Central insulin resistance and mild cognitive impairment: correlation between metabolic syndrome and hippocampal atrophy

Abstract

Background: Alzheimer’s Disease (AD) is a neurodegenerative pathology with no cure and is currently referred to as “Type 3 Diabetes” due to its metabolic basis. On the other hand, the hippocampus, the brain region responsible for memory, is strictly dependent on insulin signaling for cellular viability and, consequently, synaptic plasticity. Furthermore, patients with Metabolic Syndrome become unable to properly utilize glucose due to insulin resistance resulting from dysfunction of IRS-1 receptors, leading to the phenomenon of neuronal starvation, even in the presence of systemic hyperglycemia. In the context of AD, due to perpetuated oxidative stress and neuroinflammation, this energetic hypometabolism results in structural hippocampal atrophy and early Mild Cognitive Impairment (MCI). Objective: To correlate the severity of medial temporal lobe atrophy and cerebral hypometabolism with peripheral biomarkers of insulin resistance (fasting glucose, HOMA-IR) and their association with the development of Mild Cognitive Impairment. Methods: This is a systematic review conducted using publications from the BVS, Medscape, Google Scholar, and PubMed databases between 2012 and 2025. Correlations were established using the Scheltens Medial Temporal Atrophy (MTA) scale through magnetic resonance imaging, relationships between glucose levels and hippocampal microstructural damage, and the molecular response of cerebral insulin receptors. Results: Data analysis demonstrated that peripheral insulin resistance (elevated HOMA-IR) indicates a central metabolic blockade. Functional assessments performed through PET-Scan revealed frontotemporal hypometabolism due to impaired glucose uptake, confirming a state of “neuronal starvation” resulting from IRS-1 receptor dysfunction. In this context, Metabolic Syndrome was associated with a higher prevalence of pathological hippocampal atrophy (MTA scores ≥ 2 on magnetic resonance imaging). Glycemic levels at the upper limit of normal, even in non-diabetic individuals, were linearly correlated with loss of hippocampal microstructure and poorer mnemonic performance. Conclusion: Data analysis confirms that central insulin resistance is directly associated with Mild Cognitive Impairment, representing a critical precursor of hippocampal atrophy in individuals with metabolic syndrome, highlighting the importance of glycemic control for the preservation of cognitive functions. Suppression of insulin signaling dysfunction in the brain is effective in preventing the progression of cognitive impairment. More effective management of insulin resistance may not only mitigate the risks associated with cognitive decline but also promote improved quality of life.