Habit-learning and decision-making circuits are susceptible to glycemic variability in type 2 diabetes: a longitudinal study

Carolina Moreno^1,2Otília C. d'Almeida¹Joana Crisóstomo¹Nádia Canário¹Leonor Gomes^1,2Miguel Castelo-Branco^1*

• ¹Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT), Coimbra, Portugal
• ²Coimbra Hospital and University Center, Coimbra, Coimbra, Portugal

Type 2 diabetes mellitus (T2DM) is associated with lower gray matter (GM) volumes. However, little is known about the influence of glycemic control on brain atrophy, especially on highly susceptible regions. Our aim is to identify the effect of glycemic variability (GV) on long-term brain volumetric changes in individuals with T2DM.A longitudinal clinical, biochemical and imaging assessment was conducted on a baseline visit to 170 individuals (85 with type T2DM), from which 29 (15 with T2DM) were evaluated at a 7-year follow-up visit. Brain regional volumes were evaluated with 3T MRI, using FreeSurfer 7 longitudinal pipeline. GV metrics such as SD, M-value, MAG (mean absolute glucose change), MAGE (mean amplitude of glycemic excursion) and CoV (coefficient of variation) were calculated in both visits.Statistically significant negative correlations between GV metrics and symmetrized percent change (SPC) of GM volumes were found in specific cortical and subcortical regions of individuals with T2DM. MAGE was correlated with regionally-specific atrophy on temporal lobe(r=-0.63, p=0.021), insula(ρ=-0.62, p=0.022), thalamus(r=-0.64; p=0.024), hippocampus(r=-0.59; p=0.034), and putamen(ρ=-0.65, p=0.017). Concerning the hippocampal subregions, the presubiculum was significantly correlated with MAGE(r=-0.73; p=0.005). Baseline GV was consistently associated with temporal lobe SPC. Linear regression analysis showed that, for each increase of 1mmol/L on MAGE value, the SPC of temporal lobe decreases on average 1.2% (higher atrophy rate).The relationship between longitudinal GM atrophy and GV has a regionally-specific pattern, suggesting there is a localized brain susceptibility to intra-daily glucose fluctuations. Negative correlations between GV metrics and SPC volume of regions involved in habit-learning, decision-making and memory, highlight GV as a mediator of the neural impact of T2DM on the reward prediction-error circuits.