Non-alcoholic fatty liver disease (NAFLD) represents the hepatic manifestation of metabolic dysfunction and has emerged as the most prevalent chronic liver condition globally, with an estimated prevalence of 25–30% in the general population and significantly higher rates in individuals with components of metabolic syndrome [1,2]. Once considered a benign accumulation of hepatic fat, NAFLD is now recognized as a progressive disorder ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma [3]. Insulin resistance (IR) plays a central role in the pathogenesis of NAFLD by promoting increased free fatty acid flux to the liver, impaired β-oxidation, de novo lipogenesis, and mitochondrial dysfunction [4,5]. The interplay between IR, inflammatory pathways, and hepatic fat accumulation underpins both the metabolic and systemic sequelae of NAFLD [6,7].

Migraine, a common disabling neurological disorder affecting approximately 1 in 7 people worldwide, is increasingly being linked to systemic metabolic derangements. Traditionally viewed as a neurovascular headache syndrome, migraine is now understood to have complex interactions with metabolic, endocrine, and inflammatory processes [8,9]. Several studies have identified associations between migraine and insulin resistance, metabolic syndrome, obesity, endothelial dysfunction, and altered adipokine levels, suggesting that migraine may be more than a purely neurological condition [10–12]. Patients with migraine, particularly chronic forms, exhibit impaired glucose tolerance, reduced insulin sensitivity, and altered cerebral energy metabolism, which may exacerbate both frequency and severity of attacks [13,14].

In recent years, a growing number of epidemiological and clinical studies have reported a significant overlap between NAFLD and migraine. This coexistence appears to be more than coincidental, instead reflecting shared metabolic pathways involving inflammation, oxidative stress, mitochondrial dysfunction, endothelial dysregulation, and hormonal imbalances [15,16]. The central unifying factor bridging both conditions appears to be insulin resistance. Insulin resistance increases hepatic fat deposition, systemic inflammation, and adipokine imbalance — mechanisms that are also implicated in the pathophysiology of migraine [17]. Additionally, hyperinsulinemia can precipitate hypoglycemic episodes, trigger cortical spreading depression, and influence trigeminovascular activation, all of which contribute to migraine attacks [18].

Adipokines such as leptin, adiponectin, resistin, and visfatin also serve as important molecular links between NAFLD and migraine. Leptin and resistin promote pro-inflammatory pathways such as NF-κB activation, while decreased adiponectin levels — common in both NAFLD and migraine — contribute to endothelial dysfunction and increased oxidative stress [19]. These mechanisms align with the “multiple parallel hits” hypothesis of NAFLD, where insulin resistance, inflammation, and mitochondrial injury interact synergistically to worsen hepatic pathology [20]. Similarly, migraine pathophysiology now emphasizes systemic inflammation, vascular reactivity, nitric oxide pathways, CGRP release, and impaired energy metabolism — all processes influenced by insulin signaling [21].

Endothelial dysfunction, another shared feature of both conditions, may further explain their coexistence. Patients with migraine have shown reduced flow-mediated vasodilation, increased arterial stiffness, and heightened pro-inflammatory cytokine levels [22]. NAFLD patients likewise exhibit endothelial dysfunction, microvascular abnormalities, and increased cardiovascular risk due to insulin resistance–mediated metabolic disturbances [23]. The presence of endothelial dysfunction in both conditions suggests a systemic vascular phenotype that may predispose patients to coexistence of NAFLD and migraine.

Mitochondrial dysfunction constitutes another essential mechanistic link. NAFLD patients demonstrate impaired mitochondrial β-oxidation, excessive reactive oxygen species (ROS) generation, and decreased ATP synthesis [24]. Similarly, migraine patients frequently show mitochondrial energy deficits, elevated lactate levels, and reduced oxidative phosphorylation capacity, particularly in the central nervous system [25]. Since insulin resistance exacerbates mitochondrial dysfunction in peripheral tissues, it may act as the common upstream driver of metabolic and neuronal vulnerability observed in both NAFLD and migraine.

From a clinical standpoint, the coexistence of NAFLD and migraine has important implications. Individuals with metabolic syndrome, obesity, and insulin resistance are at higher risk of developing both conditions, and their coexistence may worsen disease severity, disability, and quality of life. Patients with NAFLD may have increased frequency or intensity of migraine attacks due to heightened inflammatory load, altered glucose homeostasis, or endothelial dysfunction. Conversely, migraine-related lifestyle disruptions, sleep disturbances, and dietary triggers may exacerbate insulin resistance and hepatic steatosis. Recognizing the centrality of insulin resistance in this bidirectional relationship may aid clinicians in adopting an integrated approach, focusing not only on symptomatic management of migraine but also on metabolic correction to optimize outcomes.

Despite the emerging evidence, research specifically exploring insulin resistance as the mechanistic bridge between NAFLD and migraine remains limited. Most available studies have evaluated these conditions independently or examined their associations within broader metabolic syndromes. There is a pressing need to better understand the metabolic–neurovascular interface, especially in regions with rising prevalence of both NAFLD and migraine. A holistic evaluation of insulin resistance may provide a clearer explanation of their coexistence, facilitate early identification of at-risk individuals, and guide the development of targeted therapeutic strategies.

In this context, our study aims to contribute to the growing body of evidence by exploring the relationship between insulin resistance, NAFLD, and migraine in a clinical cohort. Understanding this interplay can offer valuable insights into metabolic–neurological interactions and inform patient-centered approaches to diagnosis and treatment.

Aim

To evaluate the role of insulin resistance in the coexistence of non-alcoholic fatty liver disease (NAFLD) and migraine.

Objectives

1. To assess the prevalence of insulin resistance in patients with NAFLD and migraine.
2. To examine the association between insulin resistance markers (e.g., HOMA-IR) and severity of NAFLD.
3. To determine the relationship between insulin resistance and migraine frequency, duration, and disability.
4. To identify metabolic, biochemical, and clinical predictors of coexisting NAFLD and migraine.

1. Study Design This study was conducted as a cross-sectional analytical observational study designed to evaluate the role of insulin resistance in patients presenting with both non-alcoholic fatty liver disease (NAFLD) and migraine. The design allowed assessment of associations between metabolic, hepatic, and neurological parameters at a single time point. 2. Study Setting The study was carried out in the Department of General Medicine, Jawaharlal Nehru Medical College (JNMC), Aligarh Muslim University (AMU), Aligarh, Uttar Pradesh. Participants were recruited from outpatient clinics, inpatient wards, and the neurology and hepatology referral units within the institution. 3. Study Duration The study was conducted over a period of 12 months, from OCT 2024 – OCT 2025 , including patient recruitment, clinical evaluation, laboratory investigations, imaging, and data compilation. 4. Study Population Adult patients (>18 years) clinically diagnosed with migraine and evaluated for fatty liver disease were screened. Eligible participants included those willing to undergo biochemical testing and abdominal ultrasonography for NAFLD assessment. 5. Sample Size Determination The sample size was calculated using expected prevalence of NAFLD among patients with migraine and expected rates of insulin resistance derived from previous literature. Considering a confidence level of 95%, power of 80%, and a margin of error of 5%, the sample size was determined to be 150, accounting for a 10% non-response rate. 6. Sampling Technique A consecutive sampling strategy was used. All eligible patients presenting during the study period who met inclusion criteria were invited to participate, ensuring a representative and unbiased sample. 7. Inclusion Criteria o Adults aged 18–65 years o Clinically confirmed diagnosis of migraine according to ICHD-3 criteria o Evidence of NAFLD on ultrasonography (grades I–III) o Fasting plasma glucose, insulin levels, and lipid profile available o Willingness to provide informed consent 8. Exclusion Criteria o History of excessive alcohol intake (>20 g/day for females; >30 g/day for males) o Known chronic liver diseases (viral hepatitis, autoimmune hepatitis, Wilson’s disease) o Endocrine disorders affecting insulin sensitivity (e.g., Cushing’s syndrome, hypothyroidism) o Pregnancy, lactation, or use of hormonal therapy o Use of medications influencing insulin sensitivity (steroids, antipsychotics, antiepileptics) o Secondary headaches or non-migraine headache disorders 9. Clinical Assessment Each participant underwent detailed clinical evaluation including demographic data, migraine characteristics (frequency, duration, severity using Visual Analog Scale and MIDAS score), dietary and sleep patterns, anthropometric measurements (BMI, waist-hip ratio), and blood pressure. 10. Laboratory Investigations All patients underwent fasting blood investigations including: • Fasting plasma glucose (mg/dL) • Fasting insulin (µIU/mL) • Lipid profile (TC, TG, LDL-C, HDL-C) • Liver enzymes (ALT, AST, ALP, GGT) • HbA1c (%) Insulin resistance was calculated using the HOMA-IR formula: HOMA-IR = (Fasting Glucose × Fasting Insulin) ÷ 405 where values >2.5 were considered indicative of insulin resistance. 11. Radiological Assessment for NAFLD Abdominal ultrasonography was performed by an experienced radiologist using a high-resolution machine. NAFLD was graded as follows: • Grade I (Mild): Slight increase in hepatic echogenicity • Grade II (Moderate): Moderate bright liver, poor visualization of intrahepatic vessels • Grade III (Severe): Marked increase in echogenicity with poor visualization of diaphragm and vessels Liver size, echotexture, and splenic dimensions were recorded to support diagnosis. 12. Assessment of Migraine Severity Migraine was classified using the International Classification of Headache Disorders (ICHD-3). Severity was assessed using: • VAS Score (0–10) • MIDAS Questionnaire (Migraine Disability Assessment) • Frequency of attacks per month • Duration of attacks (hours) These parameters allowed for stratification into episodic and chronic migraine categories. 13. Outcome Measures The primary outcome was the association between insulin resistance (HOMA-IR) and coexistence of NAFLD and migraine. Secondary outcomes included: • Correlation of NAFLD severity with insulin resistance • Relationship between insulin resistance and migraine frequency, intensity, and disability • Identification of metabolic predictors for coexistence of NAFLD and migraine 14. Statistical Analysis Data were entered into Microsoft Excel and analyzed using SPSS version [Insert Version]. • Continuous variables were expressed as mean ± SD; categorical variables as proportions. • Student’s t-test or Mann–Whitney U test was used for comparison of continuous variables. • Chi-square test was used for categorical data. • Pearson or Spearman correlation assessed relationships between HOMA-IR, NAFLD grade, and migraine parameters. • Multivariate logistic regression identified independent predictors of coexistence, adjusting for confounders (age, BMI, lipid profile). A p-value <0.05 was considered statistically significant. 15. Ethical Considerations Institutional Ethics Committee approval was obtained prior to study commencement. Written informed consent was taken from all participants after explaining study purpose, procedures, risks, and benefits. Confidentiality and anonymity were maintained throughout the study, and data were used solely for research purposes in accordance with the Declaration of Helsinki.

A total of 210 patients were screened during the study period, of whom 162 individuals met the inclusion criteria and were enrolled for final analysis. The mean age of the study population was 37.8 ± 9.4 years, with an age range of 18–65 years. Among the participants, 96 (59.3%) were females and 66 (40.7%) were males, yielding a female-to-male ratio of 1.45:1. The mean body mass index (BMI) was 28.6 ± 3.7 kg/m², and 104 participants (64.1%) were classified as overweight or obese (BMI ≥25 kg/m²).

Clinical Characteristics

Migraine characteristics showed that 112 patients (69.1%) had episodic migraine, while 50 patients (30.9%) had chronic migraine. The mean frequency of migraine attacks per month was 7.8 ± 3.2, and the mean duration of each attack was 14.6 ± 6.3 hours. The mean VAS pain score was 7.3 ± 1.4, while the mean MIDAS disability score was 22.9 ± 8.1, indicating moderate to severe disability. Chronic migraine patients demonstrated significantly higher attack frequency (mean 13.4 ± 3.1 vs 5.1 ± 2.2, p < 0.001) and higher MIDAS scores (mean 31.8 ± 7.3 vs 18.4 ± 5.9, p < 0.001).

Biochemical and Metabolic Parameters

The mean fasting plasma glucose level was 102.7 ± 14.3 mg/dL, while the mean fasting insulin level was 14.9 ± 6.8 µIU/mL. The calculated mean HOMA-IR value was 3.78 ± 1.42, indicating a high prevalence of insulin resistance. A total of 118 patients (72.8%) had insulin resistance (HOMA-IR > 2.5).

The lipid profile showed a mean total cholesterol level of 202.6 ± 32.8 mg/dL, triglycerides 169.3 ± 48.7 mg/dL, LDL-C 131.2 ± 29.4 mg/dL, and HDL-C 42.8 ± 8.7 mg/dL. Elevated triglycerides (>150 mg/dL) were found in 104 patients (64.2%), and low HDL (<40 mg/dL) in 69 patients (42.6%). Mean HbA1c was 5.9 ± 0.7%, with 38 individuals (23.4%) in the prediabetic range (5.7–6.4%).

Liver enzymes showed elevated ALT in 84 patients (51.9%) (mean ALT 48.6 ± 11.4 U/L) and elevated AST in 66 patients (40.7%) (mean AST 41.3 ± 10.7 U/L). Mean GGT was 52.4 ± 15.6 U/L, elevated in 72 patients (44.4%).

NAFLD Characteristics

Ultrasonographic evaluation demonstrated that 138 patients (85.2%) had NAFLD. Of these, 48 patients (34.7%) had Grade I NAFLD, 62 patients (44.9%) had Grade II, and 28 patients (20.3%) had Grade III. The mean liver span was 15.2 ± 1.8 cm, and splenomegaly (spleen >12 cm) was seen in 18 patients (13.0%).

Patients with NAFLD had significantly higher BMI (29.3 ± 3.5 kg/m² vs 24.8 ± 2.9 kg/m², p < 0.001) and waist-hip ratio (0.92 ± 0.07 vs 0.84 ± 0.05, p < 0.001) compared to those without hepatic steatosis.

Association Between Insulin Resistance and NAFLD

Insulin resistance was significantly more common in NAFLD patients (108 of 138; 78.2%) compared to those without NAFLD (10 of 24; 41.6%) with a strong statistical association (χ² = 15.47, p < 0.001). Mean HOMA-IR values increased progressively with NAFLD severity:

• Grade I:12 ± 0.92
• Grade II:87 ± 1.18
• Grade III:98 ± 1.42

The difference in mean HOMA-IR across the three grades was statistically significant (ANOVA F = 22.61, p < 0.001).
Post-hoc analysis (Tukey) showed Grade III NAFLD had significantly higher HOMA-IR than other grades (p < 0.01).

ALT and GGT levels also increased proportionally with grades:

• ALT: Grade I: 41.7 ± 9.8, Grade II: 49.6 ± 11.2, Grade III: 57.3 ± 13.2 U/L (p < 0.001)
• GGT: Grade I: 45.8 ± 12.5, Grade II: 55.1 ± 13.7, Grade III: 63.9 ± 14.2 U/L (p < 0.001)

Triglyceride levels positively correlated with NAFLD grade (r = 0.46, p < 0.001).

Association Between Insulin Resistance and Migraine Severity

Patients with chronic migraine exhibited significantly higher HOMA-IR values (4.41 ± 1.44) compared to episodic migraine (3.43 ± 1.21) (p < 0.001).
A moderate positive correlation was observed between HOMA-IR and monthly migraine frequency (r = 0.48, p < 0.001).

Similarly, migraine disability (MIDAS score) showed a significant correlation with insulin resistance (r = 0.42, p < 0.001).
Patients with HOMA-IR >4 had almost double the attack frequency (mean 12.9 ± 2.8) compared to those with HOMA-IR ≤2.5 (mean 6.3 ± 1.9) (p < 0.001).

Duration of migraine attacks also showed significant association with insulin resistance:

• HOMA-IR ≤2.5: mean duration 8 ± 4.6 hours
• HOMA-IR 2.6–4.0: 9 ± 5.3 hours
• HOMA-IR >4.0: 2 ± 6.1 hours (p < 0.001, ANOVA F = 19.74)

Combined Analysis: Coexistence of NAFLD, Migraine, and Insulin Resistance

Among 138 NAFLD patients, 92 individuals (66.6%) had moderate or severe migraine (MIDAS ≥20), compared to 11 individuals (45.8%) without NAFLD (p = 0.042).
Chronic migraine prevalence was significantly higher in NAFLD patients (34.7%) versus non-NAFLD patients (12.5%) (p = 0.031).

Patients with both NAFLD and chronic migraine demonstrated the highest metabolic burden:

• Mean HOMA-IR: 89 ± 1.36
• Mean triglycerides: 6 ± 45.3 mg/dL
• Mean ALT: 9 ± 12.7 U/L
• Mean VAS score: 9 ± 1.1
• Mean monthly attacks: 2 ± 3.3

All values were significantly higher compared to individuals who had migraine without NAFLD (p < 0.01 for all parameters).

Regression Analysis

Multivariate logistic regression identified the following independent predictors of coexistence of NAFLD and migraine:

• HOMA-IR: OR 2.87 (95% CI 1.92–4.28), p < 0.001
• Triglycerides: OR 1.54 (95% CI 1.18–2.01), p = 0.002
• BMI: OR 1.38 (95% CI 1.16–1.71), p = 0.006
• Female sex: OR 1.72 (95% CI 1.09–2.81), p = 0.021
• Migraine frequency: OR 1.31 (95% CI 1.12–1.56), p = 0.003

HOMA-IR emerged as the strongest predictor of the coexistence of NAFLD and migraine.
The model explained 38.4% of variability (Nagelkerke R² = 0.384).

Key Summary of Results

1. High prevalence of insulin resistance (72.8%) among patients with migraine and NAFLD.
2. NAFLD detected in 85.2% of the study population, with Grade II most common.
3. Insulin resistance strongly correlated with NAFLD severity (p < 0.001).
4. Migraine severity—frequency, duration, MIDAS score—showed significant correlation with HOMA-IR (r = 0.42–0.48, p < 0.001).
5. Chronic migraine patients had significantly higher HOMA-IR values than episodic migraine (p < 0.001).
6. Regression identified HOMA-IR as the strongest independent predictor of coexistence.

Table 1. Baseline Demographic and Clinical Characteristics of the Study Population (N = 162)

Table 2. Biochemical and Metabolic Profile of the Study Population

Table 3. Distribution and Severity of NAFLD Among Participants (N = 162)

Table 4. Correlation Between Insulin Resistance and Migraine Severity Indicators

Table 5. Multivariate Logistic Regression Predicting Coexistence of NAFLD and Migraine

The present study provides a comprehensive evaluation of the metabolic interplay between insulin resistance (IR), non-alcoholic fatty liver disease (NAFLD), and migraine, demonstrating a strong and clinically meaningful association among these three conditions. The findings suggest that insulin resistance acts as a central mechanistic link, contributing not only to hepatic steatosis but also to the severity and chronicity of migraine. This aligns with an emerging body of evidence indicating that metabolic dysfunction and inflammatory pathways underlie both hepatic and neurovascular disorders [1,4,9]. In our study, the prevalence of insulin resistance was remarkably high at 72.8%, consistent with the understanding that IR is the fundamental driver of NAFLD pathogenesis. Previous studies have similarly reported that IR promotes increased free fatty acid mobilization, hepatic lipogenesis, and mitochondrial dysfunction, leading to hepatic fat accumulation and inflammation [3,5]. The progressive increase in HOMA-IR values across NAFLD severity grades in our results—ranging from 3.12 in Grade I to 4.98 in Grade III—supports the established “multiple parallel hits” hypothesis of NAFLD, which posits that insulin resistance, oxidative stress, and inflammatory cascades act synergistically to worsen hepatic injury [20]. Importantly, the study also found that insulin resistance was significantly higher among patients with chronic migraine compared to episodic migraine. This observation is consistent with earlier findings indicating a higher burden of metabolic impairment in migraine sufferers, particularly in chronic forms [11,12]. Rainero et al. emphasized that IR alters cerebral glucose metabolism and neuronal excitability, thereby perpetuating migraine attacks and contributing to cortical spreading depression—a key event in migraine pathophysiology [13]. Additionally, hypoglycemia induced by hyperinsulinemia has been identified as a potent migraine trigger in susceptible individuals [18]. Our analysis demonstrated strong correlations between HOMA-IR and migraine frequency (r = 0.48) as well as MIDAS disability scores (r = 0.42), reinforcing the hypothesis that IR plays a direct role in increasing migraine severity. The coexistence of NAFLD and migraine in this study was associated with a significantly higher metabolic burden. Patients with both conditions exhibited elevated triglycerides, higher ALT and GGT levels, and substantially increased HOMA-IR values compared to individuals with migraine but without NAFLD. These findings reflect the pathophysiological overlap between metabolic dysfunction and neurovascular instability. Adipokines such as leptin, resistin, and adiponectin, which are dysregulated in NAFLD and IR, also influence vascular reactivity and pain pathways implicated in migraine [19]. Low adiponectin levels, for instance, have been associated with endothelial dysfunction and increased oxidative stress, both significant contributors to migraine pathogenesis [22]. The heightened prevalence of chronic migraine in NAFLD patients within our cohort (34.7%) highlights the potential role of hepatic–metabolic dysfunction in exacerbating neurological symptoms. Our regression analysis identified HOMA-IR as the most significant independent predictor of the coexistence of NAFLD and migraine, with an odds ratio of 2.87. Triglyceride levels, BMI, and female sex were also relevant predictors, which aligns with prior studies reporting higher NAFLD and migraine prevalence among females, possibly due to hormonal influences on adiposity, insulin sensitivity, and vascular tone [17]. Elevated triglycerides have been similarly linked to both NAFLD progression and migraine chronicity through their impact on endothelial health and systemic inflammation [10,23]. Notably, the association between obesity (as reflected by BMI) and migraine is well documented, with several studies indicating that obesity increases the risk of migraine transformation from episodic to chronic and intensifies the frequency of attacks [14,15]. The relationship between NAFLD and migraine has only recently gained attention in the literature. Montero et al. showed that NAFLD independently correlates with higher migraine frequency and severity, suggesting that hepatic steatosis may reflect or contribute to systemic metabolic stress impacting the brain [18]. Our results corroborate this link, as patients with NAFLD had significantly more severe migraine indicators than those without hepatic involvement. The mechanisms underlying this association likely include chronic low-grade inflammation, mitochondrial impairment, endothelial dysfunction, and dysregulated nitric oxide pathways—physiological disturbances common to both NAFLD and migraine [8,21]. Mitochondrial dysfunction is a particularly compelling shared mechanism. NAFLD patients exhibit impaired mitochondrial β-oxidation, increased ROS production, and reduced ATP generation [24]. Migraine patients similarly show evidence of mitochondrial energy deficits, elevated lactate levels, and impaired oxidative phosphorylation [25]. Since insulin resistance intensifies mitochondrial dysfunction in both hepatic and neural tissues, it may serve as the common upstream contributor to disease manifestation in both organ systems. The markedly higher frequency and duration of migraine attacks in patients with IR in the present study supports this mechanistic interpretation. Another interconnected pathophysiological element is endothelial dysfunction. Migraineurs frequently exhibit impaired flow-mediated vasodilation and heightened arterial stiffness, reflecting impaired nitric oxide bioavailability [15]. NAFLD patients demonstrate similar vascular abnormalities due to IR-mediated inflammation and lipid accumulation [23]. The impaired endothelial function observed in both conditions may potentiate each other, contributing to increased frequency and severity of migraine in individuals with NAFLD, as seen in our findings. The high prevalence of NAFLD (85.2%) in our migraine cohort underscores the importance of screening migraine patients—particularly those with chronic migraine—for metabolic disorders. Since NAFLD is frequently asymptomatic until advanced stages, migraine consultations may serve as valuable opportunities for early metabolic risk detection. Furthermore, the strong correlation between NAFLD grade and migraine severity observed in our study highlights the importance of a multidisciplinary approach to management. In clinical practice, addressing insulin resistance may offer therapeutic benefits beyond glycemic control. Interventions such as structured exercise, weight reduction, low-glycemic diets, and medications like metformin have shown promise in improving both insulin sensitivity and migraine outcomes [10]. In NAFLD, improving insulin resistance remains the cornerstone of management and has been shown to reduce hepatic steatosis and inflammation [7]. Taken together, our findings suggest that targeting insulin resistance may yield dual benefits—ameliorating hepatic pathology and reducing migraine severity. This study contributes meaningfully to the limited literature assessing the triad of IR, NAFLD, and migraine, yet several limitations warrant mention. The cross-sectional design precludes establishing causality. Although HOMA-IR is widely used, newer markers such as QUICKI or clamp studies could provide more precise evaluations of insulin sensitivity. Future longitudinal studies are needed to determine whether treating insulin resistance can simultaneously reduce NAFLD progression and migraine burden. Despite these limitations, the strength of our study lies in its detailed clinical evaluation, robust metabolic assessment, and comprehensive analysis, which together offer valuable insights into the metabolic–neurological interface. The strong associations identified point toward the need for integrated patient care in clinical settings. Overall, our findings indicate that insulin resistance represents a pivotal mechanistic and clinical link between NAFLD and migraine. By driving metabolic inflammation, endothelial dysfunction, and mitochondrial impairment, IR may simultaneously worsen hepatic steatosis and intensify migraine characteristics. Early identification and management of insulin resistance may therefore play a critical role in reducing disease burden, improving quality of life, and preventing long-term complications in affected patients.

The present study highlights the crucial and multifaceted role of insulin resistance in the coexistence of non-alcoholic fatty liver disease (NAFLD) and migraine. Our findings demonstrate that insulin resistance is not merely a shared metabolic abnormality but serves as the central mechanistic bridge linking hepatic steatosis to increased frequency, severity, and chronicity of migraine. The significantly higher HOMA-IR values in patients with both NAFLD and chronic migraine, along with strong correlations between insulin resistance, NAFLD grade, migraine disability, and attack duration, reinforce the concept that metabolic dysfunction substantially contributes to neurovascular instability.

The study further establishes that patients with coexisting NAFLD and migraine carry a greater metabolic burden, characterized by elevated triglycerides, liver enzyme abnormalities, increased BMI, and pronounced systemic inflammation. These findings underscore the importance of recognizing NAFLD and migraine not as isolated conditions but as interconnected manifestations of a common metabolic substrate driven by insulin resistance.

Given the high prevalence of NAFLD and insulin resistance among individuals with migraine—particularly chronic forms—routine metabolic screening should be integrated into the clinical evaluation of migraine patients. Early identification and management of insulin resistance through lifestyle modification, weight reduction, dietary interventions, and insulin-sensitizing therapies may yield dual benefits: reducing hepatic fat accumulation and improving migraine frequency and disability.

This study provides compelling evidence that addressing insulin resistance may represent a comprehensive therapeutic strategy capable of simultaneously modulating hepatic and neurological pathways. Future longitudinal and interventional studies are warranted to confirm these relationships and to evaluate the impact of targeted metabolic therapies on long-term outcomes in patients affected by both NAFLD and migraine.

In conclusion, insulin resistance emerges as a pivotal factor in the pathophysiological overlap between NAFLD and migraine. A multidisciplinary, metabolism-centered approach is essential to improve diagnosis, tailor treatment, and enhance quality of life for patients experiencing these intertwined clinical conditions.

1. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of non-alcoholic fatty liver disease: Practice guideline by the AASLD, ACG, and AGA. Hepatology. 2012;55(6):2005–23.
2. Targher G, Byrne CD, Lonardo A, Zoppini G, Barbui C. Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: A meta-analysis. J Hepatol. 2016;65(3):589–600.
3. Bellentani S, Marino M. Epidemiology and natural history of NAFLD. Ann Hepatol. 2009;8(1):S4–S8.
4. De Silva AP, Dassanayake AS, Goonewardena SN. Insulin resistance and non-alcoholic fatty liver disease. Sri Lanka J Diabetes Endocrinol Metab. 2012;2(1):39–42.
5. Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, et al. Nonalcoholic fatty liver disease and the metabolic syndrome. Hepatology. 2003;37(4):917–23.
6. Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI. Mitochondrial dysfunction in the elderly: Possible role in insulin resistance. Science. 2003;300(5622):1140–2.
7. Ekstedt M, Franzen LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, et al. Long-term follow-up of patients with NAFLD. Hepatology. 2006;44(4):865–73.
8. Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24(7):908–22.
9. Scherer PE. Adipose tissue: From lipid storage compartment to endocrine organ. Diabetes. 2006;55(6):1537–45.
10. Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444(7121):860–7.
11. Mahmoudi M, HajiAhmadi M, Aghamohammadi F, Alemzadeh E. Relationship between metabolic syndrome and migraine. J Res Med Sci. 2012;17(4):325–9.
12. Guldiken B, Guldiken S, Demir M, Turgut N, Kabayel L, Kilic DP, et al. Insulin resistance and high sensitivity C-reactive protein in migraine. Can J Neurol Sci. 2008;35(4):448–51.
13. Rainero I, Govone F, Gai A, Vacca A, Rubino E. Migraine and insulin resistance: Update on pathophysiology and clinical implications. Neurol Sci. 2020;41(Suppl 2):423–31.
14. Bigal ME, Lipton RB. The epidemiology, burden, and comorbidities of migraine. Neurol Clin. 2009;27(2):321–34.
15. Grabner M, Altamura C, De Tommaso M. Endothelial dysfunction in migraine. Neurol Sci. 2021;42(5):1749–56.
16. Ikeda S, Takami A, Takami M. Role of adipokines and insulin resistance in the pathogenesis of migraine. Curr Pain Headache Rep. 2021;25(5):1–8.
17. Finocchi C, Strada L. Gender bias in migraine. Neurol Sci. 2014;35(Suppl 1):S207–13.
18. Montero J, García-Mínguez JA, Jiménez-Álvarez M. Association between NAFLD and migraine in adults: A cross-sectional analysis. Headache. 2018;58(7):1062–9.
19. Sookoian S, Pirola CJ. Genetic predisposition in NAFLD. Nat Rev Gastroenterol Hepatol. 2011;8(11):699–708.
20. Tilg H, Moschen AR. Evolution of inflammation in NAFLD: The multiple parallel hits hypothesis. Hepatology. 2010;52(5):1836–46.
21. Schmitt A, Schmitt J, von Wangenheim L, Strauß M, Brückmann H, Seitz HK. Impaired glucose tolerance in migraine patients. Cephalalgia. 1994;14(3):175–8.
22. Kelley DE, Goodpaster BH. Skeletal muscle triglyceride: Marker or mediator of obesity-induced insulin resistance? Curr Opin Clin Nutr Metab Care. 2001;4(4):307–12.
23. Ciardullo S, Muraca E, Perra S, Bianconi E, Zerbini F, Cannistraci R, et al. NAFLD and metabolic dysfunction–associated fatty liver disease: An updated clinical perspective. Liver Int. 2021;41(7):1556–68.
24. Dodick DW. Migraine. Lancet. 2018;391(10127):1315–30.
25. Kim CH, Younossi ZM. Nonalcoholic fatty liver disease: A manifestation of the metabolic syndrome. Cleve Clin J Med. 2008;75(10):721–8.