151-OR: Radiologic Evidence that Hypothalamic Tissue Is Abnormal in Adults with Obesity and Type 2 Diabetes or Impaired Glucose Homeostasis

Abstract

Gliosis, a cellular response to injury in neural tissue, is linked to diet-induced obesity in rodent models. Growing evidence also implicates reactive gliosis and inflammation of the mediobasal hypothalamus (MBH) as a potential mechanism connecting obesity to insulin resistance. We tested for radiologic evidence of MBH gliosis in humans in relation to impaired glucose homeostasis and type 2 diabetes (T2D), independent of obesity. Adults with obesity and 1) T2D not on insulin (N=17), 2) impaired glucose tolerance (IGT; N=21), or 3) normal glucose tolerance (NGT; N=29) by OGTT underwent magnetic resonance imaging to measure mean bilateral T2 relaxation time (ms) in the MBH and 3 control regions. Longer T2 relaxation time is a marker of gliosis. Groups were matched for race, sex, BMI and % body fat (P=0.99), but age differed (T2D 54 ± 8 y, IGT 46 ± 11 y, NGT 45 ± 12 y; P=0.02). Group differences in T2 relaxation time varied by brain region (interaction: chi2(6) = 65, P<0.0001, adjusted for sex and age). Bonferroni-corrected post-tests confirmed that MBH, but not control region, T2 relaxation times were longer in T2D (180 ± 26 ms) than IGT (160 ± 26 ms, P<0.0001) or NGT (152 ± 17 ms, P<0.0001) groups. Among all 67 subjects, fasting glucose, 2-hr post-glucose, and hemoglobin A1c values were each positively associated with MBH, but not control region, T2 relaxation times (interactions by region all P< 0.0001, MBH all P< 0.0001, control regions all NS). Among the 50 subjects without T2D, interactions remained significant (all P<0.0001), and greater 2-hr post-glucose and hemoglobin A1c were associated with longer MBH T2 relaxation times (β = 0.22 ms, P<0.0001 and β = 14.8 ms, P=0.002, respectively) whereas a trend was present for fasting glucose concentrations (β = 0.38 ms, P=0.06). These data provide novel evidence that the degree of inflammation and gliosis in glucose-regulating areas of the brain is related to impaired glucose homeostasis and T2D in adults with obesity. Disclosure J.L. Rosenbaum: None. L.E. Sewaybricker: None. S. Chandrasekaran: None. M. De Leon: None. M. Webb: None. S.J. Melhorn: None. E. Schur: None. Funding American Diabetes Association (1-17-ICTS-085 to E.S.)