Insulin pathways in epilepsy: Link between metabolism and brain activity

Epilepsy is a chronic neurological disorder characterized by recurrent seizures and remains a major global concern, particularly when resistance to conventional anti-epileptic drugs limits treatment success. Emerging evidence indicates that metabolic impairments, especially altered insulin signaling, play a significant role in epileptogenesis. While insulin is widely recognized as a regulator of peripheral glucose metabolism, it also functions as a neuromodulator in the central nervous system. Insulin receptors (IRs) and downstream pathways, such as phosphoinositide 3-kinase-protein kinase B and Ras-mitogen-activated protein kinase/ extracellular signal-regulated kinase, are abundantly expressed in regions involved in seizure activity, including the hippocampus, cortex, thalamus, and amygdala. Dysfunction in insulin signaling due to hypoinsulinemia, hyperinsulinemia, or insulin resistance leads to impaired glucose uptake, neurotransmitter imbalance, oxidative stress, mitochondrial dysfunction, ion-channel alterations, neuroinflammation, and disruption of the blood-brain barrier, ultimately enhancing neuronal hyperexcitability and seizure susceptibility. Increasing clinical and preclinical data also suggest a bidirectional link between epilepsy and metabolic disorders such as type 2 diabetes mellitus and metabolic syndrome. Furthermore, dysregulation of the gut-brain axis adds another dimension to insulin-related epileptic mechanisms. Novel therapeutic strategies such as metformin, ketogenic diet, glucagon-like peptide-1 receptor agonists, caloric restriction, and lifestyle modifications have demonstrated potential by improving insulin sensitivity and restoring metabolic balance. In addition, emerging molecular targets such as AMP-activated protein kinase activators, mammalian target of rapamycin inhibitors, and IR substrate modulators are under investigation. Collectively, these findings support insulin signaling as a promising target for personalized treatment approaches in refractory epilepsy and highlight the need for further translational and clinical exploration to establish metabolism-based neurotherapeutic strategies.