr) system provides a crucial energy buffer that can regenerate ATP at rates approximately 40 times faster than oxidative phosphorylation and 10 times faster than glycolysis, making it indispensable during periods of elevated metabolic demand. Mitochondrial creatine kinase (mtCK), localized to the inner mitochondrial membrane, catalyses the formation of PCr using newly synthesized ATP, which then diffuses to cytosolic sites of high energy consumption where cytosolic creatine kinase reverses the reaction, yielding ATP for immediate cellular use. This spatial and temporal compartmentalization of energy transfer is particularly critical in neurons, where rapid fluctuations in energy demand occur during action potential firing and synaptic transmission. Beyond its role as an energy buffer, creatine contributes to mitochondrial membrane stabilization through mtCK interaction with cardiolipin, a key phospholipid that preserves cristae integrity and prevents cytochrome c release under oxidative stress conditions. Additionally, creatine supplementation has been shown to activate AMP-activated receptor gamma coactivator-1 alpha (PGC-1a), promoting mitochondrial biogenesis, increasing mitochondrial DNA copy number, and enhancing oxidative phosphorylation capacity in neural tissues. Recent evidence also suggests that creatine may function as a neuromodulator, with studies detecting its presence in synaptic vesicles at concentrations higher than acetylcholine and serotonin, and demonstrating calcium-dependent release upon neuronal stimulation [11,12,13,14].

Effects On Cognitive Performance and Neuroprotection

Accumulating evidence from clinical trials and meta-analysis indicates that creatine supplementation can enhance specific domains of cognitive function, particularly under conditions of metabolic stress. A comprehensive meta-analysis by Xu et al. (2024) involving 16 randomized controlled trials demonstrated significant improvements in memory performance (standardized mean difference [SMD]= 0.31,95% CI:0.18-0.44), attention time (SMD= -0.31, 95% CI: -0.58 to -0.03), and processing speed (SMD= -0,51, 95% CI: -1.01 to -0.01) following creatine monohydrate supplementation. Subgroup analyses revealed that benefits were more pronounced in individuals with diseases, females and those aged 18-60 years. Sleep deprivation studies have provided particularly compelling evidence for creatine’s cognitive benefits under metabolic stress. McMorris et al. (2006) demonstrated that following 24 hours of sleep deprivation, participants who received creatine supplementation (5 g four times daily for 7 days) showed significantly less performance deterioration in random movement generation, choice reaction time, balance, and mood state compared to placebo. More recently, Gordji Nejad et al. (2024) used magnetic resonance spectroscopy to demonstrate that a single high dose of creatine (0.35 g/kg) during partial sleep deprivation maintained normal phosphocreatine and ATP levels in the brain and significantly improved working memory and processing speed. The neuroprotective mechanisms of creatine extend beyond energy metabolism to include antioxidant and anti-apoptotic properties. Creatine reduces reactive oxygen species (ROS) production and lipid peroxidation by supporting the glutathione antioxidant system, sustaining cellular ATP levels reduces the metabolic burden on NADPH-dependent pathways, thereby sparing NADPH for regeneration of reduced glutathione. Additionally, creatine stabilizes mitochondrial membrane potential and delays the opening of the mitochondrial permeability transition pore (mPTP), a critical event in apoptosis initiation. In cellular models of Parkinson’s disease using 6-hydroxydopamine (6-OHDA), both creatine and phosphocreatine protected striatal neurons against oxidative stress-induced cell death by reducing ROS production, preventing mitochondrial depolarization, and preserving tyrosine hydroxylase levels through activation of the PI3K/Akt/GSK3b intracellular pathway. In traumatic brain injury (TBI), a pilot study in children and adolescents found that creatine administration (0.4g/kg daily for 6 months) significantly reduced the duration of post-traumatic amnesia, intubation time, intensive care unit stay, and markedly improved headache, dizziness, and fatigue symptoms [14,15,16,17,18,19].

Insights From Neuroscience and Aging Research

Aging is associated with progressive declines in both muscle and brain creatine stores, potentially contributing to age-related cognitive impairment. Recent systematic reviews examining creatine supplementation in older adults have yielded promising but mixed results. Marshall et al. (2025) conducted a comprehensive systematic review that included six studies with 1,542 participants aged 55 years and older, finding that five of six studies (83.3%) reported positive relationship between creatine and cognition, particularly in memory and attention domains. Prokopidis et al. (2023) demonstrated that creatine supplementation significantly improved memory performance specifically in older adults aged 66-76 years, whereas no such effects were observed in younger adults. Long-term creatine supplementation (3% dietary creatine) in a D-galactose-induced aging mouse model significantly ameliorated learning and memory deficits, improved hippocampal structural plasticity, increased creatine kinase-BB (CK-BB) activity and expression, and reduced oxidative stress markers. Mechanistically, CK-BB plays a critical role in modulating neuronal structural plasticity through regulation of mitochondrial energy metabolism and potentially through effects on synaptic proteins and signalling pathways including Na+/K+- ATPase and CAMKII/CREB. In neurodegenerative disease research, creatine’s therapeutic potential has been extensively investigated with variable outcomes. Preclinical models consistently demonstrate neuroprotective effects, creatine supplementation protects against dopamine depletion in MPTP-induced Parkinson’s models, reduced neuronal damage in Huntington’s disease models, and improves mitochondrial function across multiple neurodegenerative conditions. However, large-scale clinical trials have produced less consistent results. The NINDS NET-PD LS-1 trial, one of the largest Parkinson’s disease trials, found that creatine monohydrate supplementation for at least 5 years did not slow clinical progression as measured by the Unified Parkinson’s Disease Rating Scale. In contrast, emerging pilot studies in Alzheimer’s disease suggest more promise, creatine monohydrate supplementation improved brain mitochondrial function, increased brain creatine concentrations measured by magnetic resonance spectroscopy, and showed potential differential cognitive benefits. The discrepancy between preclinical success and clinical trial outcomes may relate to factors including blood-brain barrier permeability limitations, optimal dosing regimens, disease stage at intervention, baseline creatine status, and individual variability in creatine transporter (SLC6A8) expression and function. Notably, genetic deficiencies in creatine biosynthesis (AGAT or GAMT mutations) or transport (SLC6A8 mutations) result in cerebral creatine deficiency syndromes characterized by intellectual disability, developmental delays, speech impairment, and seizures, underscoring creatine’s fundamental importance for normal brain development and function [20-31].

Creatine in Recovery and Muscle Regeneration

Role in ATP Replenishment and Fatigue Resistance

The capacity to sustain high-intensity muscular effort depends critically on the rapid resynthesis of adenosine triphosphate (ATP), a process in which creatine plays an indispensable role. During maximal exertion, skeletal muscle ATP stores, sufficient for only 1-2 seconds of intense contraction are rapidly depleted, necessitating immediate regeneration from adenosine diphosphate (ADP). Creatine supplementation increases intramuscular phosphocreatine (PCr) stores by approximately 10-40%, effectively expanding the muscle’s energy reservoir and enabling sustained work output during repeated high-intensity efforts. The phosphocreatine system operates via creatine kinase (CK), which catalyses the reversible transfer of a phosphate group from PCr to ADP, regenerating ATP at rates approximately 40 times faster than oxidative phosphorylation and 10 times faster than glycolysis. This rapid ATP buffering capacity delays the accumulation of metabolic byproducts associated with fatigue, including inorganic phosphate (Pi), hydrogens ions (H+), and adenosine monophosphate (AMP). Creatine supplementation has been consistently shown to reduce blood lactate accumulation during high-intensity resistance exercise, with studies demonstrating significant reductions in post-exercise lactate concentrations (placebo: 10.69 ± 1.81 mmol/L vs. creatine: 7.69± 1.16 mmol/L) following short-term loading protocols. By attenuating H+ formation, a primary causative agent of metabolic acidosis and muscular fatigue, creatine functions as an intracellular pH buffer, thereby extending the duration of high-intensity performance. Additionally, elevated PCr availability increases the anaerobic threshold and enhances PCr resynthesis kinetics between exercise bouts, supporting greater training volume, improved work capacity, and accelerated recovery during intermittent high-intensity activities characteristic of team sports, combat sports, and resistance training [32,33,34,35].

Impact On Muscle Recovery , Inflammation and Tissue Repair

Beyond its role in energy metabolism, creatine exerts significant protective and regenerative effects on skeletal muscle following exercise-induced damage. Exercise-induced muscle damage (EIMD), particularly from eccentric contractions, results in sarcolemmal disruption, Z-disc misalignment, elevated intracellular calcium concentrations, activation of calcium-dependent proteolytic pathways, and subsequent inflammatory response, all contributing to decreased force-generating capacity and delayed onset muscle soreness. Creatine supplementation attenuates these deleterious processes through multiple mechanisms. The molecular structure of phosphocreatine allows it to bind to phospholipid heads of sarcolemmal membrane, reducing membrane fluidity and stabilizing cellular integrity, thereby decreasing protein leakage and cellular component loss associated with muscle damage. A systematic review and meta-analysis by Yue and Rahimi (2021) demonstrated that creatine supplementation significantly improved muscle recovery following EIMD, with particular benefits observed when supplementation was continued post-exercise to maintain elevated intramuscular creatine levels during the recovery period. Creatine also modulates the inflammatory response to exercise. Studies have shown that creatine supplementation reduces markers of muscle damage and inflammation, including creatine kinase (CK), lactate dehydrogenase (LDH), tumor necrosis factor- alpha (TNF-a),  and interleukin-6 (IL-6) following intense exercise. At the cellular level, creatine reduces expression of adhesion molecules (ICAM-1 and E-selectin) on endothelial cells exposed to TNF-a, potentially limiting neutrophil recruitment and excessive inflammatory responses that can exacerbate tissue damage. Crucially, creatine supplementation enhances satellite cell proliferation and differentiation, the myogenic stem cells responsible for muscle fiber repair and regeneration. Creatine stimulates the insulin-like growth factor-1 (IGF-1)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signalling pathway, which regulates both muscle protein synthesis and satellite cell activation. Furthermore, creatine supplementation dramatically augments post-exercise muscle glycogen resynthesis particularly during the initial 24 hours of recovery, with studies showing approximately 82% greater glycogen accumulation compared to carbohydrate ingestion alone.  This enhanced glycogen restoration occurs independently of insulin sensitivity changes and likely reflects improved cellular energy status that facilitates glucose uptake and glycogen synthase activity [36,37,38,39].

Integration Into Athletic and Clinical Rehabilitation Contexts

The multifaceted recovery and regenerative benefits of creatine have led to its integration into both athletic performance protocols and clinical rehabilitation settings. In athletic populations, creatine supplementation (typically 20 g/day for 5-7 days loading phase, followed by 3-5 g/day maintenance) consistently enhances resistance training adaptations, increases lean body mass, augments maximal strength and power output, improves repeated sprint performance, and reduces recovery time between training sessions. Post-exercise creatine supplementation protocols, wherein creatine is continued during recovery periods appear particularly effective for mitigating muscle damage, promoting faster restoration of force-production capacity, and supporting training tolerance during intensified training blocks. In clinical rehabilitation contexts, creatine supplementation is emerging as a valuable adjunctive therapy for populations experiencing muscle weakness, atrophy, or functional limitations. During periods of limb immobilization, a common clinical scenario following injury or surgery, creatine supplementation does not prevent muscle atrophy during the immobilization phase itself; however, when combined with subsequent rehabilitation training, creatine significantly accelerates recovery of muscle cross-sectional area, strength, and functional capacity compared to placebo. Mechanistically, this enhanced rehabilitation response appears related to increased myogenic regulatory factor-4 (MRF-4) expression and satellite cell activity, supporting faster muscle fiber regeneration and hypertrophy. Creatine supplementation has also demonstrated efficacy in populations with spinal cord injury (SCI), chronic arthritic diseases, sarcopenia in older adults, and traumatic brain injury-related muscle dysfunction, improving work capacity, lean mass, functional outcomes, and quality of life measures. The favourable safety profile, affordability, and ease of administration make creatine a practical and accessible intervention that complements conventional physical therapy and resistance training rehabilitation protocols. Future research directions include optimization of dosing regimens for specific patient populations, investigation of long-term supplementation effects in chronic disease states, and exploration of creatine’s potential synergistic effects with other nutritional and pharmacological interventions in clinical rehabilitation contexts [40,41,42,43,44,45,46].

Creatine and Glucose Metabolism

Influence On Insulin Sensitivity And Glucose Uptake

Emerging evidence suggests that creatine supplementation may favourably influence glucose homeostasis through multiple interconnected mechanisms involving both insulin-dependent and insulin-independent pathways. At the pancreatic level, in vitro studies have demonstrated that supraphysiological creatine concentrations can potentiate glucose-stimulated insulin secretion from pancreatic β-cells, though this effect appears to be glucose-dependent—creatine increases insulin release only in the presence of glucose, acting as a potentiator rather than an initiator of secretion. The mechanism underlying this potentiation involves creatine-mediated increases in cellular ATP content within β-cells, which supports the ATP-sensitive potassium channel (K~ATP~) pathway critical for insulin granule exocytosis. However, human studies involving healthy adults and patients with type 2 diabetes mellitus (T2DM) have generally not shown increases in circulating insulin concentrations following creatine supplementation, suggesting that any effects on insulin secretion observed in vitro may not translate consistently to in vivo conditions. At the skeletal muscle level, the primary site of postprandial glucose disposal creatine exerts significant effects on glucose uptake through modulation of the glucose transporter type 4 (GLUT-4) system. In a landmark randomized controlled trial, Gualano et al. (2011) demonstrated that 12 weeks of creatine supplementation (5 g·day^−1^) combined with exercise training significantly reduced glycated hemoglobin (HbA1c) in T2DM patients (creatine: 7.4 ± 0.7% to 6.4 ± 0.4%; placebo: 7.5 ± 0.6% to 7.6 ± 0.7%; P = 0.004), representing a clinically meaningful 1.1% absolute reduction. Importantly, this improvement in glycemic control occurred without changes in insulin or C-peptide concentrations, indicating enhanced insulin sensitivity rather than increased insulin secretion. The mechanism underlying these benefits was attributed to increased GLUT-4 translocation to the sarcolemma, independent of changes in total muscle GLUT-4 protein content suggesting that creatine enhances the efficiency of glucose transporter trafficking rather than increasing transporter expression per se. Creatine also induces cellular swelling through increased intracellular water retention, which activates volume-sensitive signalling cascades that potently stimulate glycogen synthesis in both skeletal muscle and liver. Indeed, creatine supplementation has been consistently shown to augment muscle glycogen storage, with studies demonstrating approximately 18-82% greater glycogen accumulation compared to carbohydrate ingestion alone, particularly during the initial 24 hours of post-exercise recovery [47,48].

Creatine’s Interaction With AMPK and GLUT4 Pathways

The molecular mechanisms by which creatine influences glucose metabolism involve complex interactions with adenosine monophosphate-activated protein kinase (AMPK)a master metabolic sensor that regulates cellular energy homeostasis and glucose uptake. AMPK is activated by increases in the AMP:ATP ratio and decreases in the phosphocreatine:creatine (PCr:Cr) ratio, both of which signal cellular energy stress. Paradoxically, creatine supplementation which increases intramuscular PCr stores and improves cellular energy status has been shown to activate AMPK in certain contexts, suggesting that creatine’s effects on AMPK may be mediated through alterations in the PCr:Cr ratio rather than absolute ATP depletion. In L6 rat skeletal muscle cells, 48 hours of creatine supplementation resulted in approximately 2-fold increases in phosphorylation of both α-1 and α-2 AMPK isoforms, accompanied by increased glucose oxidation (40% increase) and reduced lactate production (42% decrease), indicating a metabolic shift toward oxidative glucose metabolism. The activation of AMPK by creatine appears to facilitate GLUT-4 translocation through phosphorylation of downstream substrates including Akt substrate of 160 kDa (AS160), a Rab-GTPase-activating protein whose phosphorylation inhibits its GAP activity, thereby increasing the GTP-bound form of Rab proteins that promote GLUT-4 vesicle trafficking to the plasma membrane. In the aforementioned study by Gualano et al., ancillary molecular analyses revealed that the creatine-induced improvements in glycemic control and increased GLUT-4 translocation were associated with elevated AMPK protein expression in skeletal muscle of T2DM patients. Importantly, AMPK-mediated glucose uptake operates through a phosphatidylinositol 3-kinase (PI3K)-independent pathway, distinct from insulin signalling, providing an alternative mechanism for glucose disposal that remains functional even in insulin-resistant states. Furthermore, creatine supplementation has been shown to upregulate protein kinase B (PKB/Akt1), which plays dual roles in both insulin-stimulated GLUT-4 translocation and glycogen synthase activation, potentially amplifying insulin sensitivity through this parallel signalling axis. The enhanced glycogen storage observed with creatine supplementation may also involve modulation of AMPK’s inhibitory effect on glycogen synthase elevated PCr levels directly inhibit AMPK activation in a dose-dependent manner, thereby releasing glycogen synthase from AMPK-mediated suppression and facilitating glycogen synthesis. Additionally, creatine supplementation increases citrate synthase activity, a key mitochondrial enzyme suggesting enhanced oxidative capacity that supports improved glucose oxidation and metabolic flexibility [49,50].

Potential Therapeutic Implications In Metabolic Syndrome and Diabetes

The convergence of evidence from preclinical and clinical studies positions creatine as a potentially valuable adjunctive intervention for metabolic syndrome and T2DM, conditions characterized by insulin resistance, impaired glucose tolerance, and dysregulated energy metabolism. Metabolic syndrome, a cluster of risk factors including abdominal obesity, dyslipidemia, hypertension, and hyperglycemia affects approximately 25-34% of adults globally and substantially increases cardiovascular disease and diabetes risk. Recent clinical data suggest that creatine supplementation, particularly when combined with exercise training, may address several metabolic syndrome components simultaneously. Beyond glycemic improvements, creatine has been associated with favourable effects on body composition (increased lean mass, reduced fat mass), enhanced physical capacity, and improved mitochondrial function all of which contribute to metabolic health. In animal models of insulin resistance, creatine supplementation has yielded variable but generally promising results. In Goto-Kakizaki rats, a genetic model of T2DM, 8 weeks of creatine supplementation (2% of diet) improved the insulinogenic index (glucose-to-insulin ratio), attributed primarily to reduced insulinemia, suggesting enhanced insulin sensitivity. Similarly, in transgenic Huntington’s disease mice that exhibit hyperglycemia and diabetes, creatine supplementation (1-3% of diet) significantly reduced hyperglycemia and delayed diabetes onset. However, human clinical evidence remains limited in scope and scale. A systematic review and meta-analysis by Andrade et al. (2022) analysed nine studies and found that while five studies reported benefits in at least one diabetes-related parameter, the meta-analysis revealed no significant effects on fasting blood glucose or insulin resistance indices (HOMA-IR). This discordance between individual study findings and pooled analyses likely reflects heterogeneity in study populations, supplementation protocols, exercise co-interventions, and outcome measures. Critically, the most consistent benefits of creatine on glycemic control have been observed when supplementation is combined with structured exercise training, an intervention that independently improves insulin sensitivity, increases GLUT-4 expression, enhances mitochondrial biogenesis, and activates AMPK. The synergistic interaction between creatine and exercise appears to amplify glucose uptake capacity through enhanced GLUT-4 translocation, creating a cumulative effect that neither intervention achieves independently. Safety considerations are paramount in clinical applications, creatine supplementation has demonstrated an excellent safety profile across numerous studies, with no adverse effects on renal function, hepatic function, or other health markers in individuals with T2DM. Future research priorities include large-scale, long-term randomized controlled trials in diverse T2DM populations with varying disease severity and pharmacological treatments, mechanistic studies elucidating creatine’s precise molecular targets in glucose regulation, optimization of dosing strategies and timing relative to meals and exercise, and investigation of potential synergies with established anti-diabetic medications. Moreover, emerging evidence suggests that individuals with T2DM may have impaired creatine kinase activity in skeletal muscle, potentially compromising the phosphocreatine energy buffer system and contributing to metabolic dysfunction, a finding that further supports the therapeutic rationale for creatine supplementation in this population [50,51].

Synergy with Lifestyle and Nutritional Factors

Combining Creatine With Exercise, Protein And Sleep Optimization

Creatine’s ergogenic and metabolic benefits are most pronounced when supplementation is combined with structured physical activity optimal protein intake, and sleep hygiene. Resistance and high intensity interval training amplify the creatine induced increases in lean mass, strength and muscular endurance, driven by synergistic effects on ATP replenishment, glycolytic flux, and anabolic signalling. Recent studies confirm that pre-sleep protein ingestion (30-40g casein) substantially augments overnight muscle protein synthesis rates, especially in combination with evening resistance exercise by providing sustained amino acid delivery, supporting muscle adaptation and recovery. Evidence also indicates that creatine may enhance total sleep duration and quality following resistance training, likely due to improved brain ATP buffering and reduced sleep deprivation related cognitive decline. Therefore, a lifestyle integrating regular exercise, nightly protein, and sleep optimization potentiates creatine’s cellular and functional effects [52,53,54].

Interactions With Omega-3, B Vitamins, And Other Metabolic Enhancers

Synergistic interactions with omega- 3 fatty acids, B vitamins, and other metabolic nutrients form a foundation for targeted neuro-muscular support. Omega-3s, particularly DHA and EPA, improve membrane fluidity, enhance anti-inflammatory signalling and promote synaptic plasticity, effects that complement creatine’s energy buffering and recovery roles. B vitamins (especially B2,B3,B5,B6, and B12) are integral co-factors for energy-yielding metabolism, mitochondrial respiration, and the synthesis/breakdown of glycogen and neurotransmitters, thereby amplifying the effectiveness of creatine supplementation in reducing fatigue and supporting anabolic processes. Polyphenols and antioxidants further complements creatine’s cellular protection by activating anti-inflammatory and Nrf2 pathways. For athletes and older adults, combining these nutrients with creatine can optimize muscle recovery, neuroprotection, and functional rehabilitation [55,56].

Timing, Dosage, and Formulation Considerations For Maximal Benefit

Optimal outcomes from creatine supplementation depend on precise dosing, timing, and formulation strategies. The consensus supports a loading phase of 20g/day for long-term use. Creatine monohydrate remains the most studied and best-absorbed form, other formulations offer no consistent superiority in efficacy or safety. Evidence on timing suggests similar benefits for ingestion pre or post exercise, though proximity to training may enhance intramuscular accumulation and adaptation in some populations. Daily supplementation, including rest days, ensures saturation and maintains ergogenic effects. Co-ingestion with carbohydrates and protein may further increase muscle creatine uptake via insulin-mediated pathways. Creatine’s excellent safety profile is supported by decades of clinical trials, with rare adverse events at recommended doses in healthy adults [57,58,59].

Safety Profile and Clinical Considerations

Safety Profile and Evidence Base for Long-Term Use

Creatine monohydrate is among the most extensively researched dietary supplements, with over 1,000 controlled trials and billions of servings consumed worldwide since the early 1990s. Long term supplementation up to 30 g/day for up to 14 years has shown an outstanding safety record across diverse populations, including infants, older adults, and patients with clinical conditions. Reported side effects are rare and primarily limited to transient weight gain due to increased intracellular water and muscle mass. No consistent or clinically significant pattern of adverse events has emerged from large-scale adverse event databases or clinical trials across the globe. Renal and hepatic dysfunction, frequently raised a s concerns, have not been substantiated in well controlled studies in healthy subjects or most clinical populations. Major regulatory bodies, including the FDA, have designated creatine as “generally recognized as safe” (GRAS) for intended use.

Clinical Considerations in Older Adults, Vegetarians, and Patients with Comorbidities

Older adults and vegetarians/vegans are likely to benefit more notably from creatine, owing to reduced endogenous and dietary creatine stores. Creatine supplementation supports not only muscle mass and functional capacity but also cognitive function and neuroprotection in older individuals. Those with lower baseline muscle creatine (including vegetarians) experience more pronounced improvements in cognition and working memory after creatine supplementation. In clinical contexts, creatine is safe for use in various patient populations, including those with neuromuscular disorders, cardiorespiratory disease, and recovery phases post-injury, provided there is no underlying contraindication.

Contraindications and Monitoring Parameters

Creatine supplementation is generally contraindicated in individuals with diagnosed renal failure, severe hepatic disease, or those at risk for kidney stones; caution is advised in those with diabetes and uncontrolled hypertension. Pregnant and breastfeeding women should avoid supplementation unless specifically prescribed. Prior to and during supplementation, it is recommended to monitor:

  • Renal function: serum creatinine, estimated glomerular filtration rate (eGFR) and urinalysis
  • Liver function: ALT, AST (if baseline hepatic compromise)
  • Blood pressure (for those with hypertension or diabetes)
  • Hydration status and clinical signs of gastrointestinal tolerance

Special populations, such as youth athletes or those with allergy sensitivities, should be monitored for rare airway effects or for individual intolerance. Maintaining adequate hydration (2-3L/day) is important to reduce the risk of muscle cramps and ensure renal clearance of creatinine

Future Directions in Metabolic and Neurological Research

Emerging Clinical Trials On Cognition and Aging

Recent years have seen an expansion of clinical research evaluating creatine’s impact on cognitive function and neuroprotection, particularly in aging populations. Large-scale, randomized controlled trials are now focusing on older adults to assess both short-term and long-term benefits of creatine supplementation for memory, working memory, executive function, and protection against neurodegenerative diseases (e.g., Alzheimer’s, Parkinson’s). Advanced neuroimaging (MRS, PET) and molecular biomarkers are increasingly used to elucidate mechanisms, such as improved cerebral phosphocreatine stores, synaptic plasticity, and oxidative resilience. These trials are addressing knowledge gaps related to optimal dosage, duration, baseline creatine status, and effects in populations with mild cognitive impairment, frailty, or metabolic conditions, all aiming to translate creatine’s mechanistic promise into clinical applications for healthy brain aging [60].

AI-Driven Personalization Of Creatine Supplementation

Artificial intelligence (AI) and machine learning are paving the way for personalized nutrition and supplementation strategies. By integrating genomics, metabolomics, microbiome data, lifestyle tracking (activity, sleep), and real-time metabolic biomarkers (e.g., continuous glucose monitoring), AI algorithms can predict optimal creatine dosing, timing, and combinations for individual metabolic phenotypes. Clinical decision support systems and health tech platforms are beginning to utilize these models to recommend precision supplementation dynamically adjusting protocols for improved metabolic health, recovery outcomes, and neurocognitive performance. Future research will refine these tools to accommodate variables such as creatine transporter genetics, dietary intake, renal function, and physical activity, making supplementation safer and more effective for diverse populations [61].

Bridging Metabolic Performance With Longevity Science

The intersection of creatine research with longevity science is driving a paradigm shift in preventive medicine. Beyond improving muscle and brain performance, creatine is now investigated for its effects on cellular energy metabolism, mitochondrial biogenesis, and stress resilience, all foundational to slowing biological aging and preventing age-related disease. Integration of creatine protocols with exercise, nutritional interventions, and pharmacological geroprotectors (e.g., metformin, NAD+ boosters, omega-3) is poised to enhance both health span and lifespan. Longitudinal cohort studies and “multi-omics” platforms are needed to clarify how creatine can be incorporated into comprehensive longevity programs, impacting sarcopenia, metabolic syndrome, neurodegeneration, and overall quality of life as populations continue to age [62].

Conclusion

The scientific paradigm surrounding creatine has shifted far beyond its historical roots in athletic performance, revealing a critical integrative role across brain, muscle, and metabolic health. As an energy shuttle, neuromodulator, and mitochondrial stabilizer, creatine supports neurocognitive function, accelerates recovery from physical stress, and orchestrates glucose control in metabolic tissues. This multifaceted biochemical potential underscores creatine’s value not only as a therapeutic agent in disease and rehabilitation but also as a daily instrument for preserving physiological resilience and metabolic flexibility.

Emerging clinical evidence and mechanistic insights collectively position creatine as a bridge between cellular energetics and preventive medicine—an accessible supplement that can help mitigate age-related decline, enhance cognitive and muscular reserve, and support glycemic health in populations at risk of metabolic dysfunction. AI-driven precision approaches and translational research continue to refine dosing, timing, and nutrient synergies for individualized benefits. Ultimately, the integration of creatine protocols into preventive health strategies advances the promise of improving health span and quality of life for diverse populations across the lifespan.

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