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Migraine and Metabolism: How Insulin Resistance Fuels the Brain’s Energy Crisis

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dr. Karunia Valeriani Japar

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Introduction

Migraine is recognized globally as a significant neurological disorder, impacting more than one billion people and ranking among the leading causes of disability. Sufferers contend not only with intense, recurring head pain but also a constellation of symptoms, including sensory disturbances, cognitive fog, and profound fatigue that disrupt daily functioning and diminish overall quality of life. Traditionally, clinical management has centered on symptom relief, often overlooking the underlying drivers of migraine susceptibility and chronicity. However, a paradigm, shift is underway, fuelled by emerging research that implicates metabolic disturbances in the initiation and amplification of migraine attacks.

Recent advances in neuroscience and metabolic medicine reveal that the brain’s energy requirements, and how effectively they are met. Migraine is increasingly seen as a disorder of impaired energy regulation, with a mounting body of evidence linking defects in glucose handling and insulin signalling to heightened migraine risk. Insulin resistance, once regarded primarily as a concern for metabolic and cardiovascular health, is now understood to exert powerful effects on cerebral function. Disrupted insulin action impairs neuronal glucose uptake, destabilizes neurotransmitter balance, and foster a state of neuroinflammation that can precipitate or sustain migraine episodes.

Against this evolving backdrop, migraine merges as far more than a simple headache. It is a complex neurological syndrome, often serving as a warning sign of deeper metabolic imbalances. Appreciating the intersection between metabolic health and migraine offers new insights into disease mechanisms and open pathways toward prevention and personalized treatment. By positioning energy dysregulation and insulin resistance at the forefront of migraine research and clinical care, patients and practitioners alike are empowered to pursue more effective strategies for lasting management and improved brain health.

Understanding Migraine: Clinical & Neurological perspectives

Migraine is a complex neurovascular disorder marked by distinctive clinical features and a dynamic course, often separated into recognizable neurological phases. The classic clinical features of migraine include recurrent episodes of moderate to severe throbbing or pulsatile headache, commonly unilateral but occasionally bilateral, that can last from 4-72 hours if left untreated. These headaches are frequently accompanied by neurological and systemic symptoms such as sensitivity to light (photophobia), sound (phonophobia), nausea, and vomiting. The degree of associated disability is often substantial, interfering with daily activities and social participation [1,2,3,4].

A migraine attack typically unfolds in a series of phases, each characterized by particular symptoms and neurobiological changes. The prodrome or premonitory phase, can arise hours to days before headache onset it up to 77% of patients and is more prevalent in women. Prodromal symptoms include yawning, mood changes, lethargy, neck stiffness, sensitivity to stimuli, cravings, and cognitive changes, reflecting hypothalamic activation and altered neurotransmitter signalling. The subsequent aura phase, present in about 25% migraineurs, last less than 60 minutes and consist of fully reversible neurological disturbances. Visual auras are most common (such as scintillating scotoma and field detects), but sensory (paraesthesia), language (transient dysphasia), and rarely motor symptoms may also occur. Not all migraine attacks are accompanied by aura and auras may precede, coincide with, or even follow the headache phase [1,5,6,7].

The attack, or headache phase, follows next heralded by severe craniofacial pain while additional symptoms such as nausea and vomiting, hypersensitivity to external stimuli and worsening with physical activity may predominate. Finally, the postdrome or “migraine hangover” phase may endure for up to 24 hours after pain resolution, marked by exhaustion, cognitive difficulties, and persistent hypersensitivity. Not all phases are present in every patient or every attack, and the sequence can vary [1,5,6,7].

Epidemiologically, migraine exhibits pronounced sex differences. Its prevalence is higher in women, particularly during reproductive years with a two to threefold excess compared to men. The risk escalates sharply after puberty and is strongly influenced by sex hormones, especially estrogen. Drops in estrogen concentration such as those occurring prior to menstruation, are well recognized triggers for migraine attacks, explaining the phenomenon.

The Metabolic Lens: Why Energy And Insulin Matter

The human brain, despite representing only approximately 2% of total body mass, is a remarkably energy demanding organ, consuming nearly 20% of the body’s total glucose derived energy. Neurons, in particular, exhibit the highest energy requirements among brain cells, necessitating continuous and adequate glucose delivery from the bloodstream to sustain fundamental processes such as ATP generation, maintenance of ion gradients, synaptic transmission, and neurotransmitter synthesis. This extraordinary metabolic demand renders the brain exceptionally vulnerable to disruptions in glucose supply or utilization. Even subtle perturbations in cerebral energy homeostasis can precipitate functional impairment, and emerging evidence strongly implicates such metabolic dysregulation in the pathophysiology of migraine [8,9,10,11].

Central to the brain’s glucose uptake machinery are facilitative glucose transporters (GLUTs), which mediate the movement of glucose across cellular membranes. Among these, GLUT1 is predominantly expressed at the blood-brain barrier and in astrocytes, facilitating glucose entry into the brain parenchyma, while GLUT3 serves as the primary neuronal glucose transporter, characterized by high affinity and capacity to meet the intense energy demands of firing neurons. Importantly, insulin sensitive glucose transporters, namely GLUT4 and GLUT8 are also expressed in specific brain regions, including hypothalamus, hippocampus and cortex. Unlike peripheral tissues where insulin dramatically stimulates glucose uptake via GLUT4 translocation to the plasma membrane, the role of insulin in regulating neuronal glucose transport has historically been considered less prominent. However, accumulating evidence suggest that insulin signalling does modulate neuronal glucose uptake by promoting translocation of glucose transporters to the neuronal membrane, particularly during periods of heightened metabolic demand. This insulin dependent regulation is especially relevant in brain regions involved in energy sensing and metabolic control, where GLUT4 co-localizes with insulin receptors [12,13,14,15].

Insulin resistance, a state characterized by diminished cellular responsiveness to insulin signalling, poses a significant threat to cerebral glucose metabolism and neuronal function. When insulin resistance extends to the brain, it compromises the efficiency of  glucose uptake in insulin responsive neurons and astrocytes, leading to a mismatch between the brain’s energy reserves and its metabolic expenditure. This chronic energy deficit disrupts normal neuronal activity, impairs mitochondrial function, and fosters a state of oxidative stress. Critically, such metabolic disturbances have been directly linked to migraine susceptibility. Clinical studies have demonstrated that individuals with migraine frequently exhibit peripheral insulin resistance, elevated fasting glucose and insulin levels and features of metabolic syndrome. Moreover, neuroimaging studies using magnetic resonance spectroscopy and positron emission tomography have revealed reduced brain ATP levels, abnormal glucose uptake patterns, and mitochondrial dysfunction in patients with migraine, even during interictal periods [10,11,16,17,18,19,20].

The mechanistic connection between insulin resistance and migraine is multifaceted. Insulin resistance not only impairs glucose delivery to energy hungry neurons but also disrupts mitochondrial signalling pathways, exacerbates neuroinflammation and heightens oxidative stress, all factors that lower the threshold for cortical spreading depression, a key electrophysiological event underlying migraine aura. Furthermore, fluctuations in blood glucose levels, commonly observed in insulin resistant states, can trigger migraine attacks by creating acute mismatches between energy supply and demand. Thus insulin resistance may serve as a critical metabolic link between migraine and its frequent comorbidities, including obesity, depression, cognitive impairment and cerebrovascular disease. By recognizing the centrality of energy dysregulation and insulin resistance in migraine pathogenesis, clinicians and researchers are increasingly viewing migraine not merely as a neurovascular disorder but as a manifestation of broader metabolic dysfunction, a perspective that opens new avenues for targeted therapeutic intervention[10,11,16,18,20].

Evidence Linking Insulin Resistance and Migraine

Key Studies Illustrating Higher Migraine Risk In Insulin-Resistant Individuals

Prevalence and Association Studies

Recent case-control studies have established a compelling association between insulin resistance and migraine prevalence. A landmark study by Ali et al. (2022) conducted on 30 migraine patients and 30 healthy controls demonstrated that migraine patients exhibited significantly higher waist circumference, elevated serum insulin levels, higher homeostasis model assessment-insulin resistance (HOMA-IR) values, and increased frequency of both insulin resistance and metabolic syndrome compared to controls (P-values ranging from 0.005 to 0.024). Critically, migraine patients with insulin resistance demonstrated significantly higher migraine intensity scores, tolerability scores, Migraine Severity Scale (MIGSEV) total scores, and Headache Impact Test-6 (HIT-6) scores compared to those without insulin resistance (P-values ranging from 0.002 to 0.018). Furthermore, the study revealed a significant positive correlation between MIGSEV and HIT-6 scores with fasting insulin levels and HOMA-IR values, establishing a dose-response relationship between insulin resistance severity and migraine burden.[21]

A comprehensive study by Cavestro et al. (2012) examining 135 consecutive migraine patients found that metabolic syndrome was present in 31.9% of migraineurs, with insulin resistance detected in 11.1% of the cohort. This research identified significant correlations between metabolic syndrome and several clinical parameters including age, gender, number of migraine triggers, duration of illness, and duration of individual migraine attacks. Notably, insulin resistance specifically correlated with the duration of migraine attacks, suggesting a potential mechanistic link between metabolic dysfunction and attack prolongation.[22]

Hyperinsulinemia and Migraine Risk

The relationship between hyperinsulinemia and migraine risk has been quantified in several investigations. Gruber et al. (2010) demonstrated that hyperinsulinemia in the highest quartile was associated with a 5.7-fold increased risk of migraine compared to individuals with insulin levels in the lowest quartile. This dramatic increase in risk underscores the potential significance of insulin dysregulation in migraine pathogenesis and suggests that even moderate elevations in insulin levels may substantially increase migraine susceptibility.[23]

Gender-Specific Findings in Chronic Migraine

Research by Fava et al. (2014) specifically examined insulin resistance in women with chronic migraine through a cross-sectional study design. The investigators found that chronic migraine in women was significantly associated with insulin resistance status, particularly when obesity was present as a comorbidity. This finding suggests potential sex-specific mechanisms linking metabolic dysfunction to migraine chronification, possibly mediated through hormonal interactions with insulin signalling pathways.[24]

Regional and Population-Based Evidence

A population-based study from Southeast Asia by Cavestro et al. (2012) found that among 135 migraine patients, metabolic syndrome was predominantly observed in elderly patients with longer headache duration and multiple triggers. This study is particularly significant as it demonstrated that metabolic dysfunction-migraine associations exist across diverse populations with different obesity rates compared to Western countries, suggesting that the relationship is not solely mediated by obesity but represents a more fundamental metabolic disturbance.[25]

Migraines As Part Of A Broader Metabolic Syndrome

The Metabolic Syndrome Cluster

Migraine increasingly appears to be a manifestation of systemic metabolic dysfunction rather than an isolated neurological condition. The metabolic syndrome encompasses a cluster of conditions including abdominal obesity, hypertension, dyslipidemia, and glucose dysregulation. Emerging evidence suggests that these metabolic abnormalities share common pathophysiological mechanisms with migraine, positioning the disorder within a broader context of metabolic disease.[26]

Obesity

The relationship between migraine and obesity is complex and bidirectional. Research by Tietjen et al. demonstrated that obesity was independently associated with current depression (odds ratio = 1.86, 95% CI: 1.25 to 2.78) in migraineurs. More significantly, obese migraineurs with comorbid depression exhibited markedly higher headache frequency (OR = 4.16, 95% CI: 1.92 to 8.99) and headache-related disability (OR = 7.10, 95% CI: 2.69 to 18.77) compared to normal-weight migraineurs without depression. This suggests that obesity may amplify migraine severity through metabolic and inflammatory pathways.[27]

Contemporary research examining body mass index (BMI) and migraine characteristics found that individuals with BMI ≥ 30 experienced increased chronic migraine, higher headache days per month, and greater headache severity compared to those with normal BMI. Furthermore, elevated BMI correlated significantly with migraine comorbidities including anxiety, depression, and sleep disturbances, indicating that obesity may serve as a central hub linking multiple aspects of migraine burden.[28]

Pathophysiologically, the association between obesity and migraine may be mediated through several mechanisms. Obese patients with chronic migraine and depression demonstrate significantly elevated pro-inflammatory cytokine blood levels, suggesting that chronic low-grade inflammation associated with adiposity may contribute to migraine pathogenesis. The shared features of insulin resistance and systemic inflammation between chronic migraine, obesity, depression, and other chronic pain conditions have been proposed as key factors linking these disorders.[29]

Depression and Psychiatric Comorbidity

The relationship between migraine and depression represents one of the most robust psychiatric comorbidities in neurology, with bidirectional influences that significantly impact clinical outcomes. Epidemiological studies have established that individuals with migraine are five times more likely to develop first-onset major depression compared to those without migraine, while the risk of first-onset migraine is three times higher in individuals with lifetime depressive disorders.[30]

Insulin resistance may represent a unifying pathophysiological mechanism linking migraine and depression. Both conditions demonstrate alterations in the hypothalamic-pituitary-adrenal (HPA) axis, with evidence of dysregulated cortisol responses and altered stress hormone secretion. Additionally, an imbalance favoring pro-inflammatory cytokines has been documented in both migraine and depression, with abnormally elevated inflammatory markers proposed as a pathophysiological link connecting depression, migraine, obesity, and the progression from episodic to chronic migraine.[31]

Neuroimaging studies provide compelling evidence for shared brain abnormalities in migraine with comorbid depression. Functional MRI investigations have identified altered activity in the left medial prefrontal cortex in patients with both conditions, a region implicated in self-referential mental activity and mood regulation. Furthermore, individuals with migraine and depression demonstrate distinctly decreased thalamic activity and different developmental trajectories in the right thalamus and fusiform gyrus compared to those with either condition alone, suggesting unique neurobiological signatures of this comorbidity.[32]

The grey matter volume reductions observed in chronic migraine patients may also be linked to metabolic dysfunction. Research suggests that these structural brain changes depend primarily on two features shared by chronic migraine, major depression, chronic pain syndromes, polycystic ovary syndrome, fibromyalgia, and osteoarthritis: higher incidence of insulin resistance and systemic inflammation. Intriguingly, hippocampal atrophy has been observed in individuals with impaired glucose tolerance and insulin resistance, supporting a mechanistic link between metabolic dysfunction and structural brain changes.[33]

Cognitive Impairment

Cognitive dysfunction represents the second largest cause of disability in migraine patients after pain itself. Subjective cognitive complaints, particularly regarding memory and attention, are common among migraineurs, especially those with comorbid depression, anxiety, or sleep disturbances. While objective neuropsychological assessments yield variable results, meta-analyses have demonstrated lower general cognitive function in migraine patients compared to healthy controls, particularly in language domains.[34]

The “neuroenergetic hypothesis” proposes that insulin resistance may serve as a critical pathophysiological link between migraine and cognitive impairment. Brain insulin resistance can downregulate insulin receptors in both astrocytes and neurons, triggering reductions in glucose uptake and glycogen synthesis, particularly during periods of high metabolic demand. This creates a mismatch between the brain’s energy reserve and expenditure, potentially contributing to both migraine attacks and cognitive dysfunction.[35]

Several lines of evidence support insulin resistance as a common mechanism linking migraine with cognitive decline. Insulin receptors are abundantly distributed throughout the brain and play crucial roles in neuronal glucose uptake, synaptic plasticity, and cognitive function. Arnold et al. observed that alterations in insulin levels might affect neuronal glucose uptake and metabolism through GLUT4 translocation in brain regions involved in cognitive and emotional function. Furthermore, research has suggested that insulin resistance may increase the risk of migraineurs developing dementia, particularly those suffering from migraine with aura.[36]

Brain imaging studies using Magnetic Resonance Spectroscopy (MRS) consistently demonstrate hypometabolism and reduced ATP levels in migraineurs due to abnormalities in mitochondrial oxidative phosphorylation. Specific brain areas, particularly Brodmann areas 10 and 47, show glucose hypometabolism in both subjects with insulin resistance and those with chronic migraine, strengthening the hypothesis that brain insulin resistance may trigger the neuronal stress implicated in migraine chronification and associated cognitive decline.[37]

Cerebrovascular Disease and Vascular Complications

Insulin resistance has been established as a risk factor for vascular disease and may represent an important link between migraine and cerebrovascular complications. Evidence suggests that insulin resistance increases the risk of ischemic stroke, potentially explaining the observed comorbidity between migraine, particularly migraine with aura, and vascular diseases. This vascular connection may be mediated through multiple mechanisms including endothelial dysfunction, increased inflammation, impaired fibrinolysis, and prothrombotic states associated with insulin resistance.[38]

The shared metabolic dysfunction extends beyond simple correlations. Numerous studies indicate that impaired glucose metabolism and insulin resistance are common pathophysiological features across type 2 diabetes, obesity, depression, dementia, and cerebrovascular disease. This metabolic commonality suggests that insulin resistance may serve as a central pathophysiological hub connecting migraine with its diverse comorbidities, potentially explaining the clustering of these conditions in affected individuals.[39]

The Impact Of Glucose Volatility On Migraine Onset

Hypoglycemia as a Migraine Trigger

Glucose volatility, particularly hypoglycemia and reactive hypoglycemia, represents a significant and often underrecognized trigger for migraine attacks. Clinical observations dating back decades have documented that fasting is one of the most frequently reported migraine triggers, with the mechanism likely involving glucose deficit either directly or through hormonal counterregulatory responses.[40]

Experimental studies have provided compelling evidence for glucose-related migraine precipitation. Hockaday et al. conducted a seminal study administering 50g of glucose to 10 migraineurs whose attacks were associated with fasting, following a 10-hour fast. Remarkably, 6 of 10 patients developed a migraine attack within 8 hours of the glucose challenge, demonstrating that rapid glucose fluctuations can directly trigger attacks in susceptible individuals.[41]

Reactive Hypoglycemia and Postprandial Mechanisms

Reactive hypoglycemia, also termed postprandial hypoglycemia, represents a particularly relevant mechanism in migraine pathophysiology. This condition is characterized by a pathological drop in blood glucose levels following ingestion of a high-carbohydrate load. The mechanism involves a rapid increase in blood glucose (hyperglycemia) triggering excessive insulin secretion, which then causes blood glucose to fall precipitously below normal levels.[42]

A case series by Luyckx et al. found that 30 of 47 patients with reactive hypoglycemia reported symptoms of “neuroglycopenia” occurring 2 to 4 hours after meals in everyday life, with symptoms including weakness, faintness, headache, irritability, anxiety, nervousness, palpitations, trembling, vertigo, and hunger. The symptomatic overlap between hypoglycemia and migraine prodrome is striking and includes tiredness, difficulty concentrating, blurred vision, light sensitivity, irritability, hunger, and dizziness, suggesting shared pathophysiological mechanisms.[43]

Recent research has documented cases of chronic migraine associated with postprandial hypoglycemia in adult males. Three patients with chronic migraine underwent three-hour oral glucose tolerance testing, with all demonstrating hypoglycemia at the three-hour mark. When treated with ketogenic diets restricting carbohydrates to 15g or less per day, these patients experienced significant improvement in migraine frequency and severity, supporting the hypothesis that glucose volatility plays a causal role in migraine generation.[43]

Insulin-Induced Hypoglycemia and Rebound Migraine

Clinical case reports have documented a phenomenon termed “hypoglycemia rebound migraine,” wherein profound hypoglycemia is followed by severe migraine attacks during the recovery phase after glucose normalization. Jacome (2001) described a diabetic patient who experienced recurrent episodes of profound hypoglycemia (blood glucose 20-30 mg/dL) that were followed by severe bilateral pounding headaches during recovery, even after confusion had resolved and blood glucose had normalized. This pattern suggests that rapid glucose fluctuations, rather than absolute glucose levels alone, may trigger migraine attacks.[35]

The mechanism underlying glucose volatility-induced migraine is multifaceted. Hypoglycemia activates the sympathetic nervous system, triggering release of stress hormones including adrenaline and cortisol. This hormonal cascade leads to increased blood pressure and alterations in cerebral blood flow through vasoconstriction and vasodilation. Additionally, hypoglycemia stimulates release of glutamate, an excitatory neurotransmitter, potentially causing neuronal overexcitation—a key factor in migraine pathophysiology. Fluctuations in blood glucose can also affect serotonin levels, further contributing to migraine susceptibility.[36]

Brain Energy Metabolism and The Neuroenergetic Hypothesis

The “neuroenergetic hypothesis” proposes that migraine fundamentally represents a disorder of brain energy metabolism, with glucose volatility playing a central role. According to this framework, postprandial hypoglycemia creates an episodic mismatch between the brain’s energy reserves and metabolic demands, serving as a pivotal pathophysiological mechanism in episodic migraine. Chronic brain energy deficit, potentially arising from brain insulin resistance, may drive migraine chronification.[37]

During migraine attacks, metabolic markers typically associated with energy deficit are elevated. Levels of free fatty acids, ketone bodies, glycerol, and cortisol increase during attacks—the same metabolic pattern observed during fasting or glucoprivation. This metabolic signature suggests that the brain is experiencing an energy crisis during migraine attacks, potentially explaining why ketogenic diets and other metabolic interventions show promise in migraine treatment.[38]

Astrocytes play a crucial role in this neuroenergetic framework. These cells store plasma glucose as glycogen, which is rapidly metabolized during intensive synaptic activity to support glutamate and potassium homeostasis. Extended periods of low blood glucose combined with sustained sympathetic activity during prolonged fasting may deplete glucose reserves from presynaptic astrocytes, potentially triggering cortical spreading depression and subsequent migraine aura and headache.[39]

Brain Insulin Resistance and Chronic Glucose Dysregulation

While acute hypoglycemia may trigger episodic migraine attacks, chronic insulin resistance extending to the central nervous system may represent the mechanism underlying migraine chronification. Brain insulin resistance can impair the insulin signaling cascade in neurons and astrocytes, leading to downregulation of insulin receptors and reduced glucose transporter expression. This metabolic dysfunction creates a chronic state of neuronal energy deficit, even in the presence of normal blood glucose levels.[40]

Evidence supporting brain-specific insulin resistance in migraineurs comes from neuroimaging studies. A study of young women with polycystic ovary syndrome and mild insulin resistance reported a direct association between insulin resistance and brain glucose hypometabolism, independent of overweight or obesity status. The fact that peripheral insulin resistance can extend to the brain and impair neuronal glucose metabolism provides a mechanistic link between systemic metabolic dysfunction and migraine pathophysiology.[41]

The brain regions showing glucose hypometabolism in insulin resistance overlap substantially with areas affected in chronic migraine. Brodmann area 10, involved in higher cognitive functions and emotional processing, demonstrates reduced glucose metabolism in both insulin-resistant individuals and chronic migraineurs. This anatomical convergence supports the hypothesis that brain insulin resistance serves as a pathophysiological bridge connecting systemic metabolic dysfunction to chronic migraine and its associated cognitive and emotional comorbidities.[42]

Clinical Implications of Glucose Volatility

Understanding the role of glucose volatility in migraine has important therapeutic implications. Prevention strategies include maintaining stable blood glucose through regular, balanced meals containing adequate protein and healthy fats while minimizing refined carbohydrates and high-glycemic foods. For individuals experiencing hypoglycemia-triggered migraines, immediate treatment includes rapid carbohydrate intake (15g of simple carbohydrates), followed by protein-containing snacks to prevent rebound hypoglycemia.[43]

Emerging therapeutic approaches target the underlying metabolic dysfunction. Metformin, an insulin-sensitizing medication, has shown efficacy in chronic pain relief and may benefit migraineurs with insulin resistance. Ketogenic and modified Atkins diets, which minimize glucose fluctuations and promote ketone body utilization as an alternative brain fuel source, have demonstrated promise in both episodic and chronic migraine management. These dietary interventions may be particularly effective in patients with documented glucose dysregulation or insulin resistance.[44]

Biochemistry: Serotonin, Insulin, and Neuroinflammation

Serotonin(5-hydroxytrptamine, 5-HT) is a monoamine neurotransmitter synthesized from the essential amino acid L-tryptophan through a two-step enzymatic process. The rate-limiting enzyme tryptophan hydroxylase (TPH) catalyses the hydroxylation of tryptophan to 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated by aromatic amino acid decarboxylase to form serotonin. Two TPH isoforms exist: TPH1, expressed peripherally in enterochromaffin cells and pancreatic islets, and TPH2, expressed in serotonergic neurons of the central nervous system (CNS). Serotonin exerts its diverse physiological effects through at least seven receptor families distributed throughout peripheral tissues and the CNS, regulating mood, pain perception, appetite, and metabolic functions [45,46,47].

Insulin’s Effect On Serotonin Pathways And Pain Perception

Insulin influences serotonin synthesis and signalling through multiple mechanisms that directly impact pain perception. By promoting cellular uptake of large neutral amino acids (LNAAs) while sparing tryptophan, insulin increases the plasma tryptophan-to-LNAA ratio, thereby enhancing tryptophan transport across the blood brain barrier and favouring CNS serotonin biosynthesis. This mechanism explains how insulin administration can increase brain serotonin levels despite initially reducing free tryptophan in circulation through albumin binding. Additionally, insulin enhances tryptophan hydroxylase activity in serotogenic neurons, directly accelerating serotonin levels despite initially reducing free tryptophan in circulation through albumin binding. Additionally, insulin enhances tryptophan hydroxylase activity serotonergic neurons, directly accelerating serotonin production. Beyond synthesis regulation, insulin modulates neurotransmitter reuptake by stimulating neuronal serotonin uptake while inhibiting norepinephrine reuptake [48,49,50,51,52].

The relationship between insulin and pain perception is bidirectional and clinically significant. Insulin resistance has been associated with chronic pain conditions, including fibromyalgia and idiopathic pain. In experimental models, insulin resistance correlates with lower baseline pain thresholds and prolonged recovery from nerve injury-induced hypersensitivity. Central insulin receptor expression in the spinal cord dorsal horn and hypothalamus is reduced in states of chronic pain and insulin resistance, suggesting that impaired insulin signalling contributes to central sensitization. The disruption of insulin’s neuromodulatory effects on serotonin pathways may underlie pain amplification, as reduced serotonin availability is associated with enhanced pain transmission and diminished descending inhibitory control[48,49,50,51,52].

Reciprocal Feedback Between Serotonin And Insulin Secretion

The pancreatic islet represents a critical site of serotonin insulin crosstalk. Pancreatic beta cells express both TPH1 and aromatic amino acid decarboxylase, enabling local serotonin synthesis from tryptophan. Serotonin is co-stored with insulin in secretory granules and co-released during glucose-stimulated insulin secretion. Human beta cells release serotonin in glucose dependent, pulsatile manner that parallels insulin secretion patterns. Intracellular serotonin regulates insulin exocytosis through a receptor independent mechanism termed “serotonylation”, whereby transglutaminases covalently attach serotonin to small GTPases (Rab3a and Rab27a), rendering them constitutively active and promoting insulin granule fusion with the plasma membrane[53,54].

Serotonin also exerts receptor mediated effects on pancreatic function. Activation of 5-HT2B receptors stimulates beta cells proliferation and enhances insulin secretion, while 5-HT3 receptor activation augments serotonylation-dependent insulin release. Conversely, serotonin secreted by beta cells acts as a paracrine signal on neighbouring alpha cells, where it activates 5-HT1F receptors to inhibit glucagon secretion in a glucose-dependent manner. Mice deficient in peripheral TPH1 develop diabetes characterized by impaired insulin secretion, which can be rescued by pharmacological restoration on peripheral serotonin levels. The reciprocal relationship suggests that dysregulation of either serotonin or insulin signalling can precipitate metabolic dysfunction, with implication s for type 2 diabetes pathogenesis [53,54,55,56].

Cytokines, Inflammation And The Impact Of Obesity

Chronic obesity drives systemic inflammation characterized by elevation secretion of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-a), Interleukin-6 (IL-6), and interleukin-1beta (IL-1b), from hypertrophied adipocytes and infiltrating immune cells. These cytokines are significantly elevated in obese individuals and correlate positively with body mass index and adipose. TNF-a, and IL-6 cross the blood brain barrier through saturable transport mechanisms and directly induce neuroinflammation by activating microglia and astrocytes. Obesity-induced blood brain barrier dysfunction, mediated by inflammatory cytokines and oxidative stress, further facilitates peripheral immune cell infiltration into the CNS, amplifying neuroinflammatory cascades [57,58,59,60,61,62]

Neuroinflammation profoundly disrupts both serotonin and insulin signalling. Pro-inflammatory cytokines activate indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO),rate limiting enzymes that shunt tryptophan metabolism away from serotonin synthesis toward the kynurenine pathway. This metabolic shift reduces tryptophan availability for serotonin production while generating neuroactive kynurenine metabolites, including the neurotoxic NMDA receptor agonist quinolinic acid and the neuroprotective NMDA receptor antagonist kynurenic acid. Imbalances in kynurenine pathways metabolism, driven by chronic inflammation, contribute to serotonin deficiency and are mechanistically linked to depression, anxiety, and altered pain perception. Additionally, inflammatory cytokines desensitize serotonin receptors and impair serotonin neurotransmission through direct effects on receptor expression and function [49,63,64,65].

Insulin signalling in the CNS is similarly compromised by obesity-induced inflammation. TNF-a inhibits insulin receptor substrate-1 (IRS-1) phosphorylation, disrupting downstream PI3K-Akt signalling pathways essential for insulin’s neuromodulator effects. Central insulin resistance, characterized by reduced insulin receptor expression and impaired signalling in hypothalamic and hippocampal neurons, diminishes insulin’s capacity to regulate neurotransmitter systems, including serotonin. IL-6, another adipokine elevated in obesity, directly interferes with insulin signalling in adipocytes and neurons, promoting both peripheral and central insulin resistance. The convergence of impaired serotonin synthesis, disrupted insulin signalling, and chronic neuroinflammation creates a pathophysiological triad that perpetuates metabolic dysfunction, mood disorders, and chronic pain syndromes. [49,63,64,65]

Obesity-related neuroinflammation also induces oxidative stress, mitochondrial dysfunction, and synaptic alterations in brain regions critical for mood regulation and pain modulation, including the hippocampus, prefrontal cortex, and anterior cingulate cortex. Elevated brain levels of TNF-a and IL-6 correlate with decreased serotonin concentrations, increased anxiety-like behaviours, and enhanced pain sensitivity in obese animal models. These findings underscore the multifaceted role of cytokine-mediated inflammation in linking obesity to neuropsychiatric and pain related disorders[49,62].

The Mitochondrial Connection

Mitochondrial Dysfunction In Migraine Pathogenesis: Energy Deficits, Oxidative Stress

Mitochondrial dysfunction is increasingly recognized as a central mechanisms in the pathogenesis of migraines. Brain tissue relies heavily on mitochondrial oxidative phosphorylation and the tricarboxylic acid cycle to generate ATP, which is essential for neuronal signalling, maintenance of synaptic function, and regulations of ion gradients. In migraineurs, a deficiency in mitochondrial energy production is evident, with studies showing reduced levels of high-energy phosphates (ATP and phosphocreatine), diminished  oxidative phosphorylation activity, and altered metabolite profiles (such as increased lactate and reduced N-acetylaspartate). This energy shortfall lowers the threshold for cortical spreading depression, a key neurophysiological phenomenon underlying migraine aura, and makes neurons particularly vulnerable to hyperexcitability and apoptosis [66,67].

A hallmark of mitochondrial dysfunction in migraine is enhanced oxidative stress. Damaged mitochondria produce excessive reactive oxygen species (ROS), which damage lipids, proteins, and nucleic acids, perpetuating a vicious cycle of further mitochondrial impairment. Individuals with migraine tend to have higher serum levels of oxidative stress biomarkers (such as malondialdehyde) and lower antioxidant enzyme activities (catalase, superoxide dismutase, and total antioxidant capacity), supporting the link between chronic migraine and impaired mitochondrial redeox homeostasis. Modulating endogenous antioxidant defences or supplementing with exogenous antioxidants (e.g., alpha-lipoid acid or coenzyme Q10) has shown promise in lowering migraine frequency and severity [67].

How Insulin Resistance Impairs Mitochondrial Biogenesis And Function

Insulin resistance impairs mitochondrial biogenesis and function through direct and indirect mechanisms, which likely exacerbate migraine pathophysiology. In insulin-resistant states, commonly observed in obesity and type 2 diabetes, there is a reduction in mitochondrial number and size, as well as decreased expression of key mitochondrial regulatory proteins such as PGC-1a, PGC-1b, and nuclear respiratory factor-1 (NRF-1). These changes lead to diminished oxidative capacity, lower ATP production, and increased susceptibility to oxidative stress. Insulin not only maintains mitochondrial proteostasis and coordinates mitophagy, the removal of damaged mitochondria [68,69,70].

Dysregulated insulin signalling also promotes increased production of ROS, compromises mitochondrial membrane integrity, and impairs mitochondrial quality control pathways. As a result, insulin resistance is strongly associated with the development of persistent energy deficits and oxidative damage in brain tissue. This mitochondrial vulnerability creates a biochemical environment conducive to migraine, amplifying pain sensitivity and promoting central sensitization. Individuals with insulin resistance may have lower baseline mitochondrial reserves and antioxidant capacity, making them more prone to frequent and severe migraine attacks [68,69,70,71].

Therapeutic Strategies Targeting Metabolic Health

Lifestyle Interventions: Exercise, Low Glycemic Diets

Physical exercise represents a foundational intervention for migraine management through its multifaceted effects on metabolic, neuroinflammatory, and neurovascular systems. Systematic reviews demonstrate that aerobic exercise interventions yield mean reductions in headache frequency of approximately 40% at post-treatment when exercise serves as the primary intervention, placing its efficacy on par with established pharmacological and behavioural therapies. Recent population-based analysis of National Health and Nutrition Examination Survey (NHANES) data reveals that specific exercise patterns, particularly the combination of vigorous and muscle-strengthening activities, are associated with a 52% reduction in odds for severe headaches and migraines (OR: 0.48, 95% CI: 0.26-0.90). Meta-analytitc evidence from randomized controlled trials demonstrates that aerobic exercise reduces monthly migraine days by 0.6 days at 10-12 weeks (p=0.0006), with unpooled data showing reductions in pain intensity of 20-54% and attack duration decreases of 20-27% [72,73].

The therapeutic mechanisms underlying exercise-induced migraine reduction are multifaceted and include modulation of endogenous opioids, endocannabinoids, brain-derived neutrophic factor (BDNF), and calcitonin gene-related peptide (CGRP), as well as reduction in inflammatory markers including C-reactive protein and substance P.Muscle-strengthening exercises, particularly those targeting the posterior chain (shoulders, upper, and lower back) and neck flexors, reduce nociceptive input to the trigeminocervical complex, a critical pathway in migraine pathophysiology. Exercise timing represents an important consideration, as morning exercise serves as powerful zeitgeber (circadian entertainment factor) that aligns circadian rhythms, improves sleep quality, and reduces increase migraine risk. Clinicians should prescribe morning outdoor exercise combining aerobic and resistance training at moderate intensity for 30-45 minutes three times weekly for a minimum of 8 weeks to achieve clinically meaningful reduction in migraine frequency [72,73,74].

Dietary interventions targeting glycemic control and metabolic ketosis demonstrate significant efficacy in migraine prophylaxis. Low glycemic index diets stabilize postprandial glucose and insulin fluctuations, preventing metabolic triggers of cortical spreading depression while supporting mitochondrial energy metabolism. The ketogenic diet (KD), characterized by high fat (70-80%), moderate protein (15-20%), and very low carbohydrate (<10%) macronutrient distribution, induces metabolic ketosis wherein the liver produces ketone bodies (b-hydroxybutyrate, acetoacetate, acetone) as alternative fuel substrates. These ketones restore brain excitability and energy metabolism while counteracting neuroinflammation through multiple mechanisms, including enhancement of mitochondrial ATP production, activation of anti-inflammatory pathways, and stabilization of neuronal membrane potentials [75,76,77].

Clinical trials demonstrate robust efficacy of ketogenic interventions in migraine prevention. A double-blind crossover trial comparing very low-calorie ketogenic diet (VLCKD) to non-ketogenic calorie restriction revealed significant reductions in migraine days during the ketogenic phase. Observational studies report reductions in monthly headaches from 12.5± 9.5 to 6.7 ± 8.6 (p<0.001) and decreased acute medication consumption from 11.06 ± 9.37 to 4.93 ± 7.99 days per month (p= 0.008) following three months of KD. Importantly, migraine improvement occurs independent of weight loss, as responders and non-responders show no differences in fat mass reduction, suggesting that ketosis specific mechanism rather than caloric restriction per se mediate therapeutic benefits. Modifications such as Mediterranean ketogenic diet and low-carbohydrate high-fat (LCHF) protocols offer similar benefits while enhancing dietary adherence and nutrient density [75,76,78].

Pharmacologic Interventions: Metformin And Its Evidence In Migraine Reduction

Metformin, a biguanide antidiabetic agent, demonstrates emerging therapeutic utility in migraine prophylaxis through activation of adenosine monophosphate activated protein kinase (AMPK) , a master metabolic regulator that enhances mitochondrial biogenesis, improves insulin sensitivity, and attenuates neuroinflammation. AMPK activation promotes glucose uptake independent of insulin signalling, enhances fatty acid oxidation, inhibits hepatic gluconeogenesis and stimulates mitochondrial biogenesis through upregulation of peroxisome proliferator activated receptor gamma coactivator 1-alpha (PGC-1a). In the central nervous system, metformin-induced AMPK activation suppresses microglialactivation and reduces pro-inflammatory cytokine production (TNF-a, IL-1b, IL-6), mechanisms directly implicated in migraine pathophysiology [79].

Clinical evidence supports metformin’s efficacy in migraine management, particularly in patients with insulin resistance or metabolic syndrome. Controlled trials demonstrate that metformin administration (typically 500-1500mg daily) significantly reduces migraine frequency, severity, and headache-related disability while improving quality of life. A six-month exploratory study showed that alpha-lipoic acid combined with metformin significantly reduced migraine days in patients with insulin resistance. The Mayo Clinic is currently conducting randomized controlled trials evaluating metformin for episodic migraine prevention (MPEM trial). Metformin attenuates central sensitization through regulation of spinal cord AMPK signalling and modulation of glial cell activity, providing mechanistic rationale for its analgesic properties beyond metabolic correction. The drug’s favourable safety profile, low cost, and additional metabolic benefits make it particularly attractive for migraineurs with comorbid obesity, prediabetes, or polycystic ovary syndrome [80,81,82].

Nutritional Supplements For Mitochondrial Support

Evidence-based supplementation targeting mitochondrial function represents a cornerstone of integrative migraine prophylaxis. Coenzyme Q10 (CoQ10), an essential component of the mitochondrial electron transport chain at Complex II and a potent lipophilic antioxidant, demonstrates consistent efficacy in randomized controlled trials. Meta-analysis of six studies encompassing 371 participants reveals significant reductions in migraine frequency (mean difference -1.52 attacks per month, p<0.001) and attack duration (mean difference -0.19 hours) with CoQ10 supplementation. The optimal therapeutic dosage is 300-400 mg daily, with clinical benefits typically emerging after 8-12 weeks of continuous administration. CoQ10’s mechanism involves enhancement of ATP synthesis, reduction of oxidative stress, stabilization of mitochondrial membrane potential, and modulation of inflammatory mediators including matrix metalloproteinase-9 [83,84,85].

Riboflavin (vitamin B2) at high dose supplementation (400mg daily) represents another well-validated mitochondrial intervention. Riboflavin serves as the precursor for flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), essential cofactors for mitochondrial complexes I and II in the electron transport chain. Landmark randomized controlled trials demonstrate that riboflavin supplementation for three months significantly reduces migraine frequency (59% responder rate vs. 15% placebo, p=0.005), attack days, and pain severity. Meta-analysis confirms significant improvements across multiple outcome measures including headache frequency, duration, and pain intensity. Riboflavin’s therapeutic efficacy appears related to correction of subclinical mitochondrial dysfunction, enhancement of cellular energy metabolism, and reduction of oxidative stress and neuroinflammation. The supplement exhibits an excellent safety profile with minimal adverse effects [86,87].

Magnesium supplementation, typically administered as magnesium oxide,  citrate, or glycinate at 400-600mg daily, provides level B evidence for migraine prophylaxis according to American Headache Society guidelines. Magnesium plays critical roles over 300 enzymatic reactions, including ATP synthesis, regulation of N-methyl-D-aspartate (NMDA) receptors, stabilization of neuronal membranes, and modulation of serotonin receptor function. Approximately 45% of women experience ionized magnesium status in migraine pathophysiology. Clinical trials demonstrate that oral magnesium supplementation reduces migraine frequency by approximately 41.6% compared to placebo, with particular efficacy in migraine with aura and menstrually-related migraine. Intravenous magnesium sulfate (1-2 grams) can be administered acutely in emergency settings for rapid migraine relief [88,89].

Alpha-lipoic acid (ALA),  an amphiphilic antioxidant and cofactor for mitochondrial dehydrogenase enzymes, demonstrates robust  therapeutic potential in migraine prevention. ALA enhances mitochondrial oxidative metabolism, r4educes lactate accumulation, and exhibits potent anti-inflammatory and antioxidant properties. Randomized controlled trials demonstrate that ALA supplementation at 300-600 mg daily for 12 weeks significantly reduces serum lactate levels (a marker of mitochondrial dysfunction), vascular cell adhesion molecule-1, and inflammatory markers while improving migraine severity, frequency, headache impact test (HIT-6) scores, and migraine disability assessment. A six month study showed ALA particular benefit in metabolically compromised populations. ALA also decreases serum CGRP levels in adolescent migraineurs while reducing attack frequency and severity. The supplement’s dual mitochondrial and anti-inflammatory mechanisms make it a valuable adjunctive treatment [90].

Combination formulations incorporating multiple mitochondrial nutrients demonstrate synergistic efficacy and enhanced patient compliance. Recent trials evaluating concur5rent alpha-linolenic acid and L-carnitine supplementation reveal significant reductions in migraine frequency, severity, duration, and disability scores while improving quality of life and mental health outcomes. L-carnitine facilitates long-chain fatty acid transport into mitochondria for b-oxidation, enhances energy production, and exhibits antioxidant properties, complementing other mitochondrial cofactors. Multi-nutrient protocols combining CoQ10, riboflavin, magnesium, and ALA target multiple aspects of mitochondrial dysfunction while addressing energy metabolism, oxidative stress, and inflammation comprehensively.

Conclusion

Migraine represents far more than an isolated neurological disorder, it serves as a critical warning sign of underlying metabolic dysfunction. The emerging paradigm positions migraine within a broader framework of energy dysregulation, where disrupted glucose metabolism, insulin resistance, and mitochondrial impairment converge to lower the threshold for attack initiation. Clinical evidence demonstrates that individuals with migraine frequently exhibit peripheral insulin resistance, elevated fasting glucose and insulin levels, and features of metabolic syndrome, with insulin resistant migraineurs experiencing significantly greater attack frequency, intensity, and cerebrovascular disease, underscores the systemic nature of the disorder. Recognizing migraine as a manifestation of metabolic disturbance rather than merely a vascular or neurological event fundamentally transforms clinical approach , shifting focus from reactive symptom management to proactive metabolic optimization.

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