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

Insulin resistance (IR) Insulin resistance (IR) is a central metabolic disturbance implicated in a broad range of cardiometabolic and neurological disorders. Increasing evidence suggests that IR plays a pivotal role in the initiation and progression of cerebrovascular diseases (CeVD) and contributes to neurodegeneration through shared molecular and vascular mechanisms. In the brain and its vasculature, impaired insulin signaling-particularly involving the IRS-PI3K-Akt-GSK-3β axis-interacts with inflammation, oxidative stress, endothelial dysfunction, and neurovascular unit impairment, thereby linking CeVD with Alzheimer's disease, Parkinson's disease, and cerebral small-vessel disease. Advances in the assessment of IR, ranging from traditional indices such as HOMA-IR to surrogate markers including the triglyceride-glucose (TyG) index and METS-IR, have enabled large-scale population studies and improved risk stratification for cardiometabolic disorders, with emerging relevance to cerebrovascular and cognitive outcomes. In parallel, genetic and Mendelian randomization studies support a causal contribution of IR-related traits to hypertension, atherosclerosis, and stroke risk, highlighting shared susceptibility pathways across metabolic and neurological phenotypes. This review synthesizes current evidence on the mechanisms, measurement, genetic architecture, and clinical implications of IR across cerebrovascular and related disorders. By integrating mechanistic insights with epidemiological and translational data, we propose IR as a tractable, cross-cutting therapeutic target. Future priorities include standardizing IR assessment, validating brain-relevant biomarkers, and linking mechanistic pathways to longitudinal cerebrovascular and neurodegenerative outcomes to advance precision prevention and individualized care.