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Objective: Postbariatric hypoglycemia affects >50% of individuals who have undergone Roux-en-Y gastric bypass surgery. Despite the often debilitating nature of this complication, existing treatment options are limited and often inefficient. Dasiglucagon is a stable glucagon analog available in a ready-to-use formulation and was recently shown to mitigate postbariatric hypoglycemia in experimental settings. Here, we aimed to evaluate the hypoglycemic hindering potential of dasiglucagon in an outpatient trial., Research Design and Methods: We conducted a randomized, double-blind, placebo-controlled, crossover, proof-of-concept study at the Center for Clinical Metabolic Research at Gentofte Hospital in Denmark. The study included 24 individuals who had undergone Roux-en-Y gastric bypass surgery (n = 23 women) with continuous glucose monitor-verified postbariatric hypoglycemia (≥15 min at <3.9 mmol/L three or more times per week) randomly assigned to two treatment periods of 4 weeks of self-administered subcutaneous dasiglucagon at 120 μg or placebo. The primary and key secondary outcomes were continuous glucose monitor-captured percentage of time in level 1 and 2 hypoglycemia (<3.9 and <3.0 mmol/L), respectively., Results: Compared with placebo, treatment with dasiglucagon significantly reduced time in level 1 hypoglycemia by 33% (-1.2 percentage points; 95% CI -2.0 to -0.5; P = 0.002) and time in level 2 hypoglycemia by 54% (-0.4 percentage points; 95% CI -0.6 to -0.2; P < 0.0001). Furthermore, dasiglucagon corrected hypoglycemia within 15 min in 401 of 412 self-administrations, compared with 104 of 357 placebo self-administrations (97.3% vs. 29.1% correction of hypoglycemia rate; P < 0.001). Dasiglucagon was generally well tolerated, with mostly mild to moderate adverse events of nausea., Conclusions: Compared with placebo, 4 weeks of self-administered dasiglucagon effectively reduced clinically relevant hypoglycemia in individuals who had undergone Roux-en-Y gastric bypass surgery., (© 2023 by the American Diabetes Association.)

Objective: To investigate the efficacy and safety of dasiglucagon, a novel stable glucagon analog in a liquid formulation, in Roux-en-Y gastric bypass (RYGB)-operated individuals suffering from postbariatric hypoglycemia (PBH)., Research Design and Methods: In a randomized, double-blind, placebo-controlled, crossover trial, 10 RYGB-operated participants with continuous glucose monitoring-verified PBH were randomly assigned to 3 trial days, each consisting of a 240-min standardized liquid mixed-meal test with the subcutaneous injection of placebo or 80 μg or 200 μg dasiglucagon., Results: Compared with placebo, treatment with both 80 and 200 μg dasiglucagon raised nadir plasma glucose (PG) (placebo: 3.0 ± 0.2 mmol/L [mean ± SEM]; 80 μg dasiglucagon: 3.9 ± 0.3 mmol/L, P = 0.002; 200 μg dasiglucagon: 4.5 ± 0.2 mmol/L, P = 0.0002) and reduced time in hypoglycemia (PG <3.9 mmol/L) by 70.0 min (P = 0.030 and P = 0.008)., Conclusions: Single-dose administration of dasiglucagon effectively mitigated postprandial hypoglycemia., (© 2022 by the American Diabetes Association.)

Objective: Neurotensin (NT) is released from enteroendocrine cells and lowers food intake in rodents. We evaluated postprandial NT secretion in humans after surgeries associated with accelerated small intestinal nutrient delivery, and after Roux-en-Y gastric bypass (RYGB) when glucagon-like peptide-1 (GLP-1) signalling and dipeptidyl peptidase 4 (DPP-4) were inhibited, and during pharmacological treatments influencing entero-pancreatic functions., Methods: We measured NT concentrations in plasma from meal studies: (I) after truncal vagotomy with pyloroplasty (TVP), cardia resection +TVP (CTVP), and matched controls (n = 10); (II) after RYGB, sleeve gastrectomy (SG), and in matched controls (n = 12); (III) after RYGB (n = 11) with antagonism of GLP-1 signalling using exendin(9-39) and DPP-4 inhibition using sitagliptin; (IV) after RYGB (n = 11) during a run-in period and subsequent treatment with, sitagliptin, liraglutide (GLP-1 receptor agonist), verapamil (calcium antagonist), acarbose (alpha glucosidase inhibitor), and pasireotide (somatostatin analogue), respectively., Results: (I) NT secretion was similar after TVP/CTVP (p = 0.9), but increased vs. controls (p < 0.0001). (II) NT secretion was increased after RYGB vs. SG and controls (p < 0.0001). NT responses were similar in SG and controls (p = 0.3), but early postprandial NT concentrations were higher after SG (p < 0.05). (III) Exendin (9-39) and sitagliptin did not change NT responses vs placebo (p > 0.2), but responses were lower during sitagliptin vs. exendin(9-39) (p = 0.03). (IV) Pasireotide suppressed NT secretion (p = 0.004). Sitagliptin tended to lower NT secretion (p = 0.08). Liraglutide, verapamil, and acarbose had no effect (p > 0.9)., Conclusion: Neurotensin secretion is increased after surgeries associated with accelerated gastric emptying and lowered by pasireotide., (© 2021 John Wiley & Sons Ltd.)

Background: Postbariatric hypoglycemia (PBH) is a potentially serious complication after Roux-en-Y gastric bypass (RYGB), and impaired counterregulatory hormone responses have been suggested to contribute to the condition., Objectives: We evaluated counterregulatory responses during postprandial hypoglycemia in individuals with PBH who underwent RYGB., Setting: University hospital., Methods: Eleven women with documented PBH who had RYGB underwent a baseline liquid mixed meal test (MMT) followed by 5 MMTs preceded by treatment with (1) acarbose 50 mg, (2) sitagliptin 100 mg, (3) verapamil 120 mg, (4) liraglutide 1.2 mg, and (5) pasireotide 300 μg. Blood was collected at fixed time intervals. Plasma and serum were analyzed for glucose, insulin, glucagon, epinephrine, norepinephrine, pancreatic polypeptide (PP), and cortisol., Results: During the baseline MMT, participants had nadir blood glucose concentrations of 3.3 ± .2 mmol/L. At the time of nadir glucose, there was a small but significant increase in plasma glucagon. Plasma epinephrine concentrations were not increased at nadir glucose but were significantly elevated by the end of the MMT. There were no changes in norepinephrine, PP, and cortisol concentrations in response to hypoglycemia. After treatment with sitagliptin, 8 individuals had glucose nadirs <3.2 mmol/L (versus 4 individuals at baseline), and significant increases in glucagon, PP, and cortisol responses were observed., Conclusions: In response to postprandial hypoglycemia, individuals with PBH who underwent RYGB only had minor increases in counterregulatory hormones, while larger hormone responses occurred when glucose levels were lowered during treatment with sitagliptin. The glycemic threshold for counterregulatory activation could be altered in individuals with PBH, possibly explained by recurrent hypoglycemia., (Copyright © 2020 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Post-bariatric hypoglycemia (PBH) can be a serious complication after Roux-en-Y gastric bypass (RYGB), and treatment with somatostatin analogs has been suggested. We investigated the acute effects of three different doses of pasireotide (75 μg, 150 μg, and 300 μg) on the postprandial glucose metabolism in five RYGB-operated individuals with PBH using a mixed meal test. All three doses prevented hypoglycemia but were associated with a notable increase in postprandial hyperglycemia. Moreover, all doses greatly diminished insulin, C-peptide, and glucagon-like peptide-1 responses. Considering its strong hyperglycemic potential, we suggest that pasireotide should be administered carefully in RYGB-operated individuals with PBH, and if necessary, a 75 μg dose seems sufficient to prevent hypoglycemia.

Background: Early dumping and post-bariatric hypoglycemia (PBH) are often addressed as two separate postprandial complications after Roux-en-Y gastric bypass (RYGB). The aim of the study was to evaluate the occurrence of early dumping in RYGB-operated individuals with PBH with and without treatment intervention., Methods: Eleven RYGB-operated women with documented PBH each underwent a baseline liquid mixed meal test (MMT) followed by five MMTs preceded by treatment with: acarbose 50 mg for 1 week, sitagliptin 100 mg for 1 week, verapamil 120 mg for 1 week, liraglutide 1.2 mg for 3 weeks, and pasireotide 300 μg as a single dose. Repetitive venous blood sampling and continuous electrocardiogram recordings were performed at fasting and during a 3-h postprandial period., Results: During the baseline MMT, there was a significant increase in HR (from 65 ± 2 to 90 ± 4 bpm, p < 0.0001) within 30 min after meal intake, while hypoglycemia occurred in the later postprandial period. The HR increase was accompanied by significant increases in serum albumin, plasma norepinephrine, blood glucose, serum insulin, and plasma GLP-1 concentrations. The postprandial HR changes were positively correlated with the changes in insulin and GLP-1 concentrations. Treatment with acarbose and pasireotide both reduced HR, plasma norepinephrine, and serum insulin, and pasireotide also decreased plasma GLP-1., Conclusions: RYGB-operated individuals with PBH also have large early postprandial HR increases, hemoconcentration, and sympathetic activation, consistent with early dumping. Moreover, hormone excursions associated with PBH appear to be related to measures of early dumping, suggesting a causal relationship between early dumping and PBH., Trial Registration: NCT02527993.

Aim: To investigate the effects of acarbose, sitagliptin, verapamil, liraglutide and pasireotide on post-bariatric hypoglycaemia (PBH) after Roux-en-Y gastric bypass., Materials and Methods: In a randomized crossover study, 11 women who had undergone Roux-en-Y gastric bypass and had documented hypoglycaemia were each evaluated during a baseline period without treatment and during five treatment periods with the following interventions: acarbose 50 mg for 1 week, sitagliptin 100 mg for 1 week, verapamil 120 mg for 1 week, liraglutide 1.2 mg for 3 weeks and pasireotide 300 μg as a single dose. Treatment effects were evaluated by a mixed-meal tolerance test (MMTT) and, for all treatment periods except pasireotide, by 6 days of continuous glucose monitoring (CGM)., Results: Treatment with acarbose and treatment with pasireotide both significantly lifted nadir glucose levels (mean ± SEM 3.9 ± 0.2 and 7.9 ± 0.4 vs 3.4 ± 0.2; P < .03) and reduced time in hypoglycaemia during the MMTTs. Acarbose reduced peak glucose levels and time in hyperglycaemia, whereas pasireotide greatly increased both variables. Acarbose and pasireotide reduced insulin and C-peptide levels, and pasireotide also diminished glucagon-like peptide-1 levels. Sitagliptin lowered nadir glucose values, while verapamil and liraglutide had no effect on hypoglycaemia. During the CGM periods, the treatments had no impact on hypoglycaemia, whereas acarbose and liraglutide reduced hyperglycaemia and glycaemic variability., Conclusions: In an experimental setting, treatment with acarbose and pasireotide reduced PBH. Acarbose appears to have an overall glucose-stabilizing effect, whereas pasireotide leads to increased and sustained hyperglycaemia., (© 2019 John Wiley & Sons Ltd.)

Roux-en-Y gastric bypass (RYGB) is one of the most common and successful bariatric surgeries. However, more than half of RYGB-operated individuals may suffer from post-bariatric hypoglycaemia (PBH) characterised by traditional hypoglycaemic symptoms occurring 1 to 4 hours after meal intake. The mechanisms underlying PBH most likely relate to accelerated delivery of nutrients to the small intestine resulting in unretarded nutrient absorption, large elevations in postprandial plasma glucose concentrations (constituting a potent insulin secretory stimulus), and grossly elevated postprandial plasma levels of the insulinotropic gut-derived hormone glucagon-like peptide 1 (GLP-1) potentiating glucose-stimulated insulin secretion. Based on previous findings that circulating GLP-1 concentrations increased by ~100% during insulin-induced hypoglycaemia before but not after RYGB, Almby et al. explored whether exogenous GLP-1 may protect against PBH. They performed hyperinsulinaemic hypoglycaemic clamps with concomitant infusion of the GLP-1 analogue exenatide and saline, respectively, in individuals who had undergone RYGB surgery. Infusion with exenatide during hypoglycaemia had no plasma glucose-raising effects, did not increase the counterregulatory glucagon response, and did not affect symptom scores. In the present commentary, potentially important implications derived from the study by Almby et al. published in the August issue of EJE, are discussed in the light of previous observations on GLP-1 receptor agonist treatment in PBH. While the findings by Almby et al. do not provide a solution for patients with PBH, they contribute to the knowledge base needed to address the growing problem of PBH.

Roux-en-Y gastric bypass (RYGB) is an efficient treatment for morbid obesity and reduces obesity-related co-morbidities. With the growing number of patients undergoing gastric bypass, complications now demand further attention. Postprandial hyperinsulinemic hypoglycemia (PHH) after Roux-en-Y gastric bypass is a complex condition, characterized by increased glucose variability including both hyperglycemic and hypoglycemic values. PHH seems to be more prevalent than previously suggested and is highly dependent on the choice of diagnostic tool, which has not yet been standardized. Questionnaires, an oral glucose tolerance test, a mixed meal tolerance test, and continuous glucose monitoring have been used, each with their own advantages. The condition is further complicated by a large group of asymptomatic cases. Patients with symptoms of PHH after gastric bypass are characterized by exaggerated insulin and glucagon-like peptide-1 responses compared to asymptomatic operated patients. The counter-regulatory mechanisms responsible for preventing hypoglycemia appear to be altered. The cause of these changes is not entirely understood, and it remains difficult to identify patients at risk of developing hypoglycemia. Known risk factors are female sex, longer time since surgery, and lack of prior diabetes. Management of the hypoglycemic episodes is difficult, and only dietary modifications consisting of frequent and less carbohydrate-rich meals seem to be efficient. Medical treatments and surgical procedures have been attempted in few studies and still warrant further examination., (Copyright © 2017 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)