A JournAl of the AmericAn DiAbetes AssociAtion

Integrated Physiology/Obesity120-LBManipulations of Gastrointestinal Anatomy Reveal PhysiologicMechanisms of GLP-1 RegulationNOGHMA WYNNE, RAJESH T. PATEL, ALPANA SHUKLA, MARLUS MOREIRA,SOO MIN AHN, FRANCESCO RUBINO, New York, NYGastric Bypass (GBP) combines gastric restriction and a shortcut fornutrients to the distal bowel, which is believed to increase secretion of GLP-1levels. However, GLP-1 also increases after sleeve gastrectomy (SG), a gastricrestrictive procedure that does not involve intestinal bypass. To understandthe role of gastric vs intestinal mechanisms in GLP-1 regulation, we comparedproximal intestinal bypass alone (duodenal-jejunal bypass -DJB) and gastricresection alone (SG) in Zucker Diabetic Fatty (ZDF) Rats. DJB improved oralglucose tolerance (GT) without significant increase in insulin or GLP-1 levels.In contrast, SG had only marginal effect on GT but it significantly increasedinsulin and GLP-1 (3-fold). These findings do not support a role for rapidstimulation of distal small bowel by nutrients as a primary mechanism forincreased GLP-1 after gastrointestinal bypass. Since both SG and GBP involveexclusion/resection of gastric fundus and accelerated gastric emptying, wehypothesized that increased GLP1 levels after such surgeries may resultprimarily from alteration of gastric physiology, not from distal intestinalstimulation. We therefore investigated GLP-1 response to mixed meal testafter selective, direct injection of meal stimulus in the stomach (physiologicalroute), duodenum or distal jejunum of normal anesthetized mice. Bloodsampling was obtained from the inferior vena cava. Direct duodenalstimulation (without gastric stimulation) significantly increased GLP-1 levelswhereas neither gastric nor distal-jejunal injection increased GLP-1 response.We then injected a mixed meal into a short segment of duodenum isolatedby proximal and distal clamping. This was sufficient to significantly increaseGLP-1 levels in absence of nutrients passage into the distal small bowel,supporting an important physiologic role of the duodenum in GLP-1 regulation.These findings may help develop novel strategies to pharmacologicallyincrease endogenous GLP-1.121-LBCD40 Promotes MHC II Expression on Adipose Tissue Macrophagesand Regulates CD4+ T Cells in Adipose Tissue of Mice with Diet-Induced ObesityDAVID L. MORRIS, KELSIE E. OATMAN, JENNIFER L. DELPROPOSTO, CARMELLAEVANS-MOLINA, CAREY N. LUMENG, Indianapolis, IN, Ann Arbor, MICD40 is a TNF receptor superfamily member that is expressed on macrophages,endothelial cells and adipocytes. CD40 expression is elevated onmonocytes from patients with metabolic syndrome, and CD40 activationpromotes atherogenesis in mice. We found that Cd40 mRNA levels wereelevated in whole epididymal adipose tissue (eAT) and adipose tissuemacrophages (ATMs) from male C57BL/6 mice fed a high fat diet (HFD;60%) for 20 weeks. Therefore, we tested the hypothesis that CD40 on ATMscontributes to the progression of obesity-induced inflammation and insulinresistance. Male Cd40-knockout (KO) and wild type (WT) mice were fed a HFDfor 20 weeks. Compared to WT mice, KO mice showed a trend (P=0.10) towardsprotection from HFD-induced weight gain despite having increased visceraladiposity. Stromal vascular cell number and ATM (CD11b+F4/80+) contentwere similar in eAT from obese WT and KO mice; however, the number ofMHC II+ ATMs and the expression of CD86 on ATMs were reduced in KO mice.Obese KO mice had fewer conventional CD4+Foxp3- T cells in eAT, whereas thenumber of regulatory T cells (Tregs; CD4+Foxp3+) was unaltered. Despite thesechanges, there were no significant effects of CD40 deficiency on measures ofHFD-induced insulin resistance. To examine the contribution of hematopoieticcell derived CD40, we generated bone marrow chimeric mice with (BMT-WT)and without (BMT-KO) CD40 expression on leukocytes. BMT-WT and BMT-KOmice gained similar body weight in response to HFD. Similar to the wholebody KO mice, MHC II+ ATMs and CD4+Foxp3- T cells, but not Tregs, werereduced in eAT from obese BMT-KO mice. However, hematopoietic disruptionof CD40 did not ameliorate insulin resistance. Collectively, these data indicateCD40 plays a role in obesity induced T cell-mediated inflammation in adiposetissue with obesity, but that CD40-independent mechanisms contribute to thedevelopment of HFD-induced metabolic disease in mice.Supported by: NIH (DK091976 (D.L.M), DK090262 (C.N.L.), DK078851 (C.N.L.))Obesity—Human122-LBOne Year Diabetes Remission in the Helping Evaluate Reduction inObesity (HERO) StudyMARCIO TORRE, JOHN DIXON, TED OKERSON, DAISY S. NG-MAK, DENISEGLOBE, Irvine, CA, Melbourne, AustraliaRemission of type 2 diabetes (T2D) after gastric bypass surgery has beenshown to be related to the duration of diabetes, severity of disease, and amountof weight loss/regain. Few studies have reported the impact of adjustablegastric banding (AGB) on diabetes remission. The overall objective of the HEROstudy is to examine the clinical effectiveness and safety of LAP-BAND ® APAGB over five years. Here we seek to assess diabetes remission after AGB andidentify factors associated with T2D remission 1 year after AGB.300 subjects out of 1,123 HERO enrollees who reported either having ahistory of T2D or taking an anti-diabetic medication at baseline (BL), weredefined as T2D at BL. The analysis sample included the 199 subjects whoprovided complete BL and 1 year data. Using the American Association ofClinical Endocrinologists (AACE) guidelines for T2D, diabetes remission wasdefined as HbA1c level of ≤ 6.5% and no anti-diabetic medication usage at1-yr. Multivariate logistic regression was used to examine factors associatedwith remission at 1-yr, controlling for region (US vs OUS) and years of diabetesduration.There were no differences in mean BL weight (kgs) (128 vs 131) betweenremission and non-remission groups. About 39% (77/199) had remission ofT2D at 1-yr. Patients with remission had significantly shorter T2D duration (5.5years vs 8.6 years, p=.002). At 1-yr, patients with remission had significantlygreater percent weight loss than those without remission (19.2% vs 12.2%,p