LAUSR

Studies demonstrate evidence of gliosis in the mediobasal hypothalamus (MBH) of people with obesity and T2D or impaired glucose tolerance (IGT), but whether MBH gliosis predicts worsening glucose homeostasis is unknown. The study evaluated 38 subjects with obesity (68% female, 76% White). Mean age was 47±11 y and BMI was 35±3.9 kg/m2. MRI, DXA, and 75 g OGTT were performed at baseline and DXA and OGTT repeated at 1y. Mean bilateral T2 relaxation time (ms) in the MBH and 3 control regions was measured as a marker of gliosis. Serial blood samples from OGTT were used to calculate glucose area under the curve (incremental [iAUC] and total [totalAUC]) and to model insulin sensitivity (OGIS) and beta-cell function (beta-cell glucose sensitivity). Generalized estimating equations tested associations and interactions by region. On average, measures of glucose tolerance (iAUC and totalAUC), OGIS, and beta-cell glucose sensitivity were stable over 1 y. Baseline bilateral mean MBH T2 relaxation time was not associated with changes in glucose tolerance (Δ iAUC β: -5.8 ms, 95% CI -21.0, 9.4, P=0.45; Δ totalAUC β: 1.3 ms, 95% CI -33.5, 36.0, P=0.94, adjusted for sex, age) or change in glucose sensitivity (β: 0.3 ms, 95% CI -1.0, 1.6, P=0.66) nor were interactions present. Change in OGIS over 1y was significantly negatively associated with bilateral mean MBH T2 relaxation time at baseline (β: -0.94 ms, 95% CI -1.7, -0.2, P=0.02, adjusted for sex, age); subjects with longer MBH T2 relaxation times at baseline reduced OGIS over 1 y. A formal interaction by region was not significant (chi2(7)=7.11, Pint=0.42). The relationship within the MBH was attenuated when also adjusted for change in fat mass (β: -0.70 ms 95% CI -1.4, 0.02, P=0.056). Subjects with greater radiologic evidence for MBH gliosis exhibited declines in insulin sensitivity over 1 y which were not fully accounted for by changes in adiposity. These longitudinal findings are consistent with a role for MBH gliosis in T2D pathogenesis in people with obesity. Disclosure J. L. Rosenbaum: None. S. Schoen: None. S. J. Melhorn: None. M. De leon: None. M. Webb: None. K. Utzschneider: None. E. Schur: None. Funding American Diabetes Association (1-17-ICTS-085 to E.S.)