Insulin Resistance Across Cerebrovascular and Related Disorders: Mechanisms, Measurement, Genetics, and Clinical Implications

Introduction

Insulin resistance (IR) is tightly linked to a broad spectrum of disorders, and research in this field has deepened substantially in recent years. The pathogenic role of IR in metabolic syndrome, type 2 diabetes mellitus (T2DM), cardiovascular disease, and neurological disorders is widely recognized.^1–3 Notably, studies in cerebrovascular diseases (CeVD)^4,5 and Alzheimer’s disease (AD)^6–8 indicate that IR may influence disease initiation and progression through complex molecular mechanisms. Significant associations between IR and hepatic disease,^9,10 kidney disease,¹¹ and polycystic ovary syndrome (PCOS) have also been reported.¹²

Beyond systemic metabolism, IR exerts tissue-specific effects. For example, defects in insulin receptors within the cerebral vasculature have been implicated in AD pathophysiology,¹³ and brain insulin resistance has been mechanistically linked to both Parkinson’s disease and AD across multiple studies.^14,15 Collectively, these observations suggest shared pathological pathways of IR across diseases, opening avenues for multi-disease therapeutic strategies.

Although insulin resistance has been extensively studied in metabolic disorders, its role as a unifying mechanism across cerebrovascular and neurodegenerative diseases has only recently gained attention. Existing reviews often focus on individual conditions or isolated pathways, whereas a comprehensive synthesis linking molecular mechanisms, clinical measurement, genetic evidence, and therapeutic implications across the cerebrovascular–neurodegenerative continuum remains lacking.

In this review, we focus on insulin resistance as a cross-cutting pathophysiological axis connecting cerebrovascular diseases with related neurological and systemic disorders. We integrate evidence from mechanistic studies, epidemiological and genetic investigations, and clinical research to (i) delineate shared and disease-specific pathways, (ii) critically evaluate current approaches to measuring insulin resistance, and (iii) discuss translational implications for prevention and management. By clarifying both established knowledge and unresolved gaps, this review aims to provide a framework for future research and precision interventions targeting insulin resistance in cerebrovascular and neurodegenerative disease.

Fundamental Concepts of Insulin Resistance

Definition and Mechanisms

Insulin resistance refers to a diminished biological response to insulin, resulting in impaired efficiency of insulin-mediated glycemic control. IR is a key feature of several metabolic disorders, including T2DM, obesity, and cardiovascular disease. Sharma et al emphasized that accurate assessment of IR is crucial for understanding and managing cardiometabolic diseases, underscoring the need for reliable measurement techniques to quantify individual insulin sensitivity.¹⁶

IR is also closely related to neurodegenerative diseases. Dahiya examined insulin signaling in AD and other neurodegenerative conditions, focusing on pivotal components—IRS, PI3K, Akt, and GSK-3β—whose dysregulation can contribute to neuronal injury and cognitive decline.¹⁷

In addition, Angelidi characterized severe insulin resistance syndromes—rare yet complex entities associated with profound metabolic derangements and high mortality—reinforcing that IR is not only a hallmark of metabolic dysregulation but also an integral driver of disease pathophysiology.¹⁸

Collectively, these findings suggest that insulin resistance converges on a limited set of core biological processes—disrupted insulin signaling, inflammation, oxidative stress, endothelial dysfunction, and impaired proteostasis—that operate across multiple organ systems. While disease-specific modifiers exist, particularly in relation to amyloid and tau pathology in Alzheimer’s disease or α-synuclein aggregation in Parkinson’s disease, the underlying neurovascular and metabolic disturbances are largely shared. This convergence supports the concept of insulin resistance as a common mechanistic substrate linking cerebrovascular dysfunction with neurodegeneration, rather than a series of isolated, disease-specific abnormalities.

Methods for Assessing Insulin Resistance

A variety of tools have been developed to evaluate IR. In 2023, Mu Xiaodie reported that a non-insulin-based IR index was strongly associated with diabetic kidney disease (DKD) among patients with T2DM.¹⁹ Zhao further summarized that IR is related to multiple diseases, driven by factors such as genetics, obesity, and aging, and can be addressed through exercise, diet, and pharmacotherapy.²

Population-specific assessments have also been explored. Aydin showed that both hepatic and systemic IR were associated with gallstone disease among Southwestern Indigenous Americans.²⁰ Li evaluated acupuncture as a potential first-line therapy for IR and nonalcoholic fatty liver disease (NAFLD), while noting important limitations in the evidence base.²¹ For risk prediction, Louie found that a high probability of IR was linked to greater cardiovascular risk in older adults,²² and Ke reported that the metabolic score for IR (METS-IR) strongly predicted cardiovascular risk among Chinese patients with arthritis, demonstrating a significant dose-response relationship.²³

Mechanistic and molecular correlates continue to emerge. In chronic kidney disease (CKD), Gu observed that skeletal-muscle TLR13 upregulation was associated with IR, whereas TLR13 knockdown alleviated IR.²⁴ Fernando showed that MKP-2 upregulation in obesity and fatty liver promotes IR, while MKP-2 deficiency protects against diet-induced obesity and improves insulin sensitivity.²⁵ From a genetic perspective, Mendelian randomization by Zhang identified significant genetic links between IR, hypertension, and cardiovascular disease.³ Clinically, Crocetto associated Peyronie’s disease (PD) with hypertension, T2DM, and IR, and noted a relationship between NAFLD and PD.²⁶

Regarding disease comorbidity and sex-specific issues, Ntikoudi reported that NAFLD affects ~30% of adult women globally and is associated with age, obesity, and metabolic syndrome, with higher prevalence after menopause.²⁷ Smeijer found that the endothelin-receptor antagonist atrasentan reduced IR in patients with T2DM—especially among those with marked baseline IR.²⁸

Finally, a bibliometric analysis by Zhou linked IR to ischemic stroke and highlighted the leading contribution of the United States in this research domain;⁵ another analysis by the same group identified Walter N. Kernan as a key author in the field.⁵ In 2025, Liu Jia reported significant associations between four surrogate indices of IR and the risk of gallstone disease.²⁹

Insulin Resistance and Metabolic Diseases

The Role of IR in Diabetes

IR is central to the pathogenesis of diabetes. Burillo et al described connections between T2DM and AD mediated by inflammation, cellular stress responses, autophagy, and mitochondrial dysfunction.⁷ In 2024, Fan Yajie showed that IR drives diabetic cardiomyopathy by promoting adverse myocardial remodeling and functional impairment.³⁰

The liver is a major target organ of IR. Bo demonstrated that IR increases hepatic steatosis; nevertheless, insulin retains regulatory effects on lipid metabolism even under insulin-resistant conditions.³¹ Building on the liver–diabetes interface, Niranjan discussed T2DM-related NAFLD and underscored the roles of IR and inflammation in disease progression.³²

Sakurai further highlighted that metabolic dysfunction—including IR and gut microbiome alterations—constitutes a core driver of NAFLD development.³³ Together, these findings reinforce the pivotal role of IR in diabetes and its close connections to comorbid organ disease.

Although HOMA-IR remains a widely used measure in clinical and research settings, its reliance on fasting insulin limits applicability in large-scale or non-fasting populations. In contrast, surrogate indices such as the triglyceride–glucose index and METS-IR, derived from routinely available clinical parameters, offer greater feasibility and scalability. Emerging evidence indicates that these indices are not only associated with metabolic and cardiovascular outcomes but also predict cerebrovascular events and small-vessel disease burden in population-based cohorts. Nevertheless, heterogeneity across populations, cut-off definitions, and outcome measures highlights the need for standardization and context-specific interpretation when applying these indices to neurological risk assessment.

NAFLD and Insulin Resistance

NAFLD is tightly intertwined with IR. Barber et al noted that metabolic dysfunction-associated fatty liver disease (MAFLD) has become the most common cause of chronic liver disease, with gut-related factors contributing to its pathogenesis; however, specific diagnostic and therapeutic options remain limited.³⁴ In non-obese individuals, Wu identified risk factors for NAFLD—including age, body-mass index (BMI), and metabolic biomarkers—all closely linked to IR.³⁵ Among Hispanic men, Perez-Mayorga reported that the TyG index and TG/HDL-C ratio are useful for detecting NAFLD and are strongly associated with cardiometabolic disease, further underscoring the NAFLD–IR connection.³⁶ Consistently, Tian showed that IR-related indices have value for identifying NAFLD among T2DM inpatients in Jiangsu Province.³⁷

Beyond the liver, Zhao suggested that NAFLD may increase the risks of benign prostatic hyperplasia (BPH) and prostate cancer (PCa) potentially via IR, while effects on other prostatic conditions remain unclear.¹⁰ Kong found that low birth weight elevates NAFLD risk, partly mediated by insulin and leucine-related metabolic factors.³⁸

Overall, NAFLD and IR exhibit a complex bidirectional relationship that affects hepatic health and systemic metabolism. Elucidating this relationship is essential for developing effective prevention and treatment strategies.

Cardiovascular Disease and Insulin Resistance

In the cardio-metabolic axis, Colosimo et al reported that impaired metabolic flexibility promotes both NAFLD and heart disease via IR and altered glucose–lipid handling.³⁹ Ke showed that long-term IR trajectories increase frailty risk in young adults, particularly among those with persistently high IR.⁴⁰ Zhou further suggested that IR may induce hypertension and influence cerebral small-vessel disease (SVD) in nondiabetic individuals.⁴¹

In acute cerebrovascular settings, Zhao observed elevated blood glucose and insulin levels among patients with acute CeVD,⁴ with a separate study reinforcing their correlation with disease severity.⁴

Sex-specific differences merit attention: Kumar argued that CeVD disproportionately affects women, calling for sex-specific management guidelines.⁴² In addition, Catherine documented a spectrum of neurological complications following COVID-19, including ischemic and hemorrhagic stroke.⁴³

Finally, Beltran Romero discussed atherosclerotic cardiovascular disease (ASCVD) driven by elevated LDL-cholesterol; although the direct link to cerebrovascular pathology may be weaker, statin therapy reduces overall risk and stroke mortality.⁴⁴ Collectively, these studies underscore the central and multifaceted roles of IR in cardiovascular disease. Given the methodological heterogeneity across surrogate markers, a structured comparison of commonly used insulin resistance indices is provided in Table 1.

Table 1 Comparison of Surrogate Markers for Assessing Insulin Resistance

Insulin Resistance and Neurological Disorders

Insulin Resistance in Alzheimer’s Disease

In Alzheimer’s disease (AD), insulin resistance (IR) is considered a key contributor. In 2021, Wei Zenghui reported that IR aggravates AD progression through multiple mechanisms, including links to T2DM, neuroinflammation, and oxidative stress.⁴⁵ Likewise, Kshirsagar emphasized IR as a mechanistic bridge between AD and T2DM, shaping disease pathogenesis and inflammatory regulation.⁴⁶

Converging evidence further connects obesity and metabolic dysfunction to AD via IR, inflammation, and oxidative stress (Terzo Simona, 2021).⁴⁷ Extending this nexus, Del Moro proposed that brain IR may mechanistically link migraine with AD, suggesting potential therapeutic targets.⁴⁸ Yang underscored the centrality of insulin signaling in AD pathogenesis and highlighted insulin and insulin sensitizers as promising therapeutic avenues.⁴⁹ In line with a vascular contribution to AD, Leclerc identified defects in cerebrovascular insulin receptors in patients with AD, with implications for microvascular function, cognition, and amyloid plaque formation.¹³ Experimentally, Knezovic showed that enhancing insulin signaling normalized c-fos expression in STZ-icv rats, supporting a causal role for IR in AD-related phenotypes.⁵⁰ A broader synthesis by Abdalla reviewed molecular links between diabetes and AD, focusing on the role of IR and potential treatments.⁸ Mechanistically, Kakoty indicated that brain IR alters proteostasis and autophagy regulation, thereby contributing to the pathology of both AD and Parkinson’s disease (PD).¹⁵ Consistently, Parida demonstrated that 1-deoxynojirimycin (DNJ) improves insulin signaling and reduces AD markers in a neuronal IR model.⁵¹

Related lines of research support shared metabolic pathways: Sharma discussed metabolic circuits connecting PD and T2DM, with IR as a common denominator.⁵² Lambie linked diabetic kidney disease with complications such as hypertension and cardiovascular disease, noting a pivotal role for IR in atherogenesis.⁵³

Additional work on metabolic modulators has translational relevance. Gao found that farrerol targets PTPN1 to enhance insulin sensitivity and reduce lipid accumulation in metabolic-associated fatty liver.⁵⁴ In mitochondrial diabetes, Takano reported that mitochondrial dysfunction and specific mtDNA mutations lead to β-cell defects and IR.⁵⁵ Finally, Liu observed an inverse association between adiponectin levels and IR among adolescents with NAFLD, with boys showing significant differences in HOMA-IR across adiponectin tertiles.⁵⁶

Parkinson’s Disease and Insulin Resistance

Using iPSC-derived midbrain organoids, Zagare et al demonstrated that IR is a salient feature in GBA1-mutant PD, implicating IR as a modifier of disease severity.⁵⁷ Complementing this, Sarkar et al used computational analyses to suggest a causal link between RNF213 variants and IR, potentially influencing susceptibility to Moyamoya disease.⁵⁸ Together, these studies indicate that IR, beyond its role in metabolic disease, may be a critical driver in neurodegeneration such as PD.

Detection and Treatment of Brain Insulin Resistance

Recent studies reinforce a tight connection between brain IR and diverse neurodegenerative disorders. In 2023, Yoon Ji Hye argued that AD pathogenesis may extend beyond the amyloid hypothesis to include contributions from IR.⁵⁹ In the same year, Khan Mohsin Ali reported brain IR in AD patients associated with cognitive impairment and pointed to de novo lipogenesis as a potential mediating factor.⁶⁰

Building on therapeutic implications, Ruiz-Pozo examined the relationship between IR and PD onset and symptoms, proposing novel interventions that target insulin signaling pathways.¹⁴ Collectively, these findings position brain IR as both a shared hallmark and a potential driver of neurodegenerative disease progression, thereby offering new diagnostic and therapeutic opportunities.

From a clinical perspective, these molecular alterations translate into measurable cerebrovascular and neurological phenotypes. Insulin resistance–related endothelial dysfunction and impaired cerebrovascular reactivity may reduce cerebral perfusion reserve, thereby accelerating white matter injury, lacunar infarction, and cognitive decline. In parallel, impaired neuronal insulin signaling may exacerbate synaptic dysfunction and neurodegenerative processes, providing a mechanistic bridge between metabolic dysregulation and clinical outcomes such as stroke recurrence, vascular cognitive impairment, and dementia progression.

Insulin Resistance and Other Systemic Diseases

Chronic Kidney Disease and Insulin Resistance

Chronic kidney disease (CKD) is closely associated with IR. Rivas et al analyzed hyperglycemia, insulin, and IR in critically ill patients and found that altered insulin sensitivity frequently underlies stress hyperglycemia.⁶¹ Similar dysregulation is common in CKD and contributes to clinical complexity.

Mechanistically, Hill noted that IR increases arterial stiffness and promotes cardiovascular disease partly by reducing nitric oxide bioavailability—an effect particularly pertinent in CKD, where vascular health is often compromised.⁶²

Stratifying by diabetes subtypes, Mastrototaro highlighted heterogeneity in IR and reported that severe insulin-resistant diabetes (SIRD) is associated with higher comorbidity risk.⁶³ Given the high burden of complications in CKD, managing IR requires multifactorial strategies.

Polycystic Ovary Syndrome and Insulin Resistance

In polycystic ovary syndrome (PCOS), Dubey emphasized strong ties between PCOS and metabolic abnormalities. Among women of reproductive age, PCOS substantially elevates cardiovascular risk, largely because IR is common and represents a core driver of metabolic dysregulation.¹² Thus, PCOS impacts not only reproductive health but also systemic metabolic and cardiovascular status.

Inflammatory Bowel Disease and Insulin Resistance

Regarding inflammatory bowel disease (IBD), Dogan et al reported associations between IR, metabolic syndrome, and chronic inflammatory conditions including IBD, ulcerative colitis (UC), and Crohn’s disease (CD).⁶⁴ However, Carrillo-Palau et al observed no significant difference in IR between patients with low-activity IBD and controls,⁶⁵ suggesting that while links may exist, their strength and generalizability require further clarification.

Clinical Applications of Insulin Resistance

In clinical contexts, Lecerf et al reported that insulin resistance (IR) in type 2 diabetes mellitus (T2DM) is closely associated with obesity, inflammation, gut dysbiosis, and oxidative stress, and underscored physical activity as a key countermeasure against these drivers.⁶⁶

Genetic Studies of Insulin Resistance

Recent genetic research has illuminated complex links between IR and multiple diseases. In 2023, Amin et al highlighted associations between Alzheimer’s disease (AD) and IR, emphasizing shared genetic and metabolic features with implications for early detection and treatment.⁶⁷ Consistently, Albar reviewed insulin’s regulation of cerebral glucose metabolism, cell growth, and cognition via the PI3K/AKT pathway, further supporting these connections.⁶⁸

Complementing these observations, Sedzikowska detailed how insulin modulates brain glucose metabolism, cellular growth, and neural function through the PI3K/AKT and MAPK pathways, offering mechanistic insights into the role of IR in the nervous system.⁶ Kim suggested that IR may be related to cognitive decline in older adults, although findings remain heterogeneous and warrant further study.⁶⁹

In cardiovascular disease, Kosmas noted a tight relationship between IR and cardiovascular risk, with management centered on diet, exercise, and pharmacotherapy.¹ Bruns linked IR to stress-induced cardiomyopathy and proposed glycemic control as a potential therapeutic strategy.⁷⁰

Regarding nonalcoholic fatty liver disease (NAFLD), Armandi reported close interrelations among IR, T2DM, NAFLD, and NASH, with broad effects on glucose and lipid metabolism.⁷¹ Khamseh evaluated IR/sensitivity metrics as screening tools for metabolic-associated fatty liver disease (MAFLD) and hepatic fibrosis, demonstrating meaningful predictive performance.⁷²

In chronic kidney disease (CKD), Karava explored relationships among IR, serum uric acid (sUA), relative fat mass (RFM), and relative lean mass (RLM), particularly in children with CKD.⁷³ Pham recommended that future CKD–IR studies employ longer follow-up, direct measurement methods, sensitivity analyses, and propensity-score approaches.¹¹

With respect to skeletal health, Lei suggested that IR may influence bone health, though recent findings are mixed.⁷⁴ Zhou estimated associations between IR and the prevalence and burden of cerebrovascular small-vessel disease (cSVD) among nondiabetic adults in southeastern China.⁷⁵

Finally, Song found no significant difference in insulin therapy between patients with severe coronary artery disease (CAD) and those with non-CAD T2DM, suggesting the pervasiveness of IR across cardiovascular phenotypes.⁷⁶ Collectively, these studies underscore the genetic underpinnings of IR across diseases and its intricate pathophysiology.

Genetic and Mendelian randomization studies provide important insights into the causal architecture linking insulin resistance with cerebrovascular and related traits. Collectively, these studies suggest that insulin resistance contributes to stroke risk largely through intermediate phenotypes such as hypertension, dyslipidemia, and atherosclerosis. However, limitations including pleiotropy, ancestry-specific effects, and the lack of brain-specific insulin resistance instruments currently constrain causal inference for neurological outcomes. Future studies integrating multi-ancestry genetic data with imaging and cognitive phenotypes will be essential to clarify the direct and indirect pathways through which insulin resistance influences cerebrovascular and neurodegenerative disease.

Ethical Considerations in Insulin Resistance

Emerging evidence has raised ethical and practical issues in managing IR-related conditions. Naryzhnaya et al examined hypertrophy and IR in epicardial adipose tissue (EAT) adipocytes and compared these features with CAD severity and insulin sensitivity, highlighting the potential impact of IR on cardiovascular disease and the ethical imperative for effective, equitable care.⁷⁷ Further, Gutierrez-Tordera linked peripheral IR to progression from mild cognitive impairment (MCI) to AD using metabolic profiling, deepening our understanding of IR in neurodegeneration while raising ethical questions around diagnosis, risk communication, and treatment decisions in older adults.⁷⁸ Finally, Mirjalili compared multivariable models and feature-selection approaches for IR indices in predicting CAD.⁷⁹ Beyond informing clinical practice, this work prompts ethical reflection on fair allocation of preventive resources and access to advanced risk-stratification tools. Taken together, these studies not only expand biomedical knowledge of IR, but also foreground ethical challenges related to effective management, equitable resource distribution, and multidisciplinary care planning.

Therapeutic and Preventive Implications

Given the central role of insulin resistance in cerebrovascular and neurodegenerative disorders, therapeutic strategies targeting metabolic dysfunction have important translational relevance. A mechanistic overview linking therapeutic approaches to their molecular targets and clinical contexts is summarized in Table 2. Lifestyle interventions, including weight reduction and structured physical activity, remain first-line approaches due to their broad metabolic and vascular benefits. Pharmacological insulin sensitizers, cardiometabolic agents, and pathway-directed therapies may further modulate insulin signaling and endothelial function in selected populations. Importantly, emerging evidence suggests that targeting insulin resistance may not only reduce cardiometabolic risk but also attenuate cerebrovascular injury and cognitive decline, underscoring the need for integrated prevention strategies.

Table 2 Therapeutic Approaches Addressing Insulin Resistance and Their Mechanistic and Clinical Relevance

Conclusions and Outlook

Insulin resistance represents a unifying and modifiable factor across cerebrovascular and related neurodegenerative disorders. Accumulating evidence indicates that disrupted insulin signaling within the neurovascular unit links metabolic dysfunction to vascular injury, cognitive impairment, and neurodegeneration. Advances in insulin resistance assessment and genetic epidemiology have strengthened causal inference, yet substantial gaps remain in standardization, biomarker validation, and longitudinal outcome data.

Future research should prioritize harmonized measures of insulin resistance, integration of metabolic and neurovascular biomarkers, and prospective studies evaluating whether targeting insulin resistance can prevent or delay cerebrovascular and neurodegenerative disease. Addressing these challenges will be critical to translating mechanistic insights into precision prevention and individualized management strategies for patients at risk of insulin resistance–related brain disorders.