Su2067 A Pilot Pharmacogenomic Study of the Effects of Exenatide on Gastric Emptying and Weight Loss in Patients With Accelerated Gastric Emptying

AGA Abstracts

prior to oral glucose (2 mg/g BW) gavage. PBS or GIP mAbs (10 mg/kg BW) were also injected i.p. 5 times/week to mice fed a HFD, and both body weight and food consumption were monitored weekly. At the end of the 17-week study period, magnetic resonance (MR) was used to assess fat deposition, and blood was obtained for measurements of insulin, leptin, and glucagon-like peptide-1 (GLP-1). Results: 2000 hybridoma clones were generated, with 21 positive for GIP binding, one of which yielded a mAb that effectively neutralized 1 nM of GIP. Although serum glucose levels were unchanged, the GIP mAb given i.p. nearly abolished the insulin response to GIP in the IPGTT and reduced the insulin response to oral glucose by 70%. After 17 weeks on the HFD, control mice gained 21.5±1.0 g, while mice receiving the GIP mAb gained 10.5±0.5 g, a reduction in weight gained of 46.5% (P= 0.00000007). When corrected for BW, no difference in the quantity of food consumed was detected between the 2 treatment groups. In addition, MR demonstrated that mice treated with GIP mAbs had significantly less subcutaneous (P=0.0002), omental (P=0.0005), and hepatic fat (P=0.030) than untreated animals. In response to the GIP mAb, serum insulin and leptin levels decreased from 4.3±1.1 to 1.7±0.6 ng/ml (P=0.027) and from 37.5±10.4 to 6.5±1.9 ng/ml (P=0.006), respectively, while no significant changes in serum GLP-1 levels were detected. Conclusion: Immunoneutralization of GIP in mice using a specific mAb effectively attenuates weight gain in mice fed a HFD while decreasing fat deposition. The results of these studies support the hypothesis that a reduction in GIP signaling might provide a useful method for the treatment and prevention of obesity and related disorders. Su2067 A Pilot Pharmacogenomic Study of the Effects of Exenatide on Gastric Emptying and Weight Loss in Patients With Accelerated Gastric Emptying Andres Acosta, Michael Camilleri, Jessica O'Neill, Deborah J. Eckert, Paula Carlson, Duane D. Burton, Deborah L. Rhoten, Michael Ryks, Alan R. Zinsmeister

ns=not significant; VAS=visual analog score

Background/Aim: Some patients with obesity have accelerated gastric emptying (GE) of solids and liquids when compared to normal weight patients. The transcription factor 7like 2 gene (TCF7L2; formerly TCF4) is associated with a population-attributable risk of type 2 diabetes mellitus (T2DM). The incretin hormone, glucagon-like peptide-1 (GLP-1), is produced by post-translational processing of the glucagon gene product; β-catenin-TCF7L2 heterodimer regulates glucagon gene expression in the intestinal L-cells that secrete GLP1. TCF7L2 TT genotype is associated with accelerated GE in obesity and T2DM (Clin Transl Sci 2011;4:183-7). Exenatide, a GLP-1 agonist, is currently being tested as a weight loss medication; weight loss varies from 2.0±2.8 to 5.1±0.5kg in meta-analyses of 3-month studies. Our overall hypothesis was that anti-obesity therapy is more efficacious when the pharmacological effects of the agents are matched with the disturbance of function and with genetic variations that control the receptor targeted by the drug. Our aims were to evaluate effects of exenatide, 5μg, SQ, twice daily for 30 days, on GE, satiety, satiation and weight loss in 20 obese participants with accelerated GE [GE T1/2 solids <90min (normal weight GE T1/2 solids = 121.7±29.8min (SD), Neurogastroenterol Motil 2012;24:1076-e562] and to compare effects of exenatide in obese participants with TCF7L2 CC vs. CT/TT genotype. Methods: In a randomized, double-blind, placebo-controlled study, we compared the effect of exenatide, 5μg, SQ, twice daily for 30 days, on GE, satiety, satiation and body weight in obese participants without T2DM. We measured GE of solids and liquids by scintigraphy, satiation and postprandial symptoms by Ensure® drink test, satiety by ad libitum buffet meal. Statistical analysis used ANCOVA adjusting for age and gender. Results: Exenatide had a very significant effect, delaying GE of solids (Δ 86.9min compared to baseline and Δ 72.3min compared to placebo, p<0.001), and it reduced calorie intake at a buffet meal by an average 130kcal compared to placebo. The mean weight loss was 1.30kg for exenatide and 0.51kg for placebo group. In the exenatide group, the T allele was associated with greater weight loss (-1.66±0.4kg) compared to CC genotype (-0.47±0.4kg), consistent with the hypothesis that carriers of the T allele (who generally have accelerated GE) would have a greater response to GLP-1 agonist treatment. There were no dropouts or side effects reported during the study. Conclusion: Exenatide reduces body weight and food intake, and delays GE of solids; TCF7L2 rs7903146 T allele is associated with greater weight loss. These data provide the basis for further studies of the efficacy of GLP-1 agonists on weight loss, and for optimal selection of patients based on pre-study quantitative traits of gastric function or TCF7L2 genotype. Effects of Exenatide on Gastric Emptying and Weight Loss in Patients with Accelerated Gastric Emptying

Su2068 16S Gene Sequencing Reveals a Unique Bacterial Signature in the Gut Microbiota of Pediatric Patients With Cystic Fibrosis and Pancreatic Insufficiency Judith R. Kelsen, Lindsey Albenberg, Aubrey G. Bailey, Joan Schall, Maria R. Mascarenhas, Frederic D. Bushman, Virgina A. Stallings Background: There is increasing evidence supporting the importance of the gut microbiota in the pathogenesis of disease. Additionally, alterations in the diet appear to have a significant impact on the composition of the gut microbiota. Methods: Pediatric patients with CF and documented pancreatic insufficiency based on fecal elastase were recruited. Subjects were randomized to receive either LYM-X-SORB™, an organized lipid matrix that has been shown to improve choline and fatty acid status in patients with CF, or placebo daily for 12 months. Stool samples were collected at baseline, 3 months, and 12 months for microbiota analysis. DNA was extracted using the PSP DNA extraction kit. Pyrosequencing was carried out using barcoded 16S rRNA gene primers. Sequences obtained were decoded using the QIIME pipeline. The results were compared to a cohort of pediatric control subjects from a previously published study (Hoffmann C. et al. PloS ONE 2013 8(6):e66019). A 3-day weighed food intake record was collected and analyzed at the time of each stool sample collection. Results: Stool samples were collected from 11 subjects treated with LYM-X-SORB™ and 12 subjects treated with placebo at a minimum of two time points. At baseline, the gut microbiota was significantly different in both weighted and unweighted UniFrac analysis between subjects with CF and healthy controls (p<0.01, p<0.001). Six bacterial genera were present in decreased relative abundance in subjects with CF as compared with healthy controls (p<0.01), and 2 genera, including unclassifed Enterobacteriaceae were present in increased abundance. There was no difference in microbiota structure from baseline to 12 months between the CF subjects who received LYM-X-SORB or placebo (p<0.7). There was no change in the microbiota in subjects with antibiotic exposure at the time of collection compared to those without antibiotic exposure in CF on both weighted and unweighted analyses. Similarly, diets that were higher in fiber did not demonstrate significant alteration in bacterial community structure compared to diets higher in fat at baseline, however these latter analyses were limited by small number of subjects. Conclusions: The gut microbial community structure differed between subjects with CF and healthy controls. While the limited number of subjects prevented complete exposure analysis, there were differences seen in several bacterial lineages in the CF cohort, including potentially pathogenic organisms. A larger prospective longitudinal study is necessary to further explore this important cohort. Su2069 Association of Tumor Fusobacterium Status in Pancreatic Cancers With Molecular Alterations and Patient Survival Hiroyoshi Kurihara, Katsuhiko Nosho, Kei Mitsuhashi, Yasutaka Sukawa, Yasutaka Matsunaga, Miki Ito, Shinichi Kanno, Hisayoshi Igarashi, Itaru Yamamoto, Yasushi Adachi, Tokuma Tanuma, Hiroyuki Maguchi, Masafumi Imamura, Yasutoshi Kimura, Koichi Hirata, Reo Maruyama, Hiromu Suzuki, Kohzoh Imai, Hiroyuki Yamamoto, Yasuhisa Shinomura Background & Aims: Recently, bacterial infection causing periodontal disease has attracted considerable attention as a risk factor for pancreatic cancer. Fusobacterium species (the nonspore-forming, anaerobic Gram-negative bacterium) is an oral bacterial group of the human microbiome. Some evidence suggests that Fusobacterium species promote colorectal cancer development; however, no previous studies have reported the association between Fusobacterium species and pancreatic cancer. Therefore, we hypothesized that Fusobacterium species can be present in pancreatic cancer tissue and can contribute to cancer progression. Methods: Using a database of 283 patients with pancreatic cancer (pancreatic ductal adenocarcinoma), we tested pancreatic cancer tissue specimens for Fusobacterium species using quantitative PCR. We also examined KRAS (codon 12/13/61/146), NRAS (codon12/13/61), BRAF (V600E), and PIK3CA (exon9/20) mutations; measured microRNA-21 (miR-21), miR-31, and miR143 expression levels; and microsatellite instability (MSI). In addition, we assessed epigenetic

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AGA Abstracts