248-OR: Diabetes Remission after Gastric Bypass Is Characterized by Upregulation of LXR and Antioxidant-Related Pathways in Jejunum

Abstract

We have previously shown that intestinal adaptation precedes and relates to metabolic improvement in humans after Roux-en-Y gastric bypass surgery (RYGB). Based on this, we hypothesized that persistence of this adaptation at the one-year postoperative timepoint occurs selectively in patients with persistent postoperative metabolic improvement, versus those without Type 2 diabetes (T2D) remission. RNA-seq was used to determine gene expression in jejunum collected before and 12 months (± 1 month) after RYGB. T2D was defined as HbA1c >6.5% or requiring T2D medications prescribed for prior diagnosis of diabetes. Remission was defined as HbA1c <6.5% off any T2D medications. Nine of 17 patients with T2D failed to achieve remission by 12 months. After sample quality control, jejunal biopsies from 7 patients with T2D without remission (NR), 8 patients with diabetes remission (R) and 13 patients without diabetes (ND) were analyzed via RNA-seq. Significance was defined by an FDR cutoff of 0.05. Unsupervised principal components analysis (PCA) showed no significant differences across PC1 or PC2 among the 3 groups. However, among top pathways expressed in samples from patients with T2D remission (R), LXR/RXR pathway activation was upregulated (pathway z-score= 0.333, p= 4.85E-06) but downregulated in patients without diabetes (ND, z-score= -1.508, p=.01) and in patients without remission (NR, z-score=-1.0, p=2.07E-07). Antioxidant action of vitamin C exhibited a similar pattern of activation uniquely in R and not in NR or ND (R: p=.02, z-score=0.816; NR: p=0.33, z-score=0.816; ND: p=0.03, z-score=-1.0). In summary, although jejunal remodeling may occur in patients without T2D remission, lipogenic (LXR-driven) and antioxidative pathways are uniquely upregulated in biopsies from those with remission. We hypothesize that these processes may underlie mechanisms for T2D improvement after RYGB. Disclosure M.A.Stefater-richards: None. W.F.Gourash: None. A.Courcoulas: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R56DK125816, R01DK108642, K08DK125878)