Insulin pathways in epilepsy: Link between metabolism and brain activity

INTRODUCTION

Epilepsy is a chronic neurological disorder characterized by spontaneous and recurrent seizures, affecting millions of individuals globally and posing a significant clinical and socioeconomic burden.^[1] Although numerous anti-epileptic drugs (AEDs) are available, nearly one-third of patients continue to experience drug-resistant seizures, emphasizing the urgent need to explore alternative mechanisms beyond conventional genetic and ion-channel theories.^[2] Recent research has increasingly drawn attention to metabolic dysfunction, particularly impaired insulin signaling, as a major contributor to epileptogenesis.^[3]

While insulin is well-known for its role in regulating peripheral glucose metabolism, it also acts as a critical neuromodulator in the central nervous system. Insulin receptors (IRs) and downstream signaling mediators are abundant in brain regions involved in seizure initiation and modulation, including the hippocampus, cortex, amygdala, and thalamus [Table 1].^[4] Through these receptors, insulin regulates glucose utilization, neurotransmitter balance, synaptic plasticity, mitochondrial function, and neuroinflammatory responses.^[4,5] Disturbances in insulin signaling, such as hypoinsulinemia, hyperinsulinemia, or insulin resistance, can impair neuronal homeostasis, disrupt gamma-aminobutyric acid (GABA)-glutamate equilibrium, trigger oxidative stress, and promote inflammatory cascades, ultimately lowering the seizure threshold.^[6]

Clinical and preclinical evidence increasingly supports a bidirectional association between epilepsy and metabolic disorders such as type 2 diabetes mellitus and metabolic syndrome.^[7] Episodes of glucose fluctuations, both hypoglycemia and hyperglycemia, have been reported to provoke seizures. In addition, individuals with epilepsy exhibit a higher incidence of insulin resistance and cognitive decline.^[8] Notably, therapeutic strategies targeting metabolic pathways such as the ketogenic diet, metformin, and glucagon-like peptide-1 (GLP-1) receptor agonists have demonstrated promising anti-seizure effects, reinforcing the crucial role of insulin signaling in seizure regulation.^[9]

Given these insights, insulin signaling has emerged as a prominent research focus for understanding epileptic pathophysiology and developing individualized treatment approaches. This review synthesizes current evidence on the physiological functions of insulin in the brain,^[4,10] examines how dysregulated insulin pathways contribute to seizure development, and explores emerging metabolic, pharmacological, and lifestyle-based interventions aimed at improving insulin sensitivity in refractory epilepsy.^[11]

TRANSPORT OF INSULIN ACROSS THE BLOOD-BRAIN BARRIER (BBB) AND ITS DISTRIBUTION IN THE BRAIN

Although insulin is produced in the pancreas, it plays an important role in brain physiology. Insulin reaches the brain through a receptor-mediated transport mechanism at the BBB.^[12] The endothelial cells of cerebral microvessels contain IRs that facilitate this transport. Once insulin crosses the BBB, it binds to IRs located on neurons and glial cells, allowing it to act as a neuromodulator rather than just a metabolic hormone.^[13] Within the brain, IR expression is not uniform but highly concentrated in specific regions:

These regions are essential for neuronal communication, synaptic plasticity, metabolic regulation, and seizure control.^[4,13] Any impairment in insulin transport due to receptor dysfunction, BBB damage, or insulin resistance can lead to:^[14]

• Reduced glucose utilization

• Neuronal energy failure

• Impaired synaptic signaling

• Increased neuronal hyperexcitability

• Higher risk of seizures and cognitive decline

Thus, proper transport and distribution of insulin in the brain is fundamental for maintaining neuronal homeostasis and seizure control.

Ras-MAPK/extracellular signal-regulated kinase (Erk) pathway (synaptic and cognitive role)

The Ras-MAPK/Erk pathway plays a crucial role in maintaining synaptic plasticity, neuronal development, learning ability, and overall cognitive function. After insulin binds to its receptor, IRS proteins become activated and subsequently stimulate the Ras protein.^[7,8,16] This activation triggers the MAPK signaling cascade, which ultimately leads to the phosphorylation and activation of Erk.^[19] Once activated, Erk translocates into the nucleus and modulates gene expression related to neuronal function and survival. Through this mechanism, the pathway promotes neurogenesis, regulates transcriptional activity, supports learning and memory processes, and enables synaptic remodeling.^[20] However, dysfunction in this pathway often due to impaired insulin signaling or metabolic stress can reduce synaptic adaptability and impair neuronal communication, leading to increased vulnerability to abnormal electrical discharges.^[21] This impaired signaling may contribute to the formation of hyperexcitable neuronal networks, thereby playing a potential role in seizure development and progression in epilepsy [Figure 1] and [Table 3].^[22-25]

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Figure 1:

Pathological mechanisms linking insulin dysfunction to epileptogenesis. This diagram demonstrates how alterations in insulin signaling within the brain can initiate and accelerate epileptic processes through several interconnected molecular events. Impaired glucose utilization and decreased adenosine triphosphate synthesis result in neuronal instability and hyperexcitability. Disruption of neurotransmitter balance particularly reduced GABAergic inhibition and increased glutamatergic excitation drives excitotoxicity and increases seizure probability. Ion-channel abnormalities involving Na⁺, K⁺, and Ca²⁺ channels further contribute to excessive neuronal firing and abnormal discharges. Mitochondrial dysfunction and elevated oxidative stress damage neuronal structures and aggravate hyperexcitability. In addition, compromised blood-brain barrier integrity facilitates the entry of toxins and inflammatory agents, leading to astrocytic dysfunction. Dysbiosis and gut-brain axis disturbance also elevate seizure susceptibility by altering metabolic and hormonal regulation. Together, these factors converge to create a pro-epileptic neural environment, supporting the progression of epileptogenic networks.

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MAJOR PATHWAYS LINKING INSULIN DYSFUNCTION TO EPILEPSY

Gut-brain axis modulation

Insulin dysfunction is closely linked with disturbances in gut hormones (GLP-1, leptin, and ghrelin) and gut microbiota composition. These alterations affect brain activity through vagal pathways, inflammatory signaling, and microbial metabolites (such as GABA derivatives and short-chain fatty acids).^[18,34] Metabolic disorders such as obesity and diabetes frequently involve gut dysbiosis, which can increase systemic inflammation and worsen insulin resistance. Emerging evidence shows that interventions aimed at restoring gut homeostasis such as ketogenic diets, probiotics, prebiotics, and GLP-1 agonists may not only improve insulin sensitivity but also reduce seizure frequency, highlighting a functional link between the gut-brain axis and epileptogenesis [Figure 2].^[35]

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Figure 2:

This figure illustrates how disrupted insulin signaling leads to abnormal insulin receptor substrate activation, subsequently disturbing two essential intracellular pathways phosphoinositide 3-kinase-Protein kinase B (PI3K-Akt) and Ras-mitogen-activated protein kinase (MAPK)/ extracellular signal-regulated kinase (Erk). Impairment of the PI3K-Akt pathway negatively influences mammalian target of rapamycin signaling, mitochondrial efficiency, and the functioning of the Na⁺/K⁺-ATPase pump, ultimately resulting in diminished neuronal energy production. At the same time, dysfunction in the Ras-MAPK/Erk pathway interferes with gene transcription and synaptic plasticity, leading to reduced neuronal resilience and adaptability. Elevated reactive oxygen species (ROS) levels further aggravate cellular damage. Together, these metabolic and synaptic disturbances increase neuronal hyperexcitability and enhance seizure risk, highlighting the crucial role of insulin dysregulation in the progression of epileptogenesis.

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THERAPEUTIC OPPORTUNITIES

Therapeutic modulation of insulin signaling has emerged as a promising strategy for managing epilepsy, particularly in cases of drug resistance where conventional AEDs are insufficient.^[36] Metformin, a widely used antidiabetic drug, activates the AMPK pathway and improves glucose metabolism while reducing neuroinflammation and mitochondrial stress; several preclinical studies have reported its potential to decrease seizure activity.^[37,38] Another well-established intervention is the ketogenic diet, which lowers insulin levels, increases ketone body production, enhances GABA synthesis, and improves mitochondrial efficiency, thereby stabilizing neuronal excitability.^[18,39] The diet may also influence gut microbiota, strengthening the gut–brain axis and contributing to seizure control.^[40] GLP-1 receptor agonists such as liraglutide and exenatide have demonstrated neuroprotective and anti-inflammatory effects by enhancing insulin sensitivity and synaptic plasticity, suggesting potential therapeutic value that warrants further clinical investigation.^[18] Lifestyle strategies, including physical exercise, caloric restriction, intermittent fasting, and low-glycemic diets, can also improve metabolic health and insulin responsiveness, reducing neuronal hyperexcitability.^[41] In addition, emerging therapeutic targets, such as peroxisome proliferator-activated receptors (PPAR-γ) agonists, AMPK activators, IRS modulators, and mTOR inhibitors, are currently being explored for their ability to restore metabolic homeostasis and prevent epileptogenic network formation.^[19,20,42] Together, these findings highlight the potential of insulin-focused interventions as a novel and personalized approach for the treatment of epilepsy, especially in metabolically compromised individuals.^[43]

FUTURE PROSPECTIVES

The emerging association between insulin signaling and epilepsy represents a promising direction for future neurological research, suggesting that epilepsy may have strong metabolic roots rather than being solely a neuroelectrical disorder. Although current findings have revealed multiple links between insulin resistance, neuroinflammation, and neuronal hyperexcitability, the precise molecular mechanisms remain to be fully defined. Future investigations should focus on region-specific analysis of IRs within seizure-prone brain areas, explore alterations in insulin-dependent pathways across different stages of epilepsy, and identify metabolic biomarkers capable of predicting seizure risk. Integrating genomics, metabolomics, and neuroimaging may offer crucial insights into the dynamic changes occurring during epileptogenesis. Moreover, clinical trials combining traditional AEDs with metabolic therapies such as metformin, GLP-1 receptor agonists, PPAR-γ modulators, and AMPK activators could establish novel treatment paradigms. Another promising direction involves the gut–brain axis, where microbial metabolites and gut hormones may influence insulin sensitivity and neuronal stability; hence, probiotics, ketogenic diet variations, and microbiota-based therapies should be explored further. Advanced tools such as artificial intelligence, computational modeling, and machine learning may help decode fluctuations in glucose levels and predict seizure onset with greater precision. Lifestyle-based interventions including intermittent fasting, structured exercise, and lowglycemic diets also need systematic evaluation for long-term management strategies. Ultimately, a multidisciplinary approach involving neurology, endocrinology, immunology, and computational science will be essential to develop tailored, metabolism-driven therapeutic strategies. If successfully implemented, insulin-centered research may transform epilepsy treatment and offer new hope for individuals with drug-resistant forms of the disease.

CONCLUSION

The intricate link between insulin signaling and epilepsy presents a new viewpoint in neurological research, suggesting that epilepsy extends beyond electrical disturbances and deeply involves metabolic dysregulation. Disruptions in insulin activity such as resistance, deficiency, or excess can interfere with several vital brain functions, including glucose utilization, neurotransmitter regulation, mitochondrial stability, redox balance, inflammatory control, and ion-channel modulation. These disturbances promote neuronal instability, lower the seizure threshold, and contribute to the formation of epileptic circuits. The coexistence of epilepsy with metabolic disorders such as type 2 diabetes and metabolic syndrome further reinforces the metabolic origin of epileptogenesis. Therapeutic approaches aimed at restoring insulin signaling such as metformin, ketogenic diet, GLP-1 receptor agonists, caloric restriction, exercise, and precision dietary modulation have shown potential in improving seizure control and promoting neuroprotection. In addition, emerging strategies targeting AMPK, mTOR, IRS proteins, and the gut–brain axis may open new directions for personalized therapy. To advance this field, more research is required to identify metabolic biomarkers, understand regional brain variations in insulin sensitivity, and design clinical trials combining AEDs with metabolic interventions. A multidisciplinary approach involving neuroscience, endocrinology, immunology, nutrition, and computational biology may lead to precision medicine tailored to individual metabolic profiles. Overall, insulin signaling represents a promising therapeutic target that could redefine current treatment strategies and provide hope for patients with drug-resistant epilepsy.