Increased Resting-State Functional Connectivity as a Compensatory Mechanism for Reduced Brain Volume in Prediabetes and Type 2 Diabetes

OBJECTIVE: To investigate the contribution of alterations in brain structure and function to cognitive function and their interactions in individuals with diabetes and patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: This population-based study included 2,483 participants who underwent structural MRI (n = 569 with normal glucose metabolism [NGM], n = 1,353 with prediabetes, and n = 561 with T2DM) and cognitive testing. Of these, 2145 participants also underwent functional MRI (n = 496 NGM, n = 1,170 prediabetes, and n = 479 T2DM). Multivariate linear regression models were used to assess the association of brain volume and functional connectivity with cognition, as well as the association of brain volume and functional connectivity. RESULTS: Compared with NGM participants, those with T2DM had lower brain volume in a wide range of brain regions and stronger functional connectivity between the bilateral thalamus and brain functional network (visual network and default mode network), and those with prediabetes had lower brain volume in specific local regions (subcortical gray matter volume and subcortical subregions [bilateral thalamus, bilateral nucleus accumbens, and right putamen]) and stronger functional connectivity between the right thalamus and visual network. Cognition was associated with greater right thalamus volume and lower functional connectivity between the right thalamus and visual network. Functional connectivity between the right thalamus and visual network was associated with lower right thalamus volume. CONCLUSIONS: Cognition was associated with greater brain volume and lower functional connectivity in T2DM. Increased functional connectivity may indicate a compensatory mechanism for reduced brain volume that begins in the prediabetic phase.