- Email: [email protected]
A Single-Center, Randomized, Placebo-Controlled, 16-Week Trial of Effects of Liraglutide on Weight Loss and Relationship to Change in Gastric Emptying in Obese Patients
AGA Abstracts
26656289). Liraglutide is approved for treatment of obesity with standard dose escalation over 5 weeks reaching 3mg/day. Aim: To compare effects of liraglutide, 3mg SQ /day, and placebo administered for 12 weeks on gastric emptying, gastric accommodation, satiation, postprandial symptoms and satiety in overweight or obese patients. Methods: We conducted a randomized, controlled trial of liraglutide and placebo in 40 obese participants (BMI ≥30kg/m2). All participants received nutritional and behavioral counseling. Patients followed standard liraglutide dose escalation, increasing by 0.6mg/day each week for 5 weeks. Liraglutide or placebo (saline solution) was self-administered by subcutaneous injection once per day. Liraglutide was administered at maximum tolerated dose for the next 11 weeks. All participants included in this report underwent all measurements at baseline and after a total of 12 weeks of maximum tolerated dose of liraglutide (3mg/day). We measured: gastric emptying of solids by scintigraphy over 4 hours using a 320kcal, 30% fat meal; gastric volumes (fasting and post-300mL Ensure®) by SPECT; satiation [volume to fullness (VTF), maximum tolerated volume (MTV) and postprandial symptoms] with nutrient drink test (Ensure® 30kcal/min); and satiety by kcal intake at an ad libitum buffet meal. Statistical analysis examined effects of liraglutide compared to placebo using ANCOVA with the corresponding baseline measurement as a covariate. Results: There were 4 drop-outs, and complete data were available for 28 participants. All patients on liraglutide were taking 3mg/ day at the end of 12 weeks of therapy. Patients' demographic data, baseline gastric emptying T1/2, and effects on gastric motor functions, satiation and satiety parameters with treatments are shown in the table (mean+SEM). Conclusion: Liraglutide treatment at maximum escalated dose (3mg) for 12 weeks resulted in significant and persistent slowing of gastric emptying and reduced maximum tolerated volume relative to placebo. These results suggest an important role of gastric emptying in the beneficial effects of liraglutide on weight loss. Support: NIH RO1-DK67071
Su2031 HUMANIZATION OF A GASTRIC INHIBITORY POLYPEPTIDE (GIP)NEUTRALIZING MONOCLONAL ANTIBODY (MAB) AND WEIGHT REVERSAL IN DIET-INDUCED OBESE MICE M. Michael Wolfe, Michael O. Boylan, Raghav Sood, Alice A. Newman Background: We recently generated a specific mouse GIP mAb (mAbm) and reported significant prevention of weight gain without any effect on food intake. AIM: To determine whether this GIP mAbm could reverse weight gain in obese mice and to characterize a humanized GIP mAb (mAbh). Methods: Obesity was induced in C57BL/6 mice by feeding high-fat diet (HFD; 60% calories from fat) from weaning to 18 weeks. The mice were then fed a 45% HFD and administered the GIP mAbm (45 mg/kg BW) ip weekly for 6 wks. BW was recorded weekly, and HgA1c levels were measured after wk 6. The mAbm was "humanized" by grafting its complementary determining regions onto a human IgG "scaffold". Binding affinity was determined by surface plasmon resonance, and a reporter cell line expressing GIP receptors was used in a modified Schild's assay to demonstrate mAb-dependent GIP neutralization in vitro. Finally, the GIP mAbh (10 or 30 mg/kg BW) was administered to mice ip, and blood samples were collected over 2 wks, and the Cmax and T1/2 determined. In separate studies, mice fasted for 1 h were administered either 30 mg/kg BW mAbh or vehicle ip. The mice were then fasted for an additional 5 h before glucose (1.5 g/kg BW) was given by oral gavage, and blood was collected at 0 and 15 min; the protocol was repeated 1 and 2 wks later. Plasma insulin levels were measured by ELISA. Results: After 6 wks of GIP mAbm treatment, BW was reduced by 6.0±2.7%, while BW increased in control mice by 3.6±1.4% (P<0.002). The mean HgA1c levels for mAb-treated mice trended lower (4.4±0.2%), compared to control mice (4.8±2.7%, P=NS). The binding affinity (KD) of GIP for the mAbh was 0.9 nM, compared to the original mAbm KD of 3.3 nM. Similar to the mAbm, the mAbh neutralized GIP signaling in vitro in a concentration-dependent manner, and the Schild's assay showed mAbh and mAbm equilibrium dissociation constants of 2.2 µM and 3.2 µM, respectively, indicating similarly that mAbh binds more avidly to GIP than does mAbm. The plasma Cmax values for the 10 and 30 mg/kg BW doses of GIP mAbh were 10.1±0.7 µg/ml and 32.6±1.0 µg/ml, respectively. The GIP mAbh inhibited the15-min insulin responses to oral glucose at 5 h, 1 wk, and 2 wk after treatment by 47±21% (P=0.01), 45±21% (P=0.01), and 13.8±31%, respectively. Conclusion: Treatment of high-fat fed obese mice with the GIP mAb caused significant weight loss, which was accompanied by a trend toward improvement in HgA1c levels. The anti-GIP mAbh was shown to bind GIP with a higher affinity than the mAbm, and similarly it inhibits GIP signaling in vitro more potently than the original GIP mAbm. Furthermore, the calculated T1/2 for the GIP mAbh in vivo is comparable to other biological agents, indicating that a convenient bimonthly or once per month administration of the GIP mAbh might prove a tenable agent for treating obesity and related disorders in humans.
*p=0.046; **p=0.036
Su2030 Su2032
BAR130, A HYODEOXYCHOLIC ACID DERIVATIVE AS THE FIRST EXAMPLE OF DUAL LXRα/GPBAR1 AGONIST Adriana Carino, Sabrina Cipriani, Silvia Marchianò, Michele Biagioli, Angela Zampella, Simona De Martino, Stefano Fiorucci
A SINGLE-CENTER, RANDOMIZED, PLACEBO-CONTROLLED, 16-WEEK TRIAL OF EFFECTS OF LIRAGLUTIDE ON WEIGHT LOSS AND RELATIONSHIP TO CHANGE IN GASTRIC EMPTYING IN OBESE PATIENTS Hoda C. Kadouh, Matthew Clark, Sarah A. Kalsy, Karen M. Graszer, Karen Grothe, Houssam Halawi, Ibironke Oduyebo, Disha Khemani, Alfred D. Nelson, Deborah J. Eckert, Jessica O'Neill, Andres J. Acosta Cardenas, Alan R. Zinsmeister, Michael Camilleri
Background. The liver X receptors (LXRs), activated by oxysterol and by the secondary bile acid hyodeoxycholic acid (HDCA), have been found essential in the regulation of lipid homeostasis in mammals. Unfortunately, LXRα activates lipogenic enzymes causing accumulation of lipid in the liver. In the present study, we report the identification of a side chain modified HDCA (BAR130) that represents the first example of a potent dual LXRα/GPBAR1 agonist. Aim. To investigate in vitro and in vivo effects of BAR130 a dual GPBAR1/LXRα ligand. Material and methods. HepG2 and Glutag (a mouse counterpart of intestinal L cells) cells were exposed to GW3965 or TLCA (10 µM), HDCA (10 µM) along with increasing concentrations of BAR130 (1, 5, 10, 25, 50 µM); total RNA was isolated for rt-PCR. C57BL6 mice were administered with BAR130 (30 mg/Kg daily by gavage) or vehicle (distilled water) for 2 weeks. Mice were sacrificed and blood, liver and terminal ileum collected for plasma AST, cholesterol and tryglicerides measurement, liver histopathology analysis (H/E) and for evaluation of steatosis markers genes expression (rt-PCR). Results. BAR130 transactivates LXRα and GPBAR1 with an EC50 value of 3.2±0.03 and 4.9±0.2, respectively. When administered in vitro to HepG2 cells , BAR130 increases the expression of LXRα target genes, ABCA1 and SREBP1c, in a concentration-dependent manner with an EC50 of 8.3 µM and 5.8 µM respectively. BAR130 increases the expression of pro-glucagon mRNA (a GPBAR1 target gene) in GLUTAg cells with an EC50 of 6.5 µM. Treating mice with BAR130 did not increased AST, cholesterol and tryglicerides plasma levels (Figure). Further on, rtPCR analysis of liver samples demonstrated that the BAR130 did not induce the expression of lipidogenic genes including FAS, SREBP1C and CD36. The result was confirmed by Liver histology (H/E). BAR130 increased the expression of GPBAR1 target gene GLP1 in the ileum and reduced markers of inflammation in macrophages. Conclusions. This study shows the simultaneous activation of LXRα and GPBAR1 represents a promising approach to target metabolic disorders and ground the use of BAR130 in the setting of metabolic diseases.
AGA Abstracts
Background: Obesity is associated with accelerated gastric emptying (GE) and greater calories consumed to reach satiation or to evoke satiety with an ad libitum meal. A medication which could impact GE has the potential to assist with obesity management. One possible medication, exenatide, a short-acting GLP-1 receptor agonist, 5µg SQ BID for 30 days, has been shown to delay GE and induce weight loss (PMID 26542264). GE was delayed after 3 weeks' treatment with the longer acting GLP-1 agonist, liraglutide, escalated to 1.8mg/ day, but there was no difference after 24 weeks of treatment (PMID 26656289). The effect of liraglutide, 3mg/day, on GE and weight is unclear. Aim: To compare effects on weight loss of 16 weeks' treatment of dose-escalated liraglutide (up to 3mg/day) to placebo, and the relationship of weight loss to slowing of GE on treatment. Methods: We conducted a randomized, controlled trial of liraglutide and placebo in 40 obese participants; we used liraglutide dose escalation starting at 0.6mg/day and increasing by 0.6mg/day each week to reach a 3mg dose at week 5, followed by 3mg/day dose for the next 11 weeks. Liraglutide or placebo (saline solution) was self-administered by subcutaneous injection once per day. All participants underwent standardized health behavior counseling, nutrition education sessions (using LEARN manual), as well as structured follow-up visits, for a total of 17 visits to the Clinical Research Unit. In addition, GE of solids was measured over 4 hours, using a 315kcal, 33% fat meal, by means of scintigraphy at baseline and after 16 weeks of treatment. Statistical analysis examined effects of liraglutide compared to placebo on weight loss and on the relationship of weight loss with change (∆) in GE T1/2 of solids using Spearman correlation. Results: To date, 28 participants completed all studies, 4 dropped out, and 8 are currently on treatment. The ∆ in weight between baseline and week 16 of treatment is expressed as median (IQR), as data distribution was skewed (one placebo-treated participant lost 17.1kg). Other data are mean + SEM (Table). There was an inverse relationship between ∆ GE T1/2 and ∆ weight loss (Rs= -0.33, p=0.095), suggesting that the greater the retardation of GE, the greater the weight loss. Two patients underwent cholecystectomy during the study. Conclusions: Liraglutide (3mg/day over 12 weeks after standard weekly dose escalation of 0.6mg/day) results in significant weight loss compared to placebo. Greater retardation of GE is associated with greater weight loss, suggesting the hypothesis that liraglutide's effect on weight is mediated, in part, by retardation of GE. Support: NIH R01-DK67071
S-634
AGA Abstracts
Table 2. Baseline Characteristics and Outcomes at 6 Months Between Patients Undergoing TORe + APC versus APC alone Matched Based on BMI, Amount of Weight Regain and GJA Size prior to Endoscopic Revision
# p<0.001 (signed rank test); * p=0.021 (paired-t test); minus sign in ∆ GE T1/2 (min) baseline to week 16 shows slower GE at baseline
Su2033 ARGON PLASMA COAGULATION IS EFFECTIVE IN ROUX-EN-Y GASTRIC BYPASS PATIENTS THAT DO NOT ACHIEVE WEIGHT LOSS GOALS AFTER SUTURED TRANSORAL OUTLET REDUCTION (TORE) Pichamol Jirapinyo, Paul T. Kroner, Christopher C. Thompson Background: Transoral outlet reduction (TORe) and argon plasma coagulation (APC) are effective at reducing GJA size and weight regain after Roux-en-Y gastric bypass (RYGB). While the majority respond well to TORe, a subgroup of patients fail to achieve weight loss goals. Aims: 1) To assess if APC is effective in treating weight regain in RYGB patients who have undergone TORe and failed to reach weight loss goals 2) To determine if TORe followed by APC is more effective at treating weight regain than APC monotherapy. Methods: Study Design: A retrospective study of prospectively collected data, followed by a matched cohort comparison. Part I: Efficacy of TORe+APC sequential therapy in patients who failed to achieve weight loss goals after TORe alone (defined as body mass index (BMI) higher than 25 after TORe). Part II: Efficacy oft TORe+APC sequential therapy vs APC monotherapy matched based on BMI, amount of weight regain and GJA size prior to endoscopic revision. Procedures: TORe: Endoscopic suturing device was used to apply full-thickness plications around the GJA margin. Additional stitches were placed in the pouch for a dilated pouch. APC: Coagulation (0.8 L/min and 55 Watts) over the entire circumference of GJA was performed. Additional series were carried out at 8-12 weeks until goal body weight was achieved. Patients received the same post-op diet. Primary Outcome: Weight loss at 6 months after the last endoscopic revision session as measured by percentage of total body weight loss (%TBWL). Statistical Analysis: Statistics were reported using mean±SD or median [range]. Means were compared using Student's t-test. A p-value of 0.05 was significant. Results: Part I: 44 patients underwent TORe+APC (83 APC sessions; 1.9 sessions after each TORe/patient). Baseline characteristics are shown in Table 1. At 6 months, patients lost 10.0±10.4 kg from baseline (p<0.0001), and BMI decreased from 39.6±9.1 to 36.3±9.1 kg/ m2 (p<0.0001). This represented 10.5±10.4% TBWL. Part II: 25 consecutive RYGB patients undergoing TORe+APC were matched to 25 patients undergoing APC alone based on BMI, weight regain and GJA size (Table 2). At 6 months, the TORe+APC group had higher %TBWL compared to the APC alone group (9.4±6.0% TBWL vs 5.7±5.7% TBWL, p=0.019). Conclusion: APC is effective in treating weight regain in RYGB patients who fail to meet weight loss goals after TORe. Additionally, sequential therapy with TORe followed by APC is more effective than APC monotherapy alone. Table 1. Baseline Characteristics and Outcomes at 6 Months Between Patients Undergoing TORe + APC versus APC alone
Su2034 MORPHOLOGICAL BRAIN ALTERATIONS AND CHANGES IN HEDONIC INGESTIVE BEHAVIORS ASSOCIATED WITH BARIATRIC SURGERY Arpana Gupta, Emeran A. Mayer, Elizabeth Gallagher, Ravi Bhatt, Tiffany Ju, Kristen Coveleskie, Jean Stains, Yijun Chen, Anna Balioukova, Jennifer S. Labus, Erik Dutson, Claudia P. Sanmiguel Background: In the United States, 65% of adults are considered either overweight or obese. Neuroimaging studies have identified obesity-related differences in morphological and functional scans, suggesting a possible role of the brain in the pathophysiology of obesity. Obese humans have significantly greater responses in gustatory, somatosensory, and reward-processing regions in response to palatable food and to visual food cues. It has been shown that bariatric surgery decreases the brain's reward network hyperactivity associated with obesity. Aims: To investigate morphological changes in the brain's extended reward system one month after undergoing laparoscopic sleeve gastrectomy (LSG) and the associated changes in body mass, weight loss, appetite and hedonic ingestive behaviors. Methods: Structural MRI was acquired in 16 female subjects at baseline (mean age=39.5±8.7yrs) and 1 month post surgery. Voxel-based morphometry analyses using a general linear model controlling for age were conducted in FSL-VBM to determine differences in grey-matter pre vs. post surgery and paired t-tests were run to determine the changes in clinical and behavioral variables. All significance testing was conducted at p<.05, corrected for multiple comparisons using the Family-Wise Error method. Correlations between significant changes in brain morphometry and changes in obesity and behavioral variables were conducted (p<.05). Results: Bariatric surgery resulted in significant reductions in BMI (45.0±5.3 before vs. 40.3±5.5 kg/m2 after surgery (t=16.23, p<.0001) and in adiposity (total body fat mass: 119 kg vs. 106 kg, pre vs. post surgery (t=16.82, p<.0001). LSG also resulted in decreased hedonic eating (Yale food addiction symptoms count of 3.62 pre vs. 1.19 post-surgery (t= 4.80, p<.0001). Brain Morphological Changes: After surgery, significantly decreased grey matter (GM) densities were observed in the left anterior (t=4.16,p= .03), middle, (t=5.25, p=.02), posterior (t=4.66, p=.03), and inferior insula (t=3.88, p=.04); along with the left hippocampus (t=5.14, p=.02). Correlations with Clinical variables: Postoperative reductions in total body fat mass were correlated to changes in middle insula GM (r=.53, p=.04). Changes in lean body mass were correlated with changes to the GM at the posterior insula (r=-.61, p=.01) and the inferior insula (r=-.55, p=.03). Changes in the Yale Food Addiction scores were correlated with changes in the middle insula GM (r=.59, p=.02). Conclusions: Bariatric surgery results in a significant decrease in measures of obesity and hedonic eating as well as structural changes at the brain's reward network core regions. Postoperative changes in the brain's reward network were associated with reductions in hedonic eating and adiposity, suggesting an effect of bariatric surgery on brain control of ingestive behaviors.
Su2035 IMPROVEMENT IN GLUCOSE METABOLISM AFTER BARIATRIC SURGERY: COMPARISON OF LAPAROSCOPIC ROUX-EN-Y GASTRIC BYPASS AND DUODENOJEJUNAL BYPASS Sarah Guenthert, Christine Stier, Rudolf Weiner, Jurgen Stein Background: Both Roux-en-Y gastric bypass (RYGB) and duodenojejunal bypass liner (DJBL) have been shown to induce significant weight loss and dramatically ameliorate type 2 diabetes mellitus (T2DM). Because DJBL implantation induces nutrient bypass of the duodenum, its mechanisms have been proposed to mimic those of the RYGB. This monocentric, prospective parallel group study aimed to compare these two bariatric procedures in the treatment of obesity and T2DM. Methods: Up to November 2016, a total of 45 patients were included. Twenty (6 male, mean age 51.1 ±10.9 yrs) received RYGB, and twenty-five DJBL (10 male, mean age 52.5 ±9.6 yrs). Body weight, body mass index, and glycated haemoglobin A1C (HbA1C) were documented pre-intervention and 1, 3, 9 and 12 months following each procedure. Results: Changes in metabolic parameters are shown in table 1. Conclusion: This is the first study comparing the improvement in glucose metabolism following RYGB or DJBL. As expected, our preliminary data demonstrated RYGB to be superior in terms of weight loss induction. However, both procedures have a similar impact on diabetes remission, indicating that the degree of weight loss itself is not the main determinant of improvement in glucose homeostasis in patients who have undergone these obesity procedures.
S-635
AGA Abstracts
26656289). Liraglutide is approved for treatment of obesity with standard dose escalation over 5 weeks reaching 3mg/day. Aim: To compare effects of liraglutide, 3mg SQ /day, and placebo administered for 12 weeks on gastric emptying, gastric accommodation, satiation, postprandial symptoms and satiety in overweight or obese patients. Methods: We conducted a randomized, controlled trial of liraglutide and placebo in 40 obese participants (BMI ≥30kg/m2). All participants received nutritional and behavioral counseling. Patients followed standard liraglutide dose escalation, increasing by 0.6mg/day each week for 5 weeks. Liraglutide or placebo (saline solution) was self-administered by subcutaneous injection once per day. Liraglutide was administered at maximum tolerated dose for the next 11 weeks. All participants included in this report underwent all measurements at baseline and after a total of 12 weeks of maximum tolerated dose of liraglutide (3mg/day). We measured: gastric emptying of solids by scintigraphy over 4 hours using a 320kcal, 30% fat meal; gastric volumes (fasting and post-300mL Ensure®) by SPECT; satiation [volume to fullness (VTF), maximum tolerated volume (MTV) and postprandial symptoms] with nutrient drink test (Ensure® 30kcal/min); and satiety by kcal intake at an ad libitum buffet meal. Statistical analysis examined effects of liraglutide compared to placebo using ANCOVA with the corresponding baseline measurement as a covariate. Results: There were 4 drop-outs, and complete data were available for 28 participants. All patients on liraglutide were taking 3mg/ day at the end of 12 weeks of therapy. Patients' demographic data, baseline gastric emptying T1/2, and effects on gastric motor functions, satiation and satiety parameters with treatments are shown in the table (mean+SEM). Conclusion: Liraglutide treatment at maximum escalated dose (3mg) for 12 weeks resulted in significant and persistent slowing of gastric emptying and reduced maximum tolerated volume relative to placebo. These results suggest an important role of gastric emptying in the beneficial effects of liraglutide on weight loss. Support: NIH RO1-DK67071
Su2031 HUMANIZATION OF A GASTRIC INHIBITORY POLYPEPTIDE (GIP)NEUTRALIZING MONOCLONAL ANTIBODY (MAB) AND WEIGHT REVERSAL IN DIET-INDUCED OBESE MICE M. Michael Wolfe, Michael O. Boylan, Raghav Sood, Alice A. Newman Background: We recently generated a specific mouse GIP mAb (mAbm) and reported significant prevention of weight gain without any effect on food intake. AIM: To determine whether this GIP mAbm could reverse weight gain in obese mice and to characterize a humanized GIP mAb (mAbh). Methods: Obesity was induced in C57BL/6 mice by feeding high-fat diet (HFD; 60% calories from fat) from weaning to 18 weeks. The mice were then fed a 45% HFD and administered the GIP mAbm (45 mg/kg BW) ip weekly for 6 wks. BW was recorded weekly, and HgA1c levels were measured after wk 6. The mAbm was "humanized" by grafting its complementary determining regions onto a human IgG "scaffold". Binding affinity was determined by surface plasmon resonance, and a reporter cell line expressing GIP receptors was used in a modified Schild's assay to demonstrate mAb-dependent GIP neutralization in vitro. Finally, the GIP mAbh (10 or 30 mg/kg BW) was administered to mice ip, and blood samples were collected over 2 wks, and the Cmax and T1/2 determined. In separate studies, mice fasted for 1 h were administered either 30 mg/kg BW mAbh or vehicle ip. The mice were then fasted for an additional 5 h before glucose (1.5 g/kg BW) was given by oral gavage, and blood was collected at 0 and 15 min; the protocol was repeated 1 and 2 wks later. Plasma insulin levels were measured by ELISA. Results: After 6 wks of GIP mAbm treatment, BW was reduced by 6.0±2.7%, while BW increased in control mice by 3.6±1.4% (P<0.002). The mean HgA1c levels for mAb-treated mice trended lower (4.4±0.2%), compared to control mice (4.8±2.7%, P=NS). The binding affinity (KD) of GIP for the mAbh was 0.9 nM, compared to the original mAbm KD of 3.3 nM. Similar to the mAbm, the mAbh neutralized GIP signaling in vitro in a concentration-dependent manner, and the Schild's assay showed mAbh and mAbm equilibrium dissociation constants of 2.2 µM and 3.2 µM, respectively, indicating similarly that mAbh binds more avidly to GIP than does mAbm. The plasma Cmax values for the 10 and 30 mg/kg BW doses of GIP mAbh were 10.1±0.7 µg/ml and 32.6±1.0 µg/ml, respectively. The GIP mAbh inhibited the15-min insulin responses to oral glucose at 5 h, 1 wk, and 2 wk after treatment by 47±21% (P=0.01), 45±21% (P=0.01), and 13.8±31%, respectively. Conclusion: Treatment of high-fat fed obese mice with the GIP mAb caused significant weight loss, which was accompanied by a trend toward improvement in HgA1c levels. The anti-GIP mAbh was shown to bind GIP with a higher affinity than the mAbm, and similarly it inhibits GIP signaling in vitro more potently than the original GIP mAbm. Furthermore, the calculated T1/2 for the GIP mAbh in vivo is comparable to other biological agents, indicating that a convenient bimonthly or once per month administration of the GIP mAbh might prove a tenable agent for treating obesity and related disorders in humans.
*p=0.046; **p=0.036
Su2030 Su2032
BAR130, A HYODEOXYCHOLIC ACID DERIVATIVE AS THE FIRST EXAMPLE OF DUAL LXRα/GPBAR1 AGONIST Adriana Carino, Sabrina Cipriani, Silvia Marchianò, Michele Biagioli, Angela Zampella, Simona De Martino, Stefano Fiorucci
A SINGLE-CENTER, RANDOMIZED, PLACEBO-CONTROLLED, 16-WEEK TRIAL OF EFFECTS OF LIRAGLUTIDE ON WEIGHT LOSS AND RELATIONSHIP TO CHANGE IN GASTRIC EMPTYING IN OBESE PATIENTS Hoda C. Kadouh, Matthew Clark, Sarah A. Kalsy, Karen M. Graszer, Karen Grothe, Houssam Halawi, Ibironke Oduyebo, Disha Khemani, Alfred D. Nelson, Deborah J. Eckert, Jessica O'Neill, Andres J. Acosta Cardenas, Alan R. Zinsmeister, Michael Camilleri
Background. The liver X receptors (LXRs), activated by oxysterol and by the secondary bile acid hyodeoxycholic acid (HDCA), have been found essential in the regulation of lipid homeostasis in mammals. Unfortunately, LXRα activates lipogenic enzymes causing accumulation of lipid in the liver. In the present study, we report the identification of a side chain modified HDCA (BAR130) that represents the first example of a potent dual LXRα/GPBAR1 agonist. Aim. To investigate in vitro and in vivo effects of BAR130 a dual GPBAR1/LXRα ligand. Material and methods. HepG2 and Glutag (a mouse counterpart of intestinal L cells) cells were exposed to GW3965 or TLCA (10 µM), HDCA (10 µM) along with increasing concentrations of BAR130 (1, 5, 10, 25, 50 µM); total RNA was isolated for rt-PCR. C57BL6 mice were administered with BAR130 (30 mg/Kg daily by gavage) or vehicle (distilled water) for 2 weeks. Mice were sacrificed and blood, liver and terminal ileum collected for plasma AST, cholesterol and tryglicerides measurement, liver histopathology analysis (H/E) and for evaluation of steatosis markers genes expression (rt-PCR). Results. BAR130 transactivates LXRα and GPBAR1 with an EC50 value of 3.2±0.03 and 4.9±0.2, respectively. When administered in vitro to HepG2 cells , BAR130 increases the expression of LXRα target genes, ABCA1 and SREBP1c, in a concentration-dependent manner with an EC50 of 8.3 µM and 5.8 µM respectively. BAR130 increases the expression of pro-glucagon mRNA (a GPBAR1 target gene) in GLUTAg cells with an EC50 of 6.5 µM. Treating mice with BAR130 did not increased AST, cholesterol and tryglicerides plasma levels (Figure). Further on, rtPCR analysis of liver samples demonstrated that the BAR130 did not induce the expression of lipidogenic genes including FAS, SREBP1C and CD36. The result was confirmed by Liver histology (H/E). BAR130 increased the expression of GPBAR1 target gene GLP1 in the ileum and reduced markers of inflammation in macrophages. Conclusions. This study shows the simultaneous activation of LXRα and GPBAR1 represents a promising approach to target metabolic disorders and ground the use of BAR130 in the setting of metabolic diseases.
AGA Abstracts
Background: Obesity is associated with accelerated gastric emptying (GE) and greater calories consumed to reach satiation or to evoke satiety with an ad libitum meal. A medication which could impact GE has the potential to assist with obesity management. One possible medication, exenatide, a short-acting GLP-1 receptor agonist, 5µg SQ BID for 30 days, has been shown to delay GE and induce weight loss (PMID 26542264). GE was delayed after 3 weeks' treatment with the longer acting GLP-1 agonist, liraglutide, escalated to 1.8mg/ day, but there was no difference after 24 weeks of treatment (PMID 26656289). The effect of liraglutide, 3mg/day, on GE and weight is unclear. Aim: To compare effects on weight loss of 16 weeks' treatment of dose-escalated liraglutide (up to 3mg/day) to placebo, and the relationship of weight loss to slowing of GE on treatment. Methods: We conducted a randomized, controlled trial of liraglutide and placebo in 40 obese participants; we used liraglutide dose escalation starting at 0.6mg/day and increasing by 0.6mg/day each week to reach a 3mg dose at week 5, followed by 3mg/day dose for the next 11 weeks. Liraglutide or placebo (saline solution) was self-administered by subcutaneous injection once per day. All participants underwent standardized health behavior counseling, nutrition education sessions (using LEARN manual), as well as structured follow-up visits, for a total of 17 visits to the Clinical Research Unit. In addition, GE of solids was measured over 4 hours, using a 315kcal, 33% fat meal, by means of scintigraphy at baseline and after 16 weeks of treatment. Statistical analysis examined effects of liraglutide compared to placebo on weight loss and on the relationship of weight loss with change (∆) in GE T1/2 of solids using Spearman correlation. Results: To date, 28 participants completed all studies, 4 dropped out, and 8 are currently on treatment. The ∆ in weight between baseline and week 16 of treatment is expressed as median (IQR), as data distribution was skewed (one placebo-treated participant lost 17.1kg). Other data are mean + SEM (Table). There was an inverse relationship between ∆ GE T1/2 and ∆ weight loss (Rs= -0.33, p=0.095), suggesting that the greater the retardation of GE, the greater the weight loss. Two patients underwent cholecystectomy during the study. Conclusions: Liraglutide (3mg/day over 12 weeks after standard weekly dose escalation of 0.6mg/day) results in significant weight loss compared to placebo. Greater retardation of GE is associated with greater weight loss, suggesting the hypothesis that liraglutide's effect on weight is mediated, in part, by retardation of GE. Support: NIH R01-DK67071
S-634
AGA Abstracts
Table 2. Baseline Characteristics and Outcomes at 6 Months Between Patients Undergoing TORe + APC versus APC alone Matched Based on BMI, Amount of Weight Regain and GJA Size prior to Endoscopic Revision
# p<0.001 (signed rank test); * p=0.021 (paired-t test); minus sign in ∆ GE T1/2 (min) baseline to week 16 shows slower GE at baseline
Su2033 ARGON PLASMA COAGULATION IS EFFECTIVE IN ROUX-EN-Y GASTRIC BYPASS PATIENTS THAT DO NOT ACHIEVE WEIGHT LOSS GOALS AFTER SUTURED TRANSORAL OUTLET REDUCTION (TORE) Pichamol Jirapinyo, Paul T. Kroner, Christopher C. Thompson Background: Transoral outlet reduction (TORe) and argon plasma coagulation (APC) are effective at reducing GJA size and weight regain after Roux-en-Y gastric bypass (RYGB). While the majority respond well to TORe, a subgroup of patients fail to achieve weight loss goals. Aims: 1) To assess if APC is effective in treating weight regain in RYGB patients who have undergone TORe and failed to reach weight loss goals 2) To determine if TORe followed by APC is more effective at treating weight regain than APC monotherapy. Methods: Study Design: A retrospective study of prospectively collected data, followed by a matched cohort comparison. Part I: Efficacy of TORe+APC sequential therapy in patients who failed to achieve weight loss goals after TORe alone (defined as body mass index (BMI) higher than 25 after TORe). Part II: Efficacy oft TORe+APC sequential therapy vs APC monotherapy matched based on BMI, amount of weight regain and GJA size prior to endoscopic revision. Procedures: TORe: Endoscopic suturing device was used to apply full-thickness plications around the GJA margin. Additional stitches were placed in the pouch for a dilated pouch. APC: Coagulation (0.8 L/min and 55 Watts) over the entire circumference of GJA was performed. Additional series were carried out at 8-12 weeks until goal body weight was achieved. Patients received the same post-op diet. Primary Outcome: Weight loss at 6 months after the last endoscopic revision session as measured by percentage of total body weight loss (%TBWL). Statistical Analysis: Statistics were reported using mean±SD or median [range]. Means were compared using Student's t-test. A p-value of 0.05 was significant. Results: Part I: 44 patients underwent TORe+APC (83 APC sessions; 1.9 sessions after each TORe/patient). Baseline characteristics are shown in Table 1. At 6 months, patients lost 10.0±10.4 kg from baseline (p<0.0001), and BMI decreased from 39.6±9.1 to 36.3±9.1 kg/ m2 (p<0.0001). This represented 10.5±10.4% TBWL. Part II: 25 consecutive RYGB patients undergoing TORe+APC were matched to 25 patients undergoing APC alone based on BMI, weight regain and GJA size (Table 2). At 6 months, the TORe+APC group had higher %TBWL compared to the APC alone group (9.4±6.0% TBWL vs 5.7±5.7% TBWL, p=0.019). Conclusion: APC is effective in treating weight regain in RYGB patients who fail to meet weight loss goals after TORe. Additionally, sequential therapy with TORe followed by APC is more effective than APC monotherapy alone. Table 1. Baseline Characteristics and Outcomes at 6 Months Between Patients Undergoing TORe + APC versus APC alone
Su2034 MORPHOLOGICAL BRAIN ALTERATIONS AND CHANGES IN HEDONIC INGESTIVE BEHAVIORS ASSOCIATED WITH BARIATRIC SURGERY Arpana Gupta, Emeran A. Mayer, Elizabeth Gallagher, Ravi Bhatt, Tiffany Ju, Kristen Coveleskie, Jean Stains, Yijun Chen, Anna Balioukova, Jennifer S. Labus, Erik Dutson, Claudia P. Sanmiguel Background: In the United States, 65% of adults are considered either overweight or obese. Neuroimaging studies have identified obesity-related differences in morphological and functional scans, suggesting a possible role of the brain in the pathophysiology of obesity. Obese humans have significantly greater responses in gustatory, somatosensory, and reward-processing regions in response to palatable food and to visual food cues. It has been shown that bariatric surgery decreases the brain's reward network hyperactivity associated with obesity. Aims: To investigate morphological changes in the brain's extended reward system one month after undergoing laparoscopic sleeve gastrectomy (LSG) and the associated changes in body mass, weight loss, appetite and hedonic ingestive behaviors. Methods: Structural MRI was acquired in 16 female subjects at baseline (mean age=39.5±8.7yrs) and 1 month post surgery. Voxel-based morphometry analyses using a general linear model controlling for age were conducted in FSL-VBM to determine differences in grey-matter pre vs. post surgery and paired t-tests were run to determine the changes in clinical and behavioral variables. All significance testing was conducted at p<.05, corrected for multiple comparisons using the Family-Wise Error method. Correlations between significant changes in brain morphometry and changes in obesity and behavioral variables were conducted (p<.05). Results: Bariatric surgery resulted in significant reductions in BMI (45.0±5.3 before vs. 40.3±5.5 kg/m2 after surgery (t=16.23, p<.0001) and in adiposity (total body fat mass: 119 kg vs. 106 kg, pre vs. post surgery (t=16.82, p<.0001). LSG also resulted in decreased hedonic eating (Yale food addiction symptoms count of 3.62 pre vs. 1.19 post-surgery (t= 4.80, p<.0001). Brain Morphological Changes: After surgery, significantly decreased grey matter (GM) densities were observed in the left anterior (t=4.16,p= .03), middle, (t=5.25, p=.02), posterior (t=4.66, p=.03), and inferior insula (t=3.88, p=.04); along with the left hippocampus (t=5.14, p=.02). Correlations with Clinical variables: Postoperative reductions in total body fat mass were correlated to changes in middle insula GM (r=.53, p=.04). Changes in lean body mass were correlated with changes to the GM at the posterior insula (r=-.61, p=.01) and the inferior insula (r=-.55, p=.03). Changes in the Yale Food Addiction scores were correlated with changes in the middle insula GM (r=.59, p=.02). Conclusions: Bariatric surgery results in a significant decrease in measures of obesity and hedonic eating as well as structural changes at the brain's reward network core regions. Postoperative changes in the brain's reward network were associated with reductions in hedonic eating and adiposity, suggesting an effect of bariatric surgery on brain control of ingestive behaviors.
Su2035 IMPROVEMENT IN GLUCOSE METABOLISM AFTER BARIATRIC SURGERY: COMPARISON OF LAPAROSCOPIC ROUX-EN-Y GASTRIC BYPASS AND DUODENOJEJUNAL BYPASS Sarah Guenthert, Christine Stier, Rudolf Weiner, Jurgen Stein Background: Both Roux-en-Y gastric bypass (RYGB) and duodenojejunal bypass liner (DJBL) have been shown to induce significant weight loss and dramatically ameliorate type 2 diabetes mellitus (T2DM). Because DJBL implantation induces nutrient bypass of the duodenum, its mechanisms have been proposed to mimic those of the RYGB. This monocentric, prospective parallel group study aimed to compare these two bariatric procedures in the treatment of obesity and T2DM. Methods: Up to November 2016, a total of 45 patients were included. Twenty (6 male, mean age 51.1 ±10.9 yrs) received RYGB, and twenty-five DJBL (10 male, mean age 52.5 ±9.6 yrs). Body weight, body mass index, and glycated haemoglobin A1C (HbA1C) were documented pre-intervention and 1, 3, 9 and 12 months following each procedure. Results: Changes in metabolic parameters are shown in table 1. Conclusion: This is the first study comparing the improvement in glucose metabolism following RYGB or DJBL. As expected, our preliminary data demonstrated RYGB to be superior in terms of weight loss induction. However, both procedures have a similar impact on diabetes remission, indicating that the degree of weight loss itself is not the main determinant of improvement in glucose homeostasis in patients who have undergone these obesity procedures.
S-635
AGA Abstracts