Total GLP-1 Research Articles

Efficacy of Lisosan G (fermented wheat) on reactive hypoglycemia after bariatric surgery

Introductionpost-bariatric hypoglycemia (PBH) is considered a chronic complication after gastric bypass (RYGB) impacting roughly 30 % of patients. Current treatments often focus on nutritional interventions to reduce the frequency of episodes. This prospective study evaluated the effectiveness of Lisosan G (LG), a fermented wheat-based supplement added to the diet, in mitigating PBH episodes and elucidating its mechanism of action on the gut-pancreas axis. Methods:twenty subjects with PBH, who had undergone RYGB between 2015 and 2018, were enrolled. Subjects underwent clinical examination, blood test, and a 3-hour oral glucose load test (OGTT). Then, they were monitored for 2-weeks on a free diet with continuous glucose monitoring (CGM), which was extended for another 2-weeks after introduction of LG supplementation (5 g, twice daily) on the same diet. Finally, subjects repeated OGTT and blood test. PBH was defined as interstitial glucose ≤ 54 mg/dl. Resultsafter treatment, a marked reduction in PBH time was observed (75[23–113] vs 16 [0–33], minutes, p < 0.001). During OGTT, there was an increase in glucose nadir (44 ± 11 vs 56 ± 10, mg/dl, p = 0.038), and a significantly decrease in total GLP-1 AUC (7.6 ± 4.1 vs 6.5 ± 3.8, nmol/L*min, p = 0.043), in potentiation factor ratio (p = 0.037) and in total insulin AUC (57 ± 12 vs 49 ± 9, nmol/L*min, p = 0.043). ConclusionLG effectively reduces PBH frequency and duration, probably by attenuating GLP-1 concentrations and leading to a decrease in the second phase of insulin secretion in response to glucose. These findings underscore the promise of LG as a novel adjunct therapy for PBH, particularly when added to the diet, and emphasize the need for further exploration into its microbiota-modulating and anti-inflammatory effects.

Postprandial glycemic response to a high-protein diabetes-specific nutritional shake compared to isocaloric instant oatmeal in people with type 2 diabetes: a randomized, controlled, crossover trial.

Minimizing postprandial glucose response is an important goal for overall diabetes management. Diabetes-specific nutritional shakes (DSNS) have been clinically shown to minimize postprandial glucose response in people with type 2 diabetes (T2DM) compared to high-glycemic foods. However, it is unknown how a high-protein, low-fat DSNS impacts the GLP-1 response. We tested the postprandial glucose, insulin, and GLP-1 response to a high-protein, low-fat diabetes-specific nutritional shake (DSNS-HP) compared to isocaloric instant oatmeal (IOM) in a randomized, controlled, crossover study in adults with T2DM (n = 24). Participants were randomly selected to receive IOM or DSNS-HP on two test days. Glucose, insulin, and total GLP-1 concentration were measured at baseline and 15, 30, 45, 60, 90, 120, 180, and 240 min postprandially. Compared to IOM, the glucose-positive area under the curve (pAUC) was significantly lower (P = .021). DSNS-HP significantly increased GLP-1 pAUC response by 213% (P <.001) with a corresponding increase in insulin pAUC (P = .033) compared to IOM. A high-protein, low-fat DSNS leads to favorable changes in GLP-1 response and is a suitable option to minimize blood glucose response in people with type 2 diabetes.

Network meta-analysis of the risk of dyspepsia and anorexia in patients with type 2 diabetes mellitus induced by glucagon-like peptide 1 receptor agonist hypoglycemic drugs.

The aim of this study was to investigate and evaluate the risk of dyspepsia and anorexia in patients with type 2 diabetes mellitus (T2DM) induced by glucagon-like peptide 1 receptor agonist (GLP-1 RA) hypoglycemic drugs. We searched papers in PubMed, Web of Science, Cochrane Library, Google Scholar, CNKI, Wanfang, Embase, and VIP databases, and the retrieval time limit was set from the establishment of the database to May 2023. Randomized Controlled Trials (RCTs) were collected in which the subjects were T2DM patients, the intervention was GLP-1RA compared with placebo or traditional hypoglycemic drugs, and the outcome indicators included dyspepsia and anorexia. A meta-analysis and a network meta-analysis were performed. The results of the traditional meta-analysis showed that the risk of dyspepsia and anorexia of total GLP-1 RA was 3.01 and 2.56 times that of placebo, respectively. All types of GLP-1RA were compared with placebo and the results also showed a trend towards increased risk of digestive system adverse events (DSAEs). Among all interventions included, liraglutide was the one with the highest risk of dyspepsia in patients with T2DM, and dulaglutide was the one with the highest risk of anorexia. The results of the two meta-analyses are consistent, and both clearly show that GLP-1RA can increase the risk of dyspepsia and anorexia in T2DM patients.

Adolescents with obesity treated with exenatide maintain endogenous GLP-1, reduce DPP-4, and improve glycemic control.

GLP-1 receptor agonists (GLP-1RA) are increasingly used to treat adolescent obesity. However, the effect on endogenous GLP-1 secretory patterns following treatment in adolescents is unknown. The GLP-1RA exenatide was shown to significantly lower BMI and 2-hour glucose in adolescents with obesity, in the placebo-controlled, randomized controlled trial Combat-JUDO. The aim of this study was to evaluate effects of weekly injections of 2 mg exenatide extended release on secretory patterns of endogenous hormones during OGTT. This study was a pre-planned sub-study of the Combat-JUDO trial, set at the Pediatric clinic at Uppsala University Hospital, Sweden and Paracelsus Medical University, Austria. 44 adolescents with obesity were included and randomized 1:1 to treatment:placebo. 19 patients in the treatment group and 18 in the placebo group completed the trial. Before and after treatment, GLP-1, glucose, insulin, glucagon and glicentin levels were measured during OGTT; DPP-4 and proinsulin were measured at fasting. A per-protocol approach was used in the analyses. Exenatide treatment did not affect GLP-1 levels during OGTT. Treatment significantly lowered DPP-4, proinsulin and the proinsulin-to-insulin ratio at fasting, increased glicentin levels but did not affect insulin, C-peptide or glucagon levels during OGTT. Weekly s.c. injections with 2 mg of exenatide maintains endogenous total GLP-1 levels and lowers circulating DPP-4 levels. This adds an argument in favor of using exenatide in the treatment of pediatric obesity. clinicaltrials.gov, identifier NCT02794402.

1696-P: Changes in Clinical and Metabolic Parameters Related to NAFLD in Obese Subjects Who Underwent Laparoscopic Sleeve Gastrectomy

More research is needed on the effect of laparoscopic sleeve gastrectomy (LSG) on NAFLD and related parameters. A total of 51 morbidly obese subjects with NAFLD who would undergo LSG were included, with liver biopsy performed during LSG in 46 patients. Various clinical parameters and blood biomarkers related to NAFLD were measured before and 6 months after LSG, which included fat content in the liver (LFC) and pancreas (PFC) by MRI-PDFF, liver stiffness measurement by MR elastography (MRE-LSM), and others. After LSG, there was a significant decrease in body weight and LFC: 102.0 ± 15.3 vs. 76.3 ± 14.3 kg and 19.4 ± 9.1% vs. 5.7 ± 2.9%, respectively, p &amp;lt;0.001 each. And, body fat on DXA, PFC, and visceral fat area measured by MRI, and, fasting plasma levels of total GIP and glucagon decreased significantly after bariatric surgery, with no change in total GLP-1 and peptide YY levels. Notably, there was a marked increase in plasma levels of FGF21 (547.1 ± 890.5 pg/ml vs. 1085 pg/ml ± 1883.75, p&amp;lt;0.05) and oxyntomodulin (436.0 ± 351.4 pg/ml vs. 1533.6 ± 624.4 pg/ml, p&amp;lt;0.001). These changes were accompanied by a significant reduction of NASH blood biomarkers such AKR1B10, cytokeratin 18, and complement C3. And, MRE-LSM, a marker of liver fibrosis, decreased significantly after LSG (3.1 ± 0.8 kPa vs. 2.7 ± 0.1 kPa, p &amp;lt;0.01), but enhanced liver fibrosis score did not. Only 15.2% of patients with biopsy-proven NAFLD showed more than 25% decrease in MRE-LSM, and baseline fibrosis degree was only the predictor of this decrease in MRE-LSM after LSG. Our results show that in patients with morbid obesity, marked reduction of body weight and LFC and a significant increase in plasma FGF21 and oxyntomodulin levels were observed 6 months after LSG, with the reduction of several markers of NASH. However, a meaningful MRE-LSM improvement was observed only in a small proportion of patients, which warrants long-term follow-up of patients with NASH/fibrosis who underwent LSG. Disclosure D.Lee: None. I.Park: None. Funding National Research Foundation of Korea (2021R1A5A2030333, 2019R1I1A2A02062305)

IBCOx-12 The Endoscopic Sleeve Gastroplasty Produces Durable Physiologic Changes: Results from a Randomized US Clinical Trial

Abstract Background Obesity is associated with faster gastric emptying and altered appetite. Endoscopic sleeve gastroplasty (ESG) has gained global adaptation, but our understanding of its physiologic mechanism of action and durability is limited. We sought to determine changes in gastric emptying, weight loss, and eating behaviors after ESG when compared to moderate-intensity lifestyle interventions (LS) in the short and long-term. Methods This is an a priori designed sub-study of a large ongoing multicenter US RCT (MERIT trial), where adults with BMI 30-40 kg/m2 were randomized to ESG versus moderate-intensity LS alone. We measured gastric emptying (T1/2) using a 4- hour gastric emptying breath test at baseline, 3 and 12 months into the study. We reported weight loss outcomes as percent total body weight lost (%TBWL). Changes in three eating behaviour domains (Cognitive Restraint [CR], Emotional Eating [EE], Uncontrolled Eating [UE]) were assessed using the Three-Factor Eating Questionnaire (TFEQ) at 6 months. The primary outcome was the change in T1/2 (minutes) at 3 months, and secondary outcomes were changes in T1/2 at 12 months, %TBWL, and eating behaviours. We used the t-test for the analyses. Linear regression was performed to determine the association between gastric emptying and weight loss. Results 46 patients were randomized in the study (ESG n=26; LS n=20). Baseline characteristics were similar between the two groups. Out of n=46, n=43, and n=31 subjects have reached 3 and 12 months, respectively. Three patients dropped out of the study. At 3 months, T1/2 (minutes) was delayed in the ESG group (n=24) compared to the LS group (n=19) (170.8 vs. 87.5; p&amp;lt;0.0001). At 12 months, T1/2 was still delayed in the ESG group (n=17) vs. control group (n=14) (133.4 vs. 87.6; p=0.0005), and delayed compared to baseline. %TBWL in the ESG group was 12.3%, 15.1% and 15.7% at 3, 6 and 12 months (p &amp;lt;0.01 compared to baseline), while it was 2.3%, 2.2% and 0.3% (p&amp;gt;0.05 compared to baseline) in the LS group. Greater delays in gastric emptying at 3 months correlated with weight loss at all time points. (Figure 1) At 6 months, significant improvements in the EE and UE domains were seen in both groups, but for CR, only significant improvements were seen in the ESG group. Percent total fasting ghrelin, GLP-1, and PYY increased at 12 months in the ESG group compared to LS control (51%, 51%, 6.3% vs. -9%, 4%, -10.5%). Only 1 SAE managed endoscopically with full recovery was reported in the ESG group. Conclusions ESG produces sustained physiologic alterations in appetite regulatory pathways and durable weight-loss. This provides further evidence supporting the clinical adoption of the technique as a durable and effective obesity therapy.

Gut microbiota is correlated with gastrointestinal adverse events of metformin in patients with type 2 diabetes.

Gastrointestinal discomfort is the most common adverse event in metformin treatment for type 2 diabetes. The mechanism of action of metformin is associated with gut microbiota. However, the gut microbial community structure related to metformin-induced gastrointestinal adverse events remains unclear. This study aimed to investigate it. 50 patients with newly diagnosed diabetes were treated with metformin 1500mg/d for 12 weeks. The patients were divided into two groups according to whether gastrointestinal adverse events occurred (group B) or did not occur (group A) after treatment. The fecal bacterial communities and short-chain fatty acids (SCFAs) were sequenced and compared. 70 diabetes mice were randomly divided into 8 groups and treated with metformin (Met), clindamycin (Clin) and/or SCFA, which were the Met+/Clin+, Met+/Clin-, Met-/Clin+, Met-/Clin-, Met+/SCFA+, Met+/SCFA-, Met-/SCFA+ and Met-/SCFA- group. After 4 weeks of metformin treatment, blood glucose, food intake, fecal SCFAs, gut microbiota and gut hormones were measured. Metformin increased the abundance of Phascolarctobacterium, Intestinimonas and Clostridium III. Functional prediction analysis showed that the propanoate metabolism pathway was significantly up-regulated. The concentrations of acetic acid and propanoic acid in feces were significantly increased. The abundance of Clostridium sensu stricto, Streptococcus and Akkermansia induced by metformin in group B was higher than that in group A. The propanoate metabolism pathway and propanoic acid in feces were significantly up-regulated in group B. In the animal experiments, the food intake decreased and glucose control increased in metformin groups compared with those in the control groups. The total GLP-1 level in the Met+/Clin- group was significantly higher than that in the Met-/Clin- group, while there was no statistical difference between the Met-/Clin- and Met+/Clin+ group. The total GLP-1 level in the Met-/SCFA+ group was significantly higher than that in the Met-/SCFA-group, while the levels of total GLP-1 and active GLP-1 in the Met+/SCFA- group and the Met+/SCFA+ group were significantly higher than those in the Met-/SCFA-group. Our data suggest that metformin promotes the secretion of intestinal hormones such as GLP-1 by increasing the abundance of SCFA-producing bacteria, which not only plays an anti-diabetic role, but also may causes gastrointestinal adverse events.

A single administration of barley β-glucan and arabinoxylan extracts reduces blood glucose levels at the second meal via intestinal fermentation.

Diet with barley may suppress the glycemic response after consuming the next meal ("second meal effect"). This study aimed to investigate the second meal effect and its mechanism. Mice were given a single dose of β-glucan or arabinoxylan, the primary sources of soluble fiber in barley. A single dose of β-glucan or arabinoxylan extract, followed 6 h later by a 20% glucose solution (second meal), suppressed blood glucose elevation. Arabinoxylan and β-glucan increased the levels of short-chain fatty acids (SCFAs) in the ileum and cecum, respectively. Total GLP-1 secretion in the blood increased with β-glucan and showed an increasing trend with arabinoxylan. These results suggest barley β-glucan and arabinoxylan are fermented in the intestinal tract to generate SCFAs, which may induce GLP-1 secretion and control blood glucose levels during the second meal.

Effect of a GLP-1 mimetic on the insulin response to oral sugar testing in horses

BackgroundInsulin dysregulation (ID) is the most important risk factor for the development of laminitis in horses and therapies to control it are needed.Hypothesis/objectivesTo assess the effects of a single dose of the synthetic GLP-1 analog exenatide on postprandial insulin dynamics. We hypothesized that exenatide would improve insulin sensitivity and lower postprandial blood insulin concentrations.Study designRandomized, crossover, experimental study.AnimalsSix horses (3 mares, 3 geldings; 2 with normal insulin regulation [NIR] and 4 with mild ID).MethodsHorses completed both study arms: subcutaneous administration of exenatide (or no treatment) 30 min before an oral sugar test (0.15 ml/kg of Karo Syrup). Blood samples obtained over 240 min were assayed for glucose, insulin, lactate, c-peptide and total GLP-1. The area under the curve (AUC) was calculated using the trapezoidal rule. Insulin sensitivity (SI) was estimated using a mathematical model.ResultsExenatide resulted in a postprandial decrease of 20% (effect size: 2673 µU·min/ml; 95% CI: 900 – 4446 µU·min/ml; P = 0.003) in AUC of plasma insulin (control; mean AUC insulin: 11,989 µU·min/ml; 95% CI: 9673 – 14,305 µU·min/ml, exenatide; mean AUC insulin: 9316 µU·min/ml; 95% CI: 7430 – 11,202 µU·min/ml). Exenatide resulted in an approximately threefold increase (effect size: 5.56 10–4· µU/ml−1·min−1; 95% CI: 0.95 – 10.1 10–4· µU/ml−1·min−1; P = 0.02) in estimated insulin sensitivity (control mean SI: 1.93 10–4· µU/ml−1·min−1; 95% CI: 0.005 – 3.86 10–4·µU/ml−1·min−1 vs. exenatide mean SI: 7.49 10–4· µU/ml−1·min−1; 95% CI: 3.46 – 11.52 10–4· µU/ml−1·min−1).ConclusionsThe decrease in insulin response to carbohydrates was due to an increase in whole-body insulin sensitivity. GLP-1 agonists may have therapeutic potential for ID in horses.

Association of GLP1R Polymorphisms With the Incretin Response.

Polymorphisms in the gene encoding the glucagon-like peptide-1 receptor (GLP1R) are associated with type 2 diabetes but their effects on incretin levels remain unclear. We evaluated the physiologic and hormonal effects of GLP1R genotypes before and after interventions that influence glucose physiology. Pharmacogenetic study conducted at 3 academic centers in Boston, Massachusetts. A total of 868 antidiabetic drug-naïve participants with type 2 diabetes or at risk for developing diabetes. We analyzed 5 variants within GLP1R (rs761387, rs10305423, rs10305441, rs742762, and rs10305492) and recorded biochemical data during a 5-mg glipizide challenge and a 75-g oral glucose tolerance test (OGTT) following 4 doses of metformin 500 mg over 2 days. We used an additive mixed-effects model to evaluate the association of these variants with glucose, insulin, and incretin levels over multiple timepoints during the OGTT. During the OGTT, the G-risk allele at rs761387 was associated with higher total GLP-1 (2.61 pmol/L; 95% CI, 1.0.72-4.50), active GLP-1 (2.61 pmol/L; 95% CI, 0.04-5.18), and a trend toward higher glucose (3.63; 95% CI, -0.16 to 7.42 mg/dL) per allele but was not associated with insulin. During the glipizide challenge, the G allele was associated with higher insulin levels per allele (2.01 IU/mL; 95% CI, 0.26-3.76). The other variants were not associated with any of the outcomes tested. GLP1R variation is associated with differences in GLP-1 levels following an OGTT load despite no differences in insulin levels, highlighting altered incretin signaling as a potential mechanism by which GLP1R variation affects T2D risk.

Development of drug alone and carrier-based GLP-1 dry powder inhaler formulations

The study aimed to develop two types of dry powder inhaler (DPI) formulations containing glucagon-like peptide-1(7–36) amide (GLP-1): carrier-free (drug alone, no excipients) and carrier-based DPI formulations for pulmonary delivery of GLP-1. This is the first study focusing on the development of excipient free GLP-1 DPI formulations for inhaled therapy in Type 2 diabetes. The aerosolisation performance of both DPI formulations was studied using a next generation impactor and a DPI device (Handihaler®) at flow rate of 30 L min−1. Carriers employed were either a 10% w/w glycine-mannitol prepared by spray freeze drying or commercial mannitol. Spray freeze dried (SFD) carrier was spherical and porous whereas commercial mannitol carrier exhibited elongated particles (non-porous). GLP-1 powder without excipients for inhalation was prepared using spray drying and characterised for morphology including size, thermal behaviour, and moisture content. Spray dried (SD) GLP-1 powders showed indented/dimpled particles in the particle size range of 1–5 µm (also mass median aerodynamic diameter, MMAD: <5 µm) suitable for pulmonary delivery. Across formulations investigated, carrier-free DPI formulation showed the highest fine particle fraction (FPF: 90.73% ± 1.76%, mean ± standard deviation) and the smallest MMAD (1.96 µm ± 0.07 µm), however, low GLP-1 delivered dose (32.88% ± 7.00%, total GLP-1 deposition on throat and all impactor stages). GLP-1 delivered dose was improved by the addition of SFD 10% glycine-mannitol carrier to the DPI formulation (32.88% ± 7.00%–45.92% ± 5.84%). The results suggest that engineered carrier-based DPI formulations could be a feasible approach to enhance the delivery efficiency of GLP-1. The feasibility of systemic pulmonary delivery of SD GLP-1 for Type 2 diabetes therapy can be further investigated in animal models.

Insulin clearance and incretin hormones following oral and \u201cisoglycemic\u201d intravenous glucose in type 2 diabetes patients under different antidiabetic treatments

It has not been elucidated whether incretins affect insulin clearance in type 2 diabetes (T2D). We aimed exploring possible associations between insulin clearance and endogenously secreted or exogenously administered incretins in T2D patients. Twenty T2D patients were studied (16 males/4 females, 59 ± 2 years (mean ± standard error), BMI = 31 ± 1 kg/m2, HbA1c = 7.0 ± 0.1%). Patients were treated with metformin, sitagliptin, metformin/sitagliptin combination, and placebo (randomized order). On each treatment period, oral and isoglycemic intravenous glucose infusion tests were performed (OGTT, IIGI, respectively). We also studied twelve T2D patients (9 males/3 females, 61 ± 3 years, BMI = 30 ± 1 kg/m2, HbA1c = 7.3 ± 0.4%) that underwent infusion of GLP-1(7–36)-amide, GIP, GLP-1/GIP combination, and placebo. Plasma glucose, insulin, C-peptide, and incretins were measured. Insulin clearance was assessed as insulin secretion to insulin concentration ratio. In the first study, we found OGTT/IIGI insulin clearance ratio weakly inversely related to OGTT/IIGI total GIP and intact GLP-1 (R2 = 0.13, p < 0.02). However, insulin clearance showed some differences between sitagliptin and metformin treatment (p < 0.02). In the second study we found no difference in insulin clearance following GLP-1 and/or GIP infusion (p > 0.5). Thus, our data suggest that in T2D there are no relevant incretin effects on insulin clearance. Conversely, different antidiabetic treatments may determine insulin clearance variations.

117-LB: Glucokinase Activator Dorzagliatin (HMS5552) Regulates GLP-1 Release in T2D Patients and Is Synergistic with Sitagliptin and Empagliflozin in Optimizing Beta-Cell Function

Glucokinase (GK) is a glucose sensor and plays a central role in glucose homeostasis through regulation of threshold of hormone release from α and β cell that controls blood glucose set point. Based on this concept, Dorzagliatin as a glucose sensitizer for the treatment of diabetes has completed pivotal registration trial in China with desirable outcome. GLP-1 is an important hormone involved in β cell secretory function and such plays an important role in glucose homeostasis. It has been debated over the last decade on whether GK is involved in GLP-1 secretion. The dominant reports support the GLP-1 secretory organ is intestine L cell and the secreted hormone traveled to pancreas regulating β cell secreting function. Others suggested β cell regulates GLP-1 secretion from α cell through paracrine and is mediated through GLP-1 receptor on β cell. Here we report that a glucokinase activator Dorzagliatin stimulates GLP-1 release in T2D patients and is synergistic with Sitagliptin, a DDP-IV inhibitor, to increase circulating active GLP-1 in T2D patients with AUEC0-4h of 94.9% over Dorzagliatin. Increase of total GLP-1 was observed in the Dorzagliatin treatment with AUEC0-4h increase of 103.6% and Cmax increase of 141% compared with Dorzagliatin in combination with Sitagliptin. The effect on β cell function is also seen in patients taking Dorzagliatin together with Sitagliptin and Empagliflozin, a SGLT-2 inhibitor, in the OGTT study with increased C-peptide secretion AUEC0-4h of 46.6% (p &amp;lt; 0.01) and 20.4%, Cmax of 52.5% (p &amp;lt; 0.01) and 22%, respectively. Furthermore, the C-peptide secretion increased in combination treatment with AUEC0-4h of 30.3% (p &amp;lt; 0.05) and Cmax of 31%(p &amp;lt; 0.01), compared with Empagliflozin alone. In both combination studies with Sitagliptin and Empagliflozin, reduction of glucose AUEC0-4h is 33.1% and 37.6% with reduction glucose Cmax of 13.9% and 27.8% over Sitagliptin and Empagliflozin alone. Disclosure L. Chen: Board Member; Self; Hua Medicine. J. Zhang: Employee; Self; Hua Medicine. R. Yang: Employee; Self; Hua Medicine. L. Feng: Employee; Self; Hua Medicine. Hua medicine: n/a.

Bariatric surgery restores visual cortical plasticity in nondiabetic subjects with obesity.

Obesity leads to changes in synaptic plasticity. We aimed at investigating the impact of bariatric surgery (RYGB) on visual neural plasticity (NP) and its relationship with the main gut peptides, leptin, and brain-derived neurotrophic factor (BDNF). NP was assessed testing binocular rivalry before and after 2 h of monocular deprivation (index of visual brain plasticity) in 15 subjects with obesity (age 42.3 ± 9.8 years; BMI 46.1 ± 4.9 kg/m2) before and after RYGB. Gut peptides, leptin, and BDNF were obtained at baseline and 6 months after surgery in 13 subjects. A significant reduction in BMI (p < 0.001 vs. baseline) and a significant increase of disposition index (DI, p = 0.02 vs baseline) were observed after RYGB. Total and active GLP-1 release in response to glucose ingestion significantly increased after RYGB, while no changes occurred in VIP, GIP, and BDNF levels. Fasting leptin concentration was lower after RYGB (p = 0.001 vs. baseline). Following RYGB, NP was progressively restored (p < 0.002). NP was correlated with DI and fasting glucose at baseline (r = 0.75, p = 0.01; r = -0.7, p = 0.02; respectively), but not with BMI. A positive correlation between post-pre-RYGB changes in AUCactive GLP-1 and NP was observed (r = 0.70, p < 0.01). Leptin was inversely correlated with NP 6 months after surgery (r = -0.63, p = 0.02). No correlation was observed between GIP, VIP, BDNF, and NP. Visual plasticity is altered in subjects with obesity, and it can be restored after RYGB. The improvement may be mediated by amelioration of insulin sensitivity, increased GLP-1 levels, and reduced leptin levels.

Can Metabolite and Hormone Profiles Provide a Rationale for Choosing Between Bariatric Procedures?

There are no formal guidelines for choosing among different bariatric surgery procedures for obesity treatment. So, our aim was to evaluate whether post-absorptive metabolite and hormone profiles could aid the surgeon decision when considering bariatric surgery interventions. Subjects (N=38) previously submitted to biliopancreatic diversion with duodenal switch (BPD-DS, n=9), single anastomosis duodenal-ileum bypass with sleeve gastrectomy (SADI-S, n= 9), long biliopancreatic limb Roux-en-Y gastric bypass (RYGB-M, n= 11), and classic RYGB (RYGB-C, n= 9) underwent a mixed meal test to evaluate post-absorptive glucose, total amino acid (AA), insulin, and GLP-1 profiles. Glucose, AA, insulin, and GLP-1 excursions were lower after BPD-DS when compared to other surgeries. SADI-S resulted in lower glucose but similar AA and insulin excursions when compared to RYGB-M. The highest GLP-1 excursion was observed after RYGB-M. There were no significant differences in glucose or AA post-prandial excursions between RYGB procedures, yet insulin excursion was higher after RYGB-C when compared to RYGB-M. Post-prandial metabolite excursions diverge across bariatric procedures being lowest after BPD-DS, intermediate after SADI-S, and highest after RYGB, in parallel with the anti-diabetic efficacy and malabsorption risk reported for each type of intervention. SADI-S and RYGB-M seem to elicit similar post-prandial hormonal profiles, with potentially lower risk of protein malnutrition when compared to BPD-DS. Post-absorptive metabolite and hormone profiles could provide a rationale as decision-aid when choosing among bariatric surgery interventions, as long as these findings are validated in future trials.

Ileal interposition improves metabolic syndrome parameters in a rat model of metabolic syndrome induced by monosodium glutamate

AimsMetabolic syndrome (MetS) is a cluster of metabolic abnormalities. Anatomically restructuring of the gastrointestinal system has recently been an important subject of research in the treatment of MetS and closely related diseases. The aim of this study is to ensure the remission of parameters that define MetS by ileal interposition (IT) and to examine the effect of IT on plasma total GLP-1 and pancreatic GLP-1R expression. Main methodsTo induce MetS, newborn male Wistar albino rats were given MSG (4 g/mg) on days 0, 2, 4, 6, 8, and 10. The control group was injected with saline. In the 5th month, IT or sham surgery was performed on the MetS rats. The lipid levels, abdominal obesity, insulin level, OGTT, Lee index, HOMA-IR, plasma GLP-1 and pancreas GLP-1R expression were evaluated 2 months after surgery. Key findingsThe results showed that IT significantly improved hyperinsulinemia (p = 0.013) and lipid profile (TG p = 0.0001; TCHOL p = 0.018; HDL p = 0.001). Furthermore, it normalized the Lee index (p = 0.006) and insulin resistance. The IT did not affect the secretion of the GLP-1, but the expression levels of pancreas GLP-1R were increased (p = 0.006). SignificanceIT surgery corrected the MetS parameters in this rat model. The healing effects of IT surgery could be caused by mechanisms in the target tissues of insulin. The decrease in pancreatic GLP-1R levels in the MetS groups might be a compensatory response to the harmful effects of hyperinsulinemia in these groups. These results show that IT can be useful in the treatment of MetS.

1324-P: GLP-1 Hypersecretion in Gestational Diabetes

Background and Aims: Incretins are crucial for an adequate insulin secretion in response to ingestions of nutrients. In patients with diabetes, prediabetes or a specific genetic background, this incretin effect is blunted. Data on incretin secretion and action during pregnancy are scarce. Here we investigated the incretin response during an oral glucose tolerance test (OGTT) in pregnant women with and without gestational diabetes. Methods: Pregnant women from the ongoing PREG study underwent 5-point OGTT with 75 g glucose. We measured plasma glucose, insulin and C-peptide at all time points and total GLP-1 at minute 0, 30 and 120. Indices of insulin secretion and GLP-1 increase were calculated from the difference at min 0 and 30. We used linear regression to analyze the relation of GLP-1 and glucose with insulin secretion. Results: We examined 163 women during gestational week 26.8 (±2.0 SD), GDM was present in 30 (18.4%) women. Insulin secretion was significantly lower in women with GDM (p=0.04, adjusted for BMI, age, week of gestation, insulin sensitivity). GLP-1 levels increased after glucose intake with a peak at 30 min. GLP-1 levels at minute 30 and AUCGLP-1 was significantly higher in women with GDM (by ∼20%, both p=0.03, adjusted for age, BMI and week of gestation). The GLP-1 increase was associated with insulin secretion only in GDM, but not in women with normal glucose tolerance. This association remained significant even after adjustment for increase of glucose and basal insulin levels (GDM group: p&amp;lt;0.001, non GDM: p=0.69). Conclusion: Women with GDM had lower insulin secretion despite increased GLP-1 levels during OGTT. The more pronounced GLP-1 increase in women with GDM could be part of a compensatory mechanism counteracting GLP-1 resistance. In addition to incretin resistance, this phenomenon suggests a dysfunction of glucose stimulated insulin secretion. Disclosure L. Fritsche: None. M. Heni: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker’s Bureau; Self; Novo Nordisk A/S. S.S. Eckstein: None. M.J. Winzenried: None. J. Hummel: None. A.L. Birkenfeld: None. H. Preissl: None. H. Haering: None. A. Peter: None. A. Fritsche: None. R. Wagner: Advisory Panel; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Novo Nordisk A/S. Other Relationship; Self; Eli Lilly and Company. Funding German Federal Ministry of Education and Research (01GI0925)

Glucagon-like peptide 1 levels predict cardiovascular risk in patients with acute myocardial infarction.

Glucagon-like peptide 1 (GLP-1) is a gut incretin hormone inducing post-prandial insulin secretion. Glucagon-like peptide 1 levels were recently found to be increased in patients with acute myocardial infarction. Glucagon-like peptide 1 receptor agonists improve cardiovascular outcomes in patients with diabetes. The aim of this study was to assess the predictive capacity of GLP-1 serum levels for cardiovascular outcome in patients with myocardial infarction. In 918 patients presenting with myocardial infarction [321 ST-segment elevation myocardial infarction and 597 non-ST-segment elevation myocardial infarction (NSTEMI)] total GLP-1, N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and the Global Registry of Acute Coronary Events (GRACE) score were assessed at time of hospital admission. The primary composite outcome of the study was the first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Kaplan-Meier survival plots and univariable Cox regression analyses found GLP-1 to be associated with adverse outcome [hazard ratio (HR) of logarithmized GLP-1 values: 6.29, 95% confidence interval (CI): 2.67-14.81; P < 0.0001]. After further adjustment for age, sex, family history of cardiovascular disease, smoking, diabetes, hypertension, hypercholesterinaemia, glomerular filtration rate (GFR) CKD-EPI, hs-CRP, hs-Troponin T, and NT-proBNP levels the HR remained significant at 10.98 (95% CI: 2.63-45.90; P = 0.0010). Time-dependent receiver operating characteristic curve analyses illustrated that GLP-1 levels are a strong indicator for early events. For events up to 30 days after admission, GLP-1 proved to be superior to other biomarkers including hs-Troponin T, GFR CKD-EPI, hs-CRP, and NT-proBNP. Adjustment of the GRACE risk estimate by addition of GLP-1 increased the area under the receiver operating characteristic curve over time in NSTEMI patients. In patients hospitalized for myocardial infarction, GLP-1 levels are associated with cardiovascular events.

Circulating Resistin Is Associated with Plasma Glucagon-Like Peptide-1 in Cirrhotic Patients with Hepatitis C Virus Genotype-4 Infection

ABSTRACTPurpose: Limited and contradictory data on the circulating levels of glucagon-like peptide (GLP-1) and resistin in hepatitis C virus genotype-4 (HCV-4) cirrhotic patients are present. Thus, this study aimed to evaluate their concentrations and to investigate the association between total GLP-1, resistin, and insulin resistance in those patients.Materials and Methods: Non-diabetic HCV-4 cirrhotic patients (n = 80; 40 with Child-Pugh A, 20 with Child-Pugh B, and 20 with Child-Pugh C), and 25 healthy subjects were enrolled in this study. The basal circulating levels of total GLP-1 and resistin along with serum insulin, glucose, total cholesterol, and triglycerides were measured.Results: Plasma GLP-1 and serum resistin levels were significantly higher in cirrhotic patients than controls (P < . 001). Moreover, circulating GLP-1 and resistin levels increased in a stepwise fashion in line with increasing grade of liver damage. According to Spearman’s rank correlation, both GLP-1 and resisitin correlated positively with each other, insulin, homeostatic model assessment of insulin resistance, alanine aminotransferase (ALT), total bilirubin, and international normalized ratio while they correlated negatively with albumin (P < .001). Multiple stepwise regression analysis showed that ALT, serum resistin and Child-Pugh score independently influenced the GLP-1 levels in cirrhotic patients.Conclusions: Circulating levels of GLP-1 and resistin were elevated in cirrhotic patients with HCV-4. Further, the severity of liver cirrhosis and serum resistin were the determinant factors explaining the variability of GLP-1 levels by about 84%. In addition, a positive relation was found between insulin resistance and both GLP-1 and resistin levels.

Consumption of Whole Eggs Promotes Insulin Sensitivity in Db/db Mice (OR34-01-19)

ObjectivesChicken eggs have a high nutrient density. Some country guidelines recommend that people with type 2 diabetes (T2D) limit their consumption of eggs due to its high cholesterol content. However, several clinical studies showed that egg intake is associated with a lower risk of type 2 diabetes. In the current study, we sought to explore whether egg consumption improves insulin sensitivity and subsequent blood glucose management in type 2 diabetic db/db mice. MethodsSix-week-old male db/db mice were fed a low-fat diet (LFD, 10 kCal % from fat) or LFD supplemented with 1% whole eggs (Egg) for 8 weeks. At the termination of the study, mice were fasted for 3 hrs prior to euthanization. Blood and other tissues were collected for laboratory assessments. Plasma metabolic parameters and pro-inflammatory cytokines were monitored by a clinical analyzer and ELISA, respectively. Hepatic and skeletal muscle mitochondrial respiratory activity was assessed by a Seahorse XFe Analyzer. Hepatic gene expression was analyzed by transcriptomics and confirmed by real-time PCR and/or Western blot. ResultsEgg consumption significantly increased body weight gain, lowered fasting blood glucose, insulin, and IL-6 levels, and elevated total cholesterol, HDL, LDL, and GLP-1 levels. Only the basal mitochondrial respiratory activity was decreased, and the complex II respiratory activity was increased in gastrocnemius muscles in mice fed Egg. Hepatic mitochondrial activity was not altered by diet. Mechanistically, transcriptomics results revealed that hepatic genes involved in enhanced insulin sensitivity were highly expressed, but genes in endogenous cholesterol synthesis were significantly suppressed after egg consumption. ConclusionsThe results suggest that egg consumption is beneficial to blood glucose control in type 2 diabetic mice. Type 2 diabetic animal could manage the cholesterol level through suppression of de novo cholesterol synthesis when consuming a high cholesterol diet, e.g., egg diet. Funding SourcesNational egg nutrition center grant USDA NIFA grant