Progress in Research on the Association Between Glucose Metabolism Disorders and Intracranial and Extracranial Atherosclerotic Stenosis

Abstract

Objective: Intracranial atherosclerotic stenosis (ICAS) and extracranial atherosclerotic stenosis (ECAS) are major vascular substrates for ischemic stroke. Existing reviews often discuss ICAS and ECAS together, overlooking their distinct pathological responses to glucose dysregulation, and lack systematic summary of the independent role of insulin resistance in normoglycemic individuals. This review aims to systematically summarize the molecular mechanisms, imaging features, clinical biomarkers, and intervention strategies by which glucose metabolism disorders (diabetes mellitus, insulin resistance, impaired glucose tolerance) promote ICAS and ECAS. Methods: This is a narrative review of relevant literature published in recent years, with no systematic meta-analysis performed. Results: Hyperglycemia and insulin resistance synergistically accelerate atherosclerosis through accumulation of advanced glycation end products (AGEs), enhanced oxidative stress, activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome, and phenotypic switching of vascular smooth muscle cells (VSMCs). Clinical studies have confirmed that hemoglobin A1c (HbA1c) ≥ 6.5% is positively correlated with anterior circulation ICAS (OR = 2.04, P < 0.05). The triglyceride-glucose (TyG) index is significantly positively correlated with asymptomatic ECAS (OR = 1.85) and asymptomatic ICAS (OR = 1.34). The 30-year follow-up of the Da Qing Diabetes Prevention Study showed that individuals with impaired glucose tolerance who maintained non-diabetic status through intervention had a 23% lower risk of stroke compared to those with newly diagnosed diabetes (HR = 0.77, 95%CI 0.64–0.94). Conclusion: Hyperglycemia and insulin resistance accelerate intracranial and extracranial atherosclerosis via AGEs accumulation, oxidative stress, NLRP3 inflammasome activation, and VSMC phenotypic switching. HbA1c and the TyG index can serve as clinical screening tools. Key questions remain regarding whether different subtypes of glucose metabolism disorders differentially affect intracranial versus extracranial arteries, and whether early intervention in prediabetic populations reduces stroke risk. This review provides a theoretical reference for risk stratification and individualized prevention in populations at high risk of ischemic stroke.