Disentangling the effect of brain insulin resistance on brain health ( BIR ‐ BrainHealth ): Rationale and study protocol

AIMS: Insulin signalling in the brain is crucial for systemic metabolic regulation and cognitive function. In some individuals, these effects are reduced, a phenomenon referred to as brain insulin resistance (BIR). This condition may contribute to the elevated risk of cognitive decline and dementia in diabetes, yet its prevalence, mechanisms, and clinical relevance remain poorly understood. The BIR-BrainHealth study aims to (i) quantify BIR in adults with type 1 diabetes, type 2 diabetes, and without diabetes; (ii) assess its associations with cerebrovascular function and cognitive performance; and (iii) identify biomarkers that reflect BIR. METHODS: BIR-BrainHealth is a multicentre prospective cohort study with baseline cross-sectional analyses conducted in Denmark and Germany. We plan to recruit a total of 150 adults (≈50 per group) who will undergo detailed metabolic and cognitive phenotyping, multimodal neuroimaging, and extensive biomarker profiling. Brain insulin response is assessed by cerebral blood flow changes to intranasal insulin administration measured by perfusion-weighted MRI. Additional MRI scans will be used for assessments of cerebrovascular reactivity, neurovascular coupling, blood-brain barrier integrity, and hypothalamic responses during an oral glucose tolerance test. Blood, urine, and faecal samples are collected in a biobank. CONCLUSIONS: BIR-BrainHealth will provide insight into how diabetes affects brain insulin signalling and cerebrovascular health, and how these alterations relate to cognitive performance. These findings will establish a robust foundation for future mechanistic and translational research, with the potential to advance strategies for monitoring and preventing cognitive decline. TRIAL REGISTRATION: ISRCTN: ISRCTN15687967 and ClinicalTrials.gov: NCT07374705.