Brain Insulin Resistance as a Driver of Cognitive Impairment in Type 2 Diabetes: A Systematic Review and Meta-Analysis

Background Type 2 diabetes mellitus (T2DM) is coming to be regarded as a risk factor of cognitive impairment and neurodegenerative disease, possibly through the action of brain insulin resistance and metabolic dysregulation. The strength of this connection, and the ability to reverse cognitive impairment through metabolic therapies is, however, not fully delimited. Methods PRISMA 2020 guidelines were used to conduct a systematic review and a meta-analysis (PROSPERO: CRD42025116362). Others searched were PubMed, Embase, Scopus, Web of Science, CENTRAL and ClinicalTrials.gov up to October 2025. Randomized controlled trials and observational studies that assess cognitive performance, neuroimaging-based or neurodegeneration biomarkers in adults with T2DM were incorporated. Standardized mean differences (SMDs) or odds ratios (ORs) were used to conduct random-effects meta-analyses. Results 8 studies (2 RCTs, 6 observational; N = 8,247) were involved. T2DM was also linked to higher chances of cognitive impairment (OR = 1.46, 95% CI 1.08–1.96) and accelerated progression to dementia (OR = 2.22, 95% CI 1.03477). The cognitive performance was greatly enhanced with the help of metabolic interventions (MD = 1.90; SMD = 0.60). A high neurofilament light chain and GFAP indicated incident cognitive impairment (pooled OR = 1.25). There were significant relationships between markers of glucose dysregulation and cognitive decline (pooled SMD = -0.40). Conclusion Cognitive impairment and neurodegenerative progression are significantly related to the T2DM. The impairment of cognition is partially reversible with the maximization of the metabolism, which, in turn, notes the insulin resistance in the brain as a target of therapy.