Hyperglucagonemia is a key pathophysiological driver of type 2 diabetes. Although Roux-en-Y gastric bypass (RYGB) is a highly effective treatment for diabetes, it is presently unclear how surgery alters glucagon physiology. The aim of this study was to characterize the behavior of proglucagon-derived peptide (glucagon, glucagon-like peptide-1 (GLP-1), oxyntomodulin, glicentin) secretion after RYGB surgery.Prospective study of 19 patients with obesity and pre-diabetes/diabetes undergoing RYGB. We assessed the glucose, insulin, GLP-1, glucose-dependent insulinotropic peptide (GIP), oxyntomodulin, glicentin and glucagon responses to a mixed-meal test (MMT) before and 1, 3 and 12 months after surgery. Glucagon was measured using a Mercodia glucagon ELISA using the 'Alternative' improved specificity protocol, which was validated against a reference liquid chromatography combined with mass spectrometry method.After RYGB, there were early improvements in fasting glucose and glucose tolerance and the insulin response to MMT was accelerated and amplified, in parallel to significant increases in postprandial GLP-1, oxyntomodulin and glicentin secretion. There was a significant decrease in fasting glucagon levels at the later time points of 3 and 12 months after surgery. Glucagon was secreted in response to the MMT preoperatively and postoperatively in all patients and there was no significant change in this postprandial secretion. There was no significant change in GIP secretion.There is a clear difference in the dynamics of secretion of proglucagon peptides after RYGB. The reduction in fasting glucagon secretion may be one of the mechanisms driving later improvements in glycemia after RYGB.NCT01945840.
<b>Objective:</b> Roux-en-Y gastric bypass (RYGB) is an established treatment for type 2 diabetes. The study objective was to establish RYGB’s effects on glycaemic variability (GV) and hypoglycaemia. <p><b>Research Design and Methods:</b> Prospective observational study of 10 participants with pre-diabetes/Type 2 diabetes undergoing RYGB, studied before surgery (Pre), 1 month (1m), 1 year (1y) and 2 years (2y) post-surgery with continuous glucose measurement (CGM). A mixed meal test (MMT) was performed at Pre, 1m and 1y. [ClinicalTrials.gov NCT01945840]</p> <p><b>Results:</b> After RYGB, mean CGM glucose fell (at 1m, 1y and 2y), and GV increased (at 1y and 2y). Fifty percent (5/10) of participants exhibited a percentage time in range <3.0 mmol/L [54 mg/dl] (%TIR<3.0) greater than the consensus target of 1% at 1y or 2y. Peak glucagon-like peptide-1 (GLP-1) and glucagon area-under-curve (AUC) during MMT were respectively positively and negatively associated with contemporaneous %TIR<3.0. </p> <b>Conclusions:</b> Patients undergoing RYGB are at risk of developing post-bariatric hypoglycaemia due to a combination of reduced mean glucose, increased GV and increased GLP-1 response.
Abstract Aims To determine whether a continuous infusion of a glucagon‐like peptide receptor (GLP‐1R)/glucagon receptor (GCGR) co‐agonist, G3215 is safe and well tolerated in adults with overweight or obesity. Methods A phase 1 randomized, double blind, placebo‐controlled trial of G3215 in overweight or obese participants, with or without type 2 diabetes. Results Twenty‐six participants were recruited and randomized with 23 completing a 14‐day subcutaneous infusion of G3215 or placebo. The most common adverse events were nausea or vomiting, which were mild in most cases and mitigated by real‐time adjustment of drug infusion. There were no cardiovascular concerns with G3215 infusion. The pharmacokinetic characteristics were in keeping with a continuous infusion over 14 days. A least‐squares mean body weight loss of 2.39 kg was achieved with a 14‐day infusion of G3215, compared with 0.84 kg with placebo infusion ( p < .05). A reduction in food consumption was also observed in participants receiving G3215 and there was no deterioration in glycaemia. An improved lipid profile was seen in G3215‐treated participants and consistent with GCGR activation, a broad reduction in circulating amino acids was seen during the infusion period. Conclusion An adaptive continuous infusion of the GLP‐1/GCGR co‐agonist, G3215, is safe and well tolerated offering a unique strategy to control drug exposure. By allowing rapid, response‐directed titration, this strategy may allow for mitigation of adverse effects and afford significant weight loss within shorter time horizons than is presently possible with weekly GLP‐1R and multi‐agonists. These results support ongoing development of G3215 for the treatment of obesity and metabolic disease.
Some patients suffer disabling hypoglycaemia after RYGB, typically post prandially: Post Bariatric Hypoglycaemia (PBH). We hypothesised that these patients have increased glycaemic variability (GV), as assessed by continuous glucose monitoring (CGM). Method: Prospective study of 6 patients undergoing RYGB with mixed meal tests (MMT) and CGM at baseline (BL), at 1 month and at 12 months. This cohort was compared to 15 patients with hypoglycaemia. Results: RYGB leads to improvement in postprandial glucose tolerance at 120 minutes, preceded by an early peak of glucose and insulin at 30 minutes (Figure 1). Compared to pre-surgery, hypoglycaemic patients have significantly elevated peak glucose and insulin levels at 30 minutes followed by hypoglycaemia at 120 minutes. GV increases post RYGB: mean amplitude of glycaemic excursions (MAGE) median (95% CI) at BL 3.1 (2.3-6.8); 1 m 2.8 (2.2-4.2); 12 m 4.5 (3.4-5.5). PBH patients exhibit similar GV: MAGE 4.4 (3.7-6.5). The %time in range (TIR) glucose <3.9 increases post-surgery (BL 0 (0-3.8); 1 m 1.8 (0.5-4.1); 12 m 8.0 (0-25.8) but patients with PBH exhibit similar %TIR<3.9: 6.8 (3.5-11.9). Conclusion: PBH patients exhibit exaggerated early glucose and insulin secretion to MMT. ‘Real-world’ CGM demonstrates that GV and time in hypoglycaemia is not significantly different between RYGB without PBH and patients with PBH. All patients post RYGB are at risk of hypos. Disclosure G. Tharakan: None. I.I. Ilesanmi: None. P. Behary: None. K. Alexiadou: None. C.S. Doyle: None. H. Chahal: None. S. Purkayastha: None. A. Miras: None. N. Oliver: Advisory Panel; Self; Roche Diabetes Care. Research Support; Self; Dexcom, Inc., Roche Diabetes Care. Speaker's Bureau; Self; Dexcom, Inc., Sanofi. A. Ahmed: None. S. Bloom: None. T.M. Tan: Other Relationship; Self; Novo Nordisk A/S. Funding Medical Research Council UK
Roux-en-Y gastric bypass (RYGB) is an established treatment for type 2 diabetes and obesity. The study objective was to establish RYGB's effects on glycemic variability (GV) and hypoglycemia.This was a prospective observational study of 10 participants with obesity and prediabetes or type 2 diabetes who underwent RYGB. Patients were studied before RYGB (Pre) and 1 month, 1 year, and 2 years postsurgery with continuous glucose measurement (CGM). A mixed-meal test (MMT) was conducted at Pre, 1 month, and 1 year.After RYGB, mean CGM decreased (at 1 month, 1 year, and 2 years), and GV increased (at 1 year and 2 years). Five of the 10 participants had a percent time in range (%TIR) <3.0 mmol/L (54 mg/dL) greater than the international consensus target of 1% at 1 or 2 years. Peak glucagon-like peptide-1 (GLP-1) and glucagon area under the curve during MMT were positively and negatively associated, respectively, with contemporaneous %TIR <3.0 mmol/L.Patients undergoing RYGB are at risk for development of postbariatric hypoglycemia due to a combination of reduced mean glucose, increased GV, and increased GLP-1 response.
<b>Objective:</b> Roux-en-Y gastric bypass (RYGB) is an established treatment for type 2 diabetes. The study objective was to establish RYGB’s effects on glycaemic variability (GV) and hypoglycaemia. <p><b>Research Design and Methods:</b> Prospective observational study of 10 participants with pre-diabetes/Type 2 diabetes undergoing RYGB, studied before surgery (Pre), 1 month (1m), 1 year (1y) and 2 years (2y) post-surgery with continuous glucose measurement (CGM). A mixed meal test (MMT) was performed at Pre, 1m and 1y. [ClinicalTrials.gov NCT01945840]</p> <p><b>Results:</b> After RYGB, mean CGM glucose fell (at 1m, 1y and 2y), and GV increased (at 1y and 2y). Fifty percent (5/10) of participants exhibited a percentage time in range <3.0 mmol/L [54 mg/dl] (%TIR<3.0) greater than the consensus target of 1% at 1y or 2y. Peak glucagon-like peptide-1 (GLP-1) and glucagon area-under-curve (AUC) during MMT were respectively positively and negatively associated with contemporaneous %TIR<3.0. </p> <b>Conclusions:</b> Patients undergoing RYGB are at risk of developing post-bariatric hypoglycaemia due to a combination of reduced mean glucose, increased GV and increased GLP-1 response.
Post-bariatric hypoglycaemia (PBH) is typically a post-prandial hypoglycaemia occurring about 2–4 h after eating in individuals who have undergone bariatric surgery. PBH develops relatively late after surgery and often after discharge from post-surgical follow-up by bariatric teams, leading to variability in diagnosis and management in non-specialist centres. Aim The overall aim was to improve and standardise clinical practice in the diagnosis and management of PBH. The objectives were: (1) to undertake an up-to-date review of the current literature; (2) to formulate practical and evidence-based guidance regarding the diagnosis and treatment of PBH; (3) to recommend future avenues for research in this condition. Method A scoping review was undertaken after an extensive literature search. A consensus on the guidance and confidence in the recommendations was reached by the steering group authors prior to review by key stakeholders. Outcome We make pragmatic recommendations for the practical diagnosis and management of PBH, including criteria for diagnosis and recognition, as well as recommendations for research areas that should be explored. Plain English summary Post-bariatric hypoglycaemia (PBH) is a condition that commonly affects people who have undergone weight loss surgery. In this condition, people develop low blood sugar occurring about 2–4 h after meals, leading to debilitating symptoms such as hunger, sweating, anxiety, palpitations and even blackouts and fainting. PBH is becoming more common as weight loss surgery is being taken up by more people to help with their weight and to help with diabetes. The condition often develops after the patient has been discharged from follow-up after their surgery, which can lead to inconsistent diagnosis and treatment in non-specialist healthcare centres. The lack of clear information and evidence in the existing scientific literature further contributes to the variation in care. To address this problem, the Society for Endocrinology has created new guidelines to help healthcare professionals accurately diagnose and manage this condition. The guidelines were developed with input from dietitians, surgeons and doctors specialising in weight loss, and hormone specialists.
Background Roux-en-Y gastric bypass is an established treatment option for type 2 diabetes and obesity. However, the optimal lengths for the small intestinal limbs remain controversial with variation in practice. A longer biliopancreatic limb length of 150 cm (‘Long Limb’) was hypothesised to better improve glycaemia compared to the standard Roux-en-Y gastric bypass with a biliopancreatic limb of 50 cm (‘Standard Limb’). The aim of the trial was to evaluate the short-term mechanistic outcomes and the long-term clinical outcomes and safety of Long Limb versus Standard Limb Roux-en-Y gastric bypass. Methods We undertook a prospective double-blinded randomised controlled parallel group clinical trial across two sites in London. Participants were randomly assigned (1 : 1) to Long Limb or Standard Limb Roux-en-Y gastric bypass with a fixed alimentary limb of 100 cm. Mixed-meal tolerance tests and a hyperinsulinaemic-euglycaemic clamp were used to measure postprandial gut hormone response, glucose tolerance and insulin sensitivity. The primary outcome for the mechanistic study was the secretion of active glucagon-like peptide-1 at 2 weeks after intervention. Secondary outcomes were insulin sensitivity and fasting/postprandial glucose and insulin concentrations. Clinical outcomes, including HbA1c, number of glucose-lowering medications, weight loss, blood pressure and low-density lipoprotein cholesterol, and adverse events, were collected up to 60 months postoperatively to assess the durability of postoperative weight and glycaemic improvements. Results Of the 53 participants randomised, 48 completed the 12-month mechanistic investigation (Standard Limb 24, Long Limb 24) and 38 completed the 60-month follow-up (Standard Limb 18, Long Limb 20). The 24- to 60-month extension study coincided with two waves of the COVID-19 pandemic. There was no difference between the Standard Limb and Long Limb groups for postprandial active glucagon-like peptide-1 secretion (70 ± 32 pmol/L vs. 70 ± 19 pmol/L, respectively; p = 0.43), hepatic insulin sensitivity (3.4 ± 0.9 µmol/kg/min vs. 3.4 ± 1.4 µmol/kg/min, respectively; p = 0.94) and peripheral insulin sensitivity (29.0 ± 9.1 µmol/kg/min vs. 29.2 ± 9.9 µmol/kg/min, respectively; p = 0.98) at 2 weeks post intervention. There was no difference between the Standard Limb and Long Limb groups at 60-month follow-up for glycaemic remission (33% vs. 45%, respectively; p = 0.52), percentage total weight loss (27 ± 9% vs. 26 ± 8%, respectively; p = 0.34), systolic blood pressure (127 ± 11 mmHg vs. 125 ± 14 mmHg, respectively; p = 0.63) and low-density lipoprotein cholesterol (2.0 ± 1.0 mmol/L vs. 2.4 ± 1.0 mmol/L, respectively; p = 0.27). Conclusion In conclusion, this study has demonstrated the substantial clinical benefit of Roux-en-Y gastric bypass to people living with type 2 diabetes and obesity; however, this trial did not demonstrate a clinical rationale for the elongation of the biliopancreatic limb of Roux-en-Y gastric bypass to 150 cm to enhance metabolic outcomes for type 2 diabetes and obesity. Limitations Although the surgical procedures were designed according to United Kingdom clinical practice at the time of study inception, there is substantial variation in practice internationally. Our original investigation was powered for mechanistic outcomes and is not powered to detect differences in clinical outcomes. Lastly, the loss of participants to follow-up may have limited our statistical power to detect significant differences in the clinical outcomes. We therefore cannot derive definitive conclusions on the relative clinical efficacy of the two variants of Roux-en-Y gastric bypass. Funding This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme as award number NIHR130639.
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