Insulin Resistance and Brain Sulcal Morphology in Non-Diabetic Adults

Abstract

Insulin resistance exerts direct effects on brain structure, yet most neuroimaging evidence comes from populations with established diabetes, and conventional gray matter volumetry may lack sensitivity to detect early structural changes. Here, we examined associations between insulin resistance and sulcal morphology, a measure that integrates cortical thinning, subcortical atrophy, and white matter degeneration into a single outcome, in 728 non-diabetic adults (518 men, 210 women; mean age 61.5 ± 11.6 years). Brain volumes were quantified using OpenMAP-T1, an automated deep learning-based parcellation tool, and associations between HOMA-IR and 30 cerebrospinal fluid-related regional volumes were examined using multiple linear regression adjusted for age, sex, and estimated total intracranial volume, with FDR correction for multiple comparisons. Higher HOMA-IR was significantly associated with greater frontal sulcal volumes (left: β = 596 mm³, right: β = 344 mm³; both FDR-corrected p < 0.001), with a dose-response relationship across insulin resistance categories. This association was observed only in men (sex × HOMA-IR interaction p = 0.019) and was strongest in participants younger than 70 years. Mediation analysis revealed that the relationship between BMI and frontal sulcal enlargement was largely accounted for by the indirect pathway through insulin resistance, with no significant direct effect of BMI. These findings suggest that sulcal morphology can detect metabolic effects on brain structure at a pre-diabetic stage, changes that were not apparent through frontal gray matter volumetry in the same sample, and identify insulin resistance as a potential modifiable target for preserving brain health.