Weight-independent Effects Research Articles

Gestational Diabetes Risk and Low Birth Weight After Metabolic Bariatric Surgery: a Complex Interplay to be Balanced

IntroductionMetabolic bariatric surgery (MBS) is known to improve the obstetric outcomes of women with obesity and to prevent gestational diabetes (GD). To what extent does MBS decreases GD, without incurring at additional risks is a matter of concern.MethodsA retrospective case–control study to compare the pregnancy outcomes of women previously submitted to MBS to those of age and preconception body mass index (PC BMI) matched non-operated controls.ResultsPregnancies of women after MBS (n = 79) and matched controls (n = 79) were included. GD was significantly less frequent after MBS (7.6% vs. 19%; p = 0.03). Fasting blood glucose (76.90 ± 0.77 vs 80.37 ± 1.15 mg/dl, p < 0.05; 70.08 ± 1.34 vs. 76.35 ± 0.95 mg/dl; p < 0.05, first and second trimesters respectively) and birth weight (2953.67 ± 489.51 g vs. 3229.11 ± 476.21 g; p < 0.01) were significantly lower after MBS when compared to controls. The occurrence of small-for-gestational-age (SGA) was more frequent after MBS (22.8% vs. 6.3%; p < 0.01), but no longer significant after controlling for smoking habits (15.5% vs. 6%, p = 0.14). There were no significant differences in gestational weight gain, prematurity rate nor mode of delivery between groups.ConclusionMBS was associated with a lower prevalence of GD than observed in non-operated women with the same age and BMI. After controlling for smoking, this occurred at the expense of a lower birth weight. Our data reinforces the hypothesis that MBS has body weight independent effects on glucose kinetics during pregnancy with distinctive impacts for mother and offspring, which need to be balanced.Graphical

THU272 Early Time Restricted Feeding As a Weight Neutral Approach To Improved Glycemic Variation

Abstract Disclosure: S. Nasserifar: None. J. Bruno: None. S. Vanegas: None. C. Popp: None. J.M. Walker: None. J.O. Aleman Diaz: None. Abstract: Early time-restricted feeding (eTRF) is a type of intermittent fasting that involves restricting caloric intake to the first 6-8 hours of the day. Various studies suggest that eTRF improves cardiometabolic health and glycemic variation. However, it is unclear whether these effects are a consequence of weight loss that frequently accompanies this dietary intervention or due to the metabolic effects of the feeding strategy itself. To address this, we conducted a randomized 7-day isocaloric crossover supervised feeding study comparing eTRF (80% of calories consumed before 1 pm) to a usual feeding pattern (UFP, 50% of calories consumed after 4 pm) among 10 participants with prediabetes and obesity in a metabolic ward. Participants were randomized 1:1 to eTRF or UFP for days 1-7, and then subsequently crossed over to the alternate arm on days 8-14. In order to determine the weight-independent effects of this intervention, food was provided to meet participants’ calculated caloric needs for weight maintenance. To assess glycemia, continuous glucose monitoring was utilized throughout the study period and OGTTs were performed at baseline, crossover point (day 7), and at the end of the study (day 14). Subjects’ weights were stable across the study duration. Compared to the control (UFP), eTRF resulted in decreased mean amplitude of glycemic excursion (MAGE) of 2.5 mmol/L ± 0.2 vs 2.9 mmol/L ± 0.3 (p&amp;lt;0.05) and decreased time above range of 3.1 % ± 1.3 vs 6.7 % ± 1.7 (p= 0.02). Time in range was similar between the two groups (eTRF 75.4 % ± 4.7 vs UFP 74.9 % ± 4.8 (p=0.88)). There was no significant difference in AUC of OGTT between the study groups (eTRF 16391 ± 1595 vs UFP 1586 ± 1586). In conclusion, our study findings suggest that eTRF can improve glycemic variation and decrease time above range in a weight independent manner. Ongoing studies will elucidate the signaling and metabolomic implications of the observed glycemic improvement. Presentation: Thursday, June 15, 2023

Weight-independent effects of Roux-en-Y gastric bypass surgery on remission of nonalcoholic fatty liver disease in mice.

Obesity is a driver of non-alcoholic fatty liver disease (NAFLD), and interventions that decrease body weight, such as bariatric surgery and/or calorie restriction (CR), may serve as effective therapies. This study compared the effects of Roux-en-Y gastric bypass surgery (RYGB) and CR on hepatic function in mice with obesity and NAFLD. C57BL/6J mice were fed a high-fat diet to promote obesity. At 16 weeks of age, mice were randomized to sham surgery (sham), RYGB, or CR weight matched to RYGB (WM). Body weight/composition, food intake, and energy expenditure (EE) were measured throughout treatment. Liver histopathology was evaluated from H&E-stained sections. Hepatic enzymes and glycogen content were determined by ELISA. Transcriptional signatures were revealed via RNA sequencing. RYGB reduced hepatic lipid content and adiposity while increasing EE and lean body mass relative to WM. Hepatic glycogen and bile acid content were increased after RYGB relative to sham and WM. RYGB activated enterohepatic signaling and genes regulating hepatic lipid homeostasis. RYGB improved whole-body composition and hepatic lipid homeostasis to a greater extent than CR in mice. RYGB was associated with discrete remodeling of the hepatic transcriptome, suggesting that surgery may be mechanistically additive to CR.

114-LB: Early Time-Restricted Feeding Reduces Time in Elevated Glucose Range in Adults With Prediabetes

Objective: Early time-restricted feeding (eTRF) is an intermittent fasting strategy restricting caloric intake to the first 6-8 hours of the day. While previous studies have shown that eTRF improves glycemia, it is unclear if the effect is due to associated weight loss or metabolic benefits of the feeding strategy itself. In this study, we evaluated the weight-independent effects of eTRF on glycemia using multiple CGM-based time in range (TIR) metrics. Methods: We conducted a randomized 7-day isocaloric crossover supervised feeding study comparing eTRF (80% of calories consumed between 8am-1pm) to a usual feeding pattern (UFP, 50% of calories consumed after 4pm) among participants with prediabetes and BMI &amp;gt; 28 kg/m2 in a metabolic ward. Participants were randomized 1:1 to eTRF or UFP for days 1-7, then crossed over to the other arm on days 8-14. Food intake was tailored to meet weight stable caloric needs. Participants also wore blinded Abbott Freestyle Libre CGMs throughout the study period. We evaluated time spent below 70 mg/dL (TBR&amp;lt;70), in 70-140 mg/dL (TIR70-140), and in 140-180 mg/dL (TIR140-180) glucose range per arm. Further, we compared TIR140-180 between arms stratified by time of day: Daytime and Overnight (6am-12am and 12am-6am CGM readings, respectively) using linear mixed effect regression adjusting for type and order of intervention. Results: We analyzed data from 10 participants (age 58 (10) years, 50% female, 80% Black, BMI: 37.3 (5.4) kg/m2, HbA1c: 5.8 (0.1)%). Weight change over the study period was not significant (p=0.08). Compared to UFP, eTRF was associated with a decrease in TIR140-180 overall (3.3%, p=0.01) and during Daytime (4.3%, p=0.02) but not Overnight (0.4%, p=0.73). We observed no significant differences in TBR&amp;lt;70 (p=0.28) and TIR70-140 (p=0.88) between arms. Conclusion: eTRF may improve glucose control in adults with prediabetes and high BMI by reducing daytime excursions into the elevated 140-180 mg/dL range. Disclosure S. Barua: None. J. Bruno: None. S. Nasserifar: None. S. M. Vanegas: None. C. Popp: None. J. M. Walker: None. J. O. Aleman: Advisory Panel; Intellihealth, Consultant; Novo Nordisk, Employee; Veterans Administration, Research Support; NIH - National Institutes of Health, Veterans Administration. Funding Shapiro-Silverberg Foundation; The Rockefeller University; Doris Duke Charitable Foundation; American Heart Association (17-SFRN33490004); National Institutes of Health (K08DK117064); National Heart, Lung, and Blood Institute (5T32HL098129-12)

774-P: Weight-Independent Effects of CT-868, a Signaling Biased Dual GLP-1/GIP Receptor Modulator, on Glucose Homeostasis in Overweight and Obese Adults with Type 2 Diabetes

GLP-1 and GIP can deliver complementary pharmacology when combined. CT-868 (CT) is a biased dual GLP-1 and GIP receptor modulator that exhibits no arrestin coupling or receptor internalization at either receptor. Its effects on insulin (INS) secretion via graded glucose infusion (GGI), glucose (GLUC) homeostasis in response to a mixed meal tolerance test (MMTT), gastric emptying (GE), and food intake (FI) were investigated in a randomized, double-blind crossover study in 20 overweight and obese adults with T2D split into 2 groups: CT vs placebo (PL), n=7 and CT vs PL vs liraglutide (LI), n = 13, the latter as a fixed 3rd period. Mean age and BMI were 52.2 years and 32.7 kg/m2 with 55% males. Treatments were administered for 4 days to minimize weight loss with 14 days washout between periods. GGI data showed robust INS secretion for CT-868 vs PL [change in ISR/GLUC at GIRmax (pmol/kg/min): CT 1.1 (0.1), PL 0.1 (0.2), LI 1.0 (0.3)]. MMTT based GLUC iAUC0-240 was significantly reduced for CT vs PL [72(46) vs 392(48)mmol/L*min] and numerically lower vs. LI [187(55) mmol/L*min] accompanied by significantly decreased INS iAUC0-240 vs both PL and LI: CT 1178(846), PL 5833(873), LI 4613(1253) mU/L*min. As both CT and LI had similar delayed GE vs PL, the reduced GLUC and INS excursion seen with CT suggests improved INS sensitivity or enhanced INS independent GLUC disposal. CT demonstrated minimal suppression of glucagon during MMTT vs LI that showed glucagon lowering. FI was lower for CT vs PL accompanied by reduction in hunger and appetite as assessed by VAS. There were no significant body weight changes in any treatment period. GI side effects were mostly mild and transient. This data supports a robust weight-independent effect of CT-868 (vs unbiased liraglutide) on glucose disposal with minimal suppression of glucagon. Further delineation of CT-868's longer term effects in overweight and obese patients with both T2D and T1D is underway. Disclosure M.Chakravarthy: Employee; Carmot Therapeutics, Inc. M.Hernandez: None. M.Elliott: Employee; Carmot Therapeutics, Inc. A.Macias: None. S.K.Hansen: Board Member; Carmot Therapeutics, Inc. M.Hompesch: Board Member; ProSciento, Consultant; Wiley-Blackwell, Employee; ProSciento, Stock/Shareholder; ProSciento.

Weight versus weight-independent effects of Roux-en-Y gastric bypass on type 2 diabetes.

Weight versus weight-independent effects of Roux-en-Y gastric bypass on type 2 diabetes.

Gastric bypass alters diurnal feeding behavior and reprograms the hepatic clock to regulate endogenous glucose flux.

The molecular clock machinery regulates several homeostatic rhythms, including glucose metabolism. We previously demonstrated that Roux-en-Y gastric bypass (RYGB) has a weight-independent effect on glucose homeostasis and transiently reduces food intake. In this study we investigate the effects of RYGB on diurnal eating behavior as well as on the molecular clock and this clock's requirement for the metabolic effects of this bariatric procedure in obese mice. We find that RYGB reversed the high-fat diet-induced disruption in diurnal eating pattern during the early postsurgery phase of food reduction. Dark-cycle pair-feeding experiments improved glucose tolerance to the level of bypass-operated animals during the physiologic fasting phase (Zeitgeber time 2, ZT2) but not the feeding phase (ZT14). Using a clock gene reporter mouse model (mPer2Luc), we reveal that RYGB induced a liver-specific phase shift in peripheral clock oscillation with no changes to the central clock activity within the suprachiasmatic nucleus. In addition, we show that weight loss effects were attenuated in obese ClockΔ19 mutant mice after RYGB that also failed to improve glucose metabolism after surgery, specifically hepatic glucose production. We conclude that RYGB reprograms the peripheral clock within the liver early after surgery to alter diurnal eating behavior and regulate hepatic glucose flux.

Weight-dependent and weight-independent effects of dulaglutide on blood pressure in patients with type 2 diabetes

BackgroundPatients with type 2 diabetes (T2D) treated with glucagon-like peptide-1 receptor agonists may experience reductions in weight and blood pressure. The primary objective of the current study was to determine the weight-dependent and weight-independent effects of ~ 6 months treatment with dulaglutide 1.5 mg treatment in participants with T2D.MethodsMediation analysis was conducted for five randomized, placebo-controlled trials of dulaglutide 1.5 mg to estimate the weight-dependent (i.e., mediated by weight) and weight-independent effects from dulaglutide vs. placebo on change from baseline for systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure. A random-effects meta-analysis combined these results. To investigate a dose response between dulaglutide 4.5 mg and placebo, mediation analysis was first conducted in AWARD-11 to estimate the weight-dependent and weight-independent effects of dulaglutide 4.5 mg vs. 1.5 mg, followed by an indirect comparison with the mediation result for dulaglutide 1.5 mg vs. placebo.ResultsBaseline characteristics were largely similar across the trials. In the mediation meta-analysis of placebo-controlled trials, the total treatment effect of dulaglutide 1.5 mg after placebo-adjustment on SBP was − 2.6 mmHg (95% CI − 3.8, − 1.5; p < 0.001) and was attributed to both a weight-dependent effect (− 0.9 mmHg; 95% CI: − 1.4, − 0.5; p < 0.001) and a weight-independent effect (− 1.5 mmHg; 95% CI: − 2.6, − 0.3; p = 0.01), accounting for 36% and 64% of the total effect, respectively. For pulse pressure, the total treatment effect of dulaglutide (− 2.5 mmHg; 95% CI: − 3.5, − 1.5; p < 0.001) was 14% weight-dependent and 86% weight-independent. For DBP there was limited impact of dulaglutide treatment, with only a small weight-mediated effect. Dulaglutide 4.5 mg demonstrated an effect on reduction in SBP and pulse pressure beyond that of dulaglutide 1.5 mg which was primarily weight mediated.ConclusionsDulaglutide 1.5 mg reduced SBP and pulse pressure in people with T2D across the placebo-controlled trials in the AWARD program. While up to one third of the effect of dulaglutide 1.5 mg on SBP and pulse pressure was due to weight reduction, the majority was independent of weight. A greater understanding of the pleotropic effects of GLP-1 RA that contribute to reduction in blood pressure could support developing future approaches for treating hypertension.Trial registrations (clinicaltrials.gov) NCT01064687, NCT00734474, NCT01769378, NCT02597049, NCT01149421, NCT03495102

237-LB: Weight-Independent Effects of Roux-en-Y Gastric Bypass Surgery on Remission of Nonalcoholic Fatty Liver Disease in Mice

Introduction: Obesity is the primary determinant of nonalcoholic fatty liver disease (NAFLD) . Interventions that decrease body weight, such as bariatric surgery and/or calorie restriction (CR) , may serve as effective therapies for NAFLD. The purpose of this study was to compare the effects of Roux-en-Y gastric bypass surgery (RYGB) to CR on hepatic function in mice with obesity and NAFLD. Methods: 6-week-old male C57BL/6J mice were fed a two-choice chow/high-fat diet (HFD) to promote diet-induced obesity. At 16 weeks of age, mice were randomized to (1) sham surgery (Sham) , (2) RYGB, or (3) sham + weight-matched calorie restriction to RYGB (WM) . Mice were euthanized at 36 weeks for determination of NAFLD/NASH and hepatic function. Body weight/composition and food intake were measured weekly during the treatment period. ANCOVA-adjusted energy expenditure (EE) was determined 3 and 17 weeks after treatment. Hepatic lipid content and NAFLD scores were determined from H&amp;E-stained tissue sections. Hepatic enzymes and glycogen content were determined by ELISA. Results: RYGB &amp; WM achieved a similar reduction in body weight relative to baseline. RYGB decreased adiposity to a greater extent than WM relative to baseline and Sham (-4.4±0.6 vs. -1.3±0.6 Δg, P&amp;lt;0.001) . Decreased body weight was attributable to lower food intake in WM compared to RYGB and Sham (P&amp;lt;0.0001) . WM decreased EE relative to RYGB and Sham (WM:8.6±0.4 vs. RYGB:10.4±0.4 vs. Sham:10.5±0.6 kcals/day, P&amp;lt;0.001) . RYGB decreased hepatic lipid content to a greater extent than WM (92.6 vs. 76.5 % reduction, P=0.02) . RYGB and WM similarly decreased AST and ALT activity relative to Sham. RYGB increased hepatic glycogen relative to both Sham and WM (P&amp;lt;0.001) . Conclusions: RYGB and WM improve hepatic function and decrease the severity of NAFLD through shared and discrete mechanisms of action. RYGB decreases hepatic lipid content to a greater extent than WM independent of food intake, indicating that evading the expected metabolic adaptation in EE after weight loss likely accounts for the additive hepatic benefit of RYGB. Disclosure C. L. Axelrod: None. I. M. Langohr: None. W. S. Dantas: None. R. Townsend: None. V. L. Albaugh: None. J. P. Kirwan: None. H. Berthoud: None. Funding National Institutes of Health (U54GM104940)

Peptide-YY3-36/glucagon-like peptide-1 combination treatment of obese diabetic mice improves insulin sensitivity associated with recovered pancreatic β-cell function and synergistic activation of discrete hypothalamic and brainstem neuronal circuitries

ObjectiveObesity-linked type 2 diabetes (T2D) is a worldwide health concern and many novel approaches are being considered for its treatment and subsequent prevention of serious comorbidities. Co-administration of glucagon like peptide 1 (GLP-1) and peptide YY3-36 (PYY3-36) renders a synergistic decrease in energy intake in obese men. However, mechanistic details of the synergy between these peptide agonists and their effects on metabolic homeostasis remain relatively scarce. MethodsIn this study, we utilized long-acting analogues of GLP-1 and PYY3-36 (via Fc-peptide conjugation) to better characterize the synergistic pharmacological benefits of their co-administration on body weight and glycaemic regulation in obese and diabetic mouse models. Hyperinsulinemic-euglycemic clamps were used to measure weight-independent effects of Fc-PYY3-36 + Fc-GLP-1 on insulin action. Fluorescent light sheet microscopy analysis of whole brain was performed to assess activation of brain regions. ResultsCo-administration of long-acting Fc-IgG/peptide conjugates of Fc-GLP-1 and Fc-PYY3-36 (specific for PYY receptor-2 (Y2R)) resulted in profound weight loss, restored glucose homeostasis, and recovered endogenous β-cell function in two mouse models of obese T2D. Hyperinsulinemic-euglycemic clamps in C57BLKS/J db/db and diet-induced obese Y2R-deficient (Y2RKO) mice indicated Y2R is required for a weight-independent improvement in peripheral insulin sensitivity and enhanced hepatic glycogenesis. Brain cFos staining demonstrated distinct temporal activation of regions of the hypothalamus and hindbrain following Fc-PYY3-36 + Fc-GLP-1R agonist administration. ConclusionsThese results reveal a therapeutic approach for obesity/T2D that improved insulin sensitivity and restored endogenous β-cell function. These data also highlight the potential association between the gut–brain axis in control of metabolic homeostasis.

125-LB: Differential Influences of Gastric Bypass and Sleeve Gastrectomy on Glucose-Reducing Effects of DPP-4 Inhibitor

The two most commonly performed bariatric surgical procedures, gastric bypass (GB) and sleeve gastrectomy (SG), induce diabetes remission before any significant weight loss. While the role of entero-insular axis after SG remains unknown, weight-independent glycemic effects of GB have been attributed to larger systemic appearance of glucose and incretin effect. We examined the effect of increasing endogenous incretins 2-3 fold with a DPP-4 inhibitor on glycemic effects of GB and SG. Glucose and islet-cell secretory responses were measured in 4 subjects with a history of GB, 4 with SG and 4 non-surgical controls (CN) during 50-gram oral glucose ingestion with and without 200 mg sitagliptin orally on two separate days. GB, SG, and CN groups were matched for BMI, FFM, HbA1c, age, fasting glucose and insulin levels; GB and SG were matched for weight loss and time postsurgery; none had diabetes. Compared to SG-treated subjects and controls, subjects with prior GB had lower prandial glycemia (AUCGlucose 3hr) (P &amp;lt; 0.001), and higher AUCGlucagon 3hr (P &amp;lt; 0.0001). The expected differences in prandial insulin response pattern to glucose ingestion among surgical and controls was observed; however, AUCInsulin 3hr and AUCC-peptide 3hr were similar between groups. Sitagliptin did not change AUCGlucose 3hr in GB-treated subjects, whereas the prandial glucose response was reduced by 21 ± 13 % in SG-treated and non-surgical controls by sitagliptin. Enhanced endogenous incretins diminished early glucagon (AUCGlucagon 1hr) in all 3 groups (P &amp;lt; 0.05), improved β-cell glucose sensitivity in CN (P &amp;lt; 0.05), but it had no effect on beta-cell function in GB or SG subjects. Sitagliptin had no effect on insulin clearance or insulin sensitivity in fasting or fed states. These findings indicate that glucose metabolism after SG, similar to non-operated controls, is enhanced by incretins, which are at maximum in GB group and thus not influenced by DPP-4 inhibition. Disclosure H. Honka: None. M. S. Rayas: Research Support; Self; National Center for Advancing Translational Sciences. R. A. Defronzo: Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk. A. Gastaldelli: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Consultant; Self; Eli Lilly and Company, Inventiva Pharma, Research Support; Self; Gilead Sciences, Inc., Speaker’s Bureau; Self; Novo Nordisk. M. Salehi: None. Funding National Institutes of Health (TR002646); National Institute of Diabetes and Digestive and Kidney Diseases (DK105379)

Restricting carbohydrates and calories in the treatment of type 2 diabetes: a systematic review of the effectiveness of 'low-carbohydrate' interventions with differing energy levels.

Abstract There are two proven dietary approaches to shift type 2 diabetes (T2D) into remission: low-energy diets (LEDs) and low-carbohydrate diets (LCDs). These approaches differ in their rationale and application yet both involve carbohydrate restriction, either as an explicit goal or as a consequence of reducing overall energy intake. The aims of this systematic review were to identify, characterise and compare existing clinical trials that utilised ‘low-carbohydrate’ interventions with differing energy intakes. Electronic databases CENTRAL, CINAHL, Embase, MEDLINE and Scopus were searched to identify controlled clinical trials in adults with T2D involving low-carbohydrate intake (defined as &lt;130 g carbohydrate/d) and reporting weight and glycaemic outcomes. The initial database search yielded 809 results, of which fifteen studies met the inclusion criteria. Nine out of fifteen studies utilised LCDs with moderate or unrestricted energy intake. Six trials utilised LEDs (&lt;1200 kcal/d), with all except one incorporating meal replacements as part of a commercial weight loss programme. Interventions using both restricted and unrestricted (ad libitum) energy intakes produced clinically significant weight loss and reduction in glycated haemoglobin (HbA1c) at study endpoints. Trials that restricted energy intake were not superior to those that allowed ad libitum low-carbohydrate feeding at 12 and 24 months. An association was observed across studies between average weight loss and reduction in HbA1c at 6, 12 and 24 months, indicating that sustained weight loss is key to T2D remission. Further research is needed to specifically ascertain the weight-independent effects of carbohydrate restriction on glycaemic control in T2D.

Comparing Diabetes Outcomes: Weight-independent Effects of Sleeve Gastrectomy Versus Matched Patients With Similar Weight Loss.

To determine if sleeve gastrectomy has weight-independent benefits on diabetes outcomes. Weight loss is recommended when treating conditions such as diabetes, hypertension, and hyperlipidemia. Bariatric surgery has been shown to improve or resolve metabolic conditions, but weight loss outcomes vary by procedure type. Using data from a statewide bariatric surgery registry, a total of 988 patients with a preoperative diagnosis of diabetes who underwent either laparoscopic sleeve gastrectomy (LSG) or laparoscopic adjustable gastric banding (LAGB) were included in the study. The patients were matched based on age, race, sex, preoperative body mass index (BMi) and weight loss at 1 year after surgery. Chi-square comparisons were conducted for medication discontinuation for diabetes. Secondary outcome measures included discontinuation of medications for hypertension and hyperlipidemia. The mean age of patients was 53.9 years, 75.5% were female, 89.3% were White. Mean preoperative BMi was 44.8 kg/m2 and 75.7% had noninsulin dependent diabetes, whereas 24.3% had insulin dependent diabetes. Mean % BMi loss at 1 year is similar between the 2 groups (8.3% vs 8.1%, P = 0.3811). LSG patients had significantly higher rates of discontinuation of oral diabetes medication (70.4% vs 46.0%, P < 0.0001), insulin (51.7% vs 38.3%, P = 0.0341), anti-hypertensive (41.1% vs 26.0%, P < 0.0001), and cholesterol-lowering medications (40.1% vs 27.8%, P = 0.0016) when compared to LAGB patients. Despite similar preoperative characteristics and postoperative weight loss, LSG patients experienced significantly higher rates of medication discontinuation for diabetes, hypertension, and hyperlipidemia than LAGB. These results suggest that LSG may have weight-independent effects on metabolic disease and should be considered in the treatment of diabetes, regardless of perceived weight loss outcomes.

SAT-110 Long-Term Impact of Gastric Bypass versus Sleeve Gastrectomy on Nonalcoholic Fatty Liver Disease: Retrospective Observations from Michigan Bariatric Surgery Cohort

Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in obese patients. Bariatric surgery is highly effective for treatment of NAFLD. We have previously reported 4 and 5-year weight loss outcomes in patients who underwent bariatric surgery at Michigan Medicine from 2008 to 2013. The aim of this study was to assess the impact of weight loss surgery on persistence of NAFLD up to 5 years post-surgery. Retrospective data on weight, blood pressure, lipid panel, A1c, liver enzymes, NAFLD Fibrosis scores (NFS) and imaging were analyzed with respect to the type of surgery [sleeve gastrectomy (SG) or Roux-en Y gastric bypass (GB)] at baseline and yearly for 5 years. Patients were assessed for presence of underlying NAFLD based on liver biopsy, imaging, or clinical diagnosis (ICD-9 or 10 codes) prior to surgery. Persistent NAFLD was assessed based on presence of hepatic steatosis on abdominal imaging (ultrasound, CT or MRI) over follow-up. Follow up data were available on 221 patients with NAFLD at baseline (GB =128, SG=93); median age 47 years (IQR 40-54) with 73% females and a median BMI of 46.2 kg/m2 (IQR 41.2-52.4). Median BMI was higher in the SG group versus GB owing to the criteria for approval in 2008-2012 (48.1 kg/m2 vs. 45.3 kg/m2, p=0.01). Median NFS was higher in SG vs GB (0.04 vs -0.50, p =0.01). Only 38 patients (17.2%) had a liver biopsy, among which 25 (65.8%) showed non-alcoholic steatohepaitis (NASH) and 3 (7.9%) demonstrated cirrhosis. Both groups had a reduction in NFS over follow up with median NFS significantly lower at all-time points in the GB group, p<0.01); improvement in NFS was more pronounced in the GB group at year 1, p=0.03. Overall, 83 patients (37.5%) had follow-up abdominal imaging with 28 (33.7%) having evidence of persistent NAFLD; 28.7% at 1-2 years, 16.3% at 2-4 years, and 55% at >4 years post-surgery. The nadir of BMI occurred at 1 year (median 31.3 and 37.2, in BG versus SG, respectively), with a peak at year 4 for GB (median 35.6) and year 5 for SG (median 40.4). At all-time points, the median weight loss was highest in the GB group. All metabolic parameters remained improved compared to baseline. The following differences were noted in the GB group versus SG group: LDL was significantly lower at year 1, 2 and 5; cholesterol significantly lower at year 1 and 2; significantly larger reduction in hemoglobin A1c at year 2, 4 and 5; and reduction in TG significantly higher at year 1. In a multivariable model integrating type of surgery, baseline diabetes and baseline hyperlipidemia, baseline hyperlipidemia was independently associated with persistent NAFLD (OR: 3.2, 95% CI 1.04-10.10, p=0.04). Change in weight was not predictive of persistent NAFLD. In conclusion, these observations suggest that bariatric surgery may have a weight-independent effect on NAFLD. Further studies are needed to examine the effect of disease severity and co-morbidities on NAFLD resolution after bariatric surgery.

MON-112 Gelesis100 Reduces Insulin Resistance in Patients Who Are Overweight or Have Obesity with High Insulin Resistance: Results of the GLOW Study

Background: Overweight and obesity are predisposing conditions for the development of prediabetes and type 2 diabetes. Insulin resistance caused by excess adiposity is a key factor in this process. Methods: The effect of Gelesis100, a novel hydrogel, was assessed in patients who were overweight or had obesity, without antidiabetic medications, and who completed the Gelesis Loss Of Weight (GLOW; NCT02307279) study. GLOW was a multicenter, double-blind, placebo-controlled pivotal study with patients randomized to 2.25 g of Gelesis100 or placebo in capsules taken with 500 mL of water before lunch and dinner while on a hypocaloric diet (-300 kcal/day) for 24 weeks. Insulin resistance was measured by homeostasis model assessment-insulin resistance (HOMA-IR). Data were analyzed using analysis of covariance and Logit models comparing Gelesis100 to placebo arms in 2 subgroups of patients based on baseline HOMA-IR (subgroup 1, HOMA-IR ≥ 3.0, subgroup 2, HOMA-IR < 3.0). Results: The overall population included 290 patients (132 males, 158 females, 91 in subgroup 1, 199 in subgroup 2, 155 on Gelesis100, 135 on placebo), who were normoglycemic, had prediabetes, or had untreated type 2 diabetes. Statistically significant difference in reduction of HOMA-IR was observed in subgroup 1 (mean baseline HOMA-IR = 5.0) but not in subgroup 2 (mean baseline HOMA-IR = 1.8). Indeed, placebo-subtracted HOMA-IR changes (mean, SE) were -22.3 ± 9.5% (P = 0.0212) and -9.0 ± 9.5% (P = 0.3432) in subgroup 1 and subgroup 2, respectively. Furthermore, in subgroup 1, patients who lost < 5% body weight (n = 44, mean body weight loss = 1.3%) had a statistically significant placebo-subtracted HOMA-IR change of -27.6 ± 13.2% (P = 0.0435), while patients who lost ≥ 5% body weight (n = 47, mean body weight loss = 9.7%) had no statistically significant placebo-subtracted HOMA-IR change (-15.6 ± 13.6%, P = 0.2584). The effect on HOMA-IR decrease was driven by significant reduction in fasting serum insulin. Safety and tolerability of Gelesis100 demonstrated no increased risk compared to placebo. Conclusion: Treatment with Gelesis100 results in a significantly higher reduction in insulin resistance compared to placebo as assessed by HOMA-IR in patients who are overweight or have obesity with elevated baseline HOMA-IR. The results also suggest a potential weight-independent effect of Gelesis100 in the reduction of insulin resistance. If these findings are confirmed in future studies with larger subgroups, Gelesis100 could become a potential new treatment for insulin-resistant clinical conditions associated with overweight and obesity.

Metabolic surgery for the treatment of type 2 diabetes in patients with BMI lower than 35kg/m2 : Why caution is still needed.

Bariatric surgery has shifted from being a risky procedure to an evidence-based one, with proven benefits on all-cause mortality, cardiovascular disease, cancer, and diabetes control. The procedure has an overall positive result on type 2 diabetes mellitus (T2DM), with a substantial number of patients achieving disease remission. This has resulted in several studies assessing possible weight-independent effects of bariatric surgery on glycemic improvement, in addition to recommendation of the procedure to patients with class 1 obesity and T2DM, for whom the procedure was classically not indicated, and adoption of a new term, "metabolic surgery," to highlight the overall metabolic benefit of the procedure beyond weight loss. Recently, the Diabetes Surgery Summit (DSS) has included metabolic surgery in its T2DM treatment algorithm. Although the discussion brought by this consensus is highly relevant, the recommendation of metabolic surgery for patients with uncontrolled T2DM and a body mass index of 30 to 35kg/m2 still lacks enough evidence. This article provides an overall view of the metabolic benefits of bariatric/metabolic surgery in patients with class 1 obesity, compares the procedure against clinical treatment, and presents our rationale for defending caution on recommending the procedure to less obese individuals.

Lorcaserin and metabolic disease: weight-loss dependent and independent effects.

SummaryObjectiveWeight management pharmacotherapies can improve metabolic diseases through weight‐dependent and weight‐independent effects. Lorcaserin is a selective 5‐hydroxytryptamine 2C receptor agonist. The objective of this analysis is to quantify the relative contribution of weight loss to the treatment effects of lorcaserin 10 mg twice a day on key metabolic parameters.MethodsThis retrospective analysis evaluated 6,897 patients with overweight or obesity (with or without diabetes mellitus) across three randomized, placebo‐controlled, double‐blind, 52‐week clinical trials that evaluated lorcaserin 10 mg twice daily (BID; NCT00395135, NCT00603902, and NCT00603291); 509 patients from only one of the studies had type 2 diabetes mellitus. A mediation analysis was applied to help rank the relative contribution of weight loss to metabolic study outcomes.ResultsAccording to this mediation analysis, lorcaserin 10 mg BID improved a spectrum of adiposopathic metabolic abnormalities with varying contributions attributable to weight loss. Improvements in waist circumference and blood pressure were almost exclusively attributable to weight loss. Less than 50% of the improvement in glucose parameters (fasting blood glucose and haemoglobin A1c) were attributable to weight loss.ConclusionsAcross Phase III clinical trials, lorcaserin 10 mg BID improved multiple cardiometabolic parameters through both weight‐loss dependent and independent mechanisms.

Bile acid profiles within the enterohepatic circulation in a diabetic rat model after bariatric surgeries.

Bile acids (BAs), which are synthesized in the liver and cycled in the enterohepatic circulation, have been recognized as signaling molecules by activating their receptors in the intestine and liver. Serum taurine-conjugated BAs have been shown to be elevated after bariatric surgeries although the postoperative BA profiles within the enterohepatic circulation have not been investigated. Clarification of these profiles could help explain the mechanisms by which bariatric surgery leads to BA profile alterations and subsequent metabolic effects. We performed duodenal-jejunal bypass (DJB), sleeve gastrectomy (SG), and sham procedures in an obese diabetic rat model induced by high-fat diet and streptozotocin. The weight loss and antidiabetic effects were evaluated postsurgery. BA profiles in the systemic serum and within the enterohepatic circulation were analyzed, together with the expression of related BA transporters and enzymes at week 12 after surgery. Compared with sham, SG induced sustained weight loss, and both DJB and SG significantly improved glucose tolerance and insulin sensitivity with enhanced glucagon-like peptide 1 secretion. Similar to changes in the serum, BAs, especially taurine-conjugated species, were also elevated in the enterohepatic circulation (bile and portal vein) after DJB and SG. In addition, the expression of key BA transporters and conjugational enzymes was elevated postoperatively, whereas the enzymes responsible for BA synthesis were decreased. In conclusion, DJB and SG elevated BA levels in the systemic serum and enterohepatic circulation, especially taurine-conjugated species, which likely indicates increased ileal reabsorption and hepatic conjugation rather than synthesis. NEW & NOTEWORTHY Bile acids (BAs) have been implicated as potential mediators of the weight-independent effects of bariatric surgery. For the first time, we discovered that duodenal-jejunal bypass and sleeve gastrectomy elevated BAs, particularly the taurine-conjugated species in the enterohepatic circulation, likely through the promotion of ileal reabsorption and hepatic conjugation rather than BA synthesis. These findings will improve our understanding of BA metabolism after bariatric surgery and their subsequent metabolic effects.

Glycemic Control after Sleeve Gastrectomy and Roux-En-Y Gastric Bypass in Obese Subjects with Type 2 Diabetes Mellitus

BackgroundRoux-en-Y gastric bypass (LRYGB) has weight-independent effects on glycemia in obese type 2 diabetic patients, whereas sleeve gastrectomy (LSG) is less well characterized. This study aims to compare early weight-independent and later weight-dependent glycemic effects of LRYGB and LSG.MethodsEighteen LRYGB and 15 LSG patients were included in the study. Glucose, insulin, GLP-1, and GIP levels were monitored during a modified 30 g oral glucose tolerance test before surgery and 2 days, 3 weeks, and 12 months after surgery. Patients self-monitored glucose levels 2 weeks before and after surgery.ResultsPostoperative fasting blood glucose decreased similarly in both groups (LRYGB vs. SG; baseline—8.1 ± 0.6 vs. 8.2 ± 0.4 mmol/l, 2 days—7.8 ± 0.5 vs. 7.4 ± 0.3 mmol/l, 3 weeks—6.6 ± 0.4 vs. 6.6 ± 0.3 mmol/l, respectively, P < 0.01 vs. baseline for both groups; 12 months—6.6 ± 0.4 vs. 5.9 ± 0.4, respectively, P < 0.05 for LRYGB and P < 0.001 for LSG vs. baseline, P = ns between the groups at all times). LSG, but not LRYGB, showed increased peak insulin levels 2 days postoperatively (mean ± SEM; LSG + 58 ± 14%, P < 0.01; LRYGB − 8 ± 17%, P = ns). GLP-1 levels increased similarly at 2 days, but were higher in LRYGB at 3 weeks (AUC; 7525 ± 1258 vs. 4779 ± 712 pmol × min, respectively, P < 0.05). GIP levels did not differ. Body mass index (BMI) decreased more after LRYGB than LSG (− 10.1 ± 0.9 vs. − 7.9 ± 0.5 kg/m2, respectively, P < 0.05).ConclusionLRYGB and LSG show very similar effects on glycemic control, despite lower GLP-1 levels and inferior BMI decrease after LSG.

A randomized study of dietary composition during weight-loss maintenance: Rationale, study design, intervention, and assessment

BackgroundWhile many people with overweight or obesity can lose weight temporarily, most have difficulty maintaining weight loss over the long term. Studies of dietary composition typically focus on weight loss, rather than weight-loss maintenance, and rely on nutrition education and dietary counseling, rather than controlled feeding protocols. Variation in initial weight loss and insufficient differentiation among treatments confound interpretation of results and compromise conclusions regarding the weight-independent effects of dietary composition. The aim of the present study was to evaluate three test diets differing in carbohydrate-to-fat ratio during weight-loss maintenance. Design and dietary interventionsFollowing weight loss corresponding to 12±2% of baseline body weight on a standard run-in diet, 164 participants aged 18 to 65years were randomly assigned to one of three test diets for weight-loss maintenance through 20weeks (test phase). We fed them high-carbohydrate (60% of energy from carbohydrate, 20% fat), moderate-carbohydrate (40% carbohydrate, 40% fat), and low-carbohydrate (20% carbohydrate, 60% fat) diets, controlled for protein content (20% of energy). During a 2-week ad libitum feeding phase following the test phase, we assessed the effect of the test diets on body weight. OutcomesThe primary outcome was total energy expenditure, assessed by doubly-labeled water methodology. Secondary outcomes included resting energy expenditure and physical activity, chronic disease risk factors, and variables to inform an understanding of physiological mechanisms by which dietary carbohydrate-to-fat ratio might influence metabolism. Weight change during the ad libitum feeding phase was conceptualized as a proxy measure of hunger.