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Aim: Gestational diabetes mellitus (GDM) has been associated with reduced postprandial glucagon-like peptide 1 (GLP-1) responses. As pregnancy induces changes in gallbladder motility and bile acids stimulate GLP-1 secretion, we investigated postprandial gallbladder emptying and GLP-1 responses in women with GDM., Methods: Women with and without GDM underwent two 240-min mixed meal tests; one during third trimester of pregnancy and one 3-6 months postpartum. We evaluated ultrasonography-assessed gallbladder emptying, plasma concentrations of glucometabolic hormones including GLP-1, paracetamol absorption (proxy for gastric emptying) and circulating factors known to affect gallbladder dynamics., Results: Fifteen women with GDM and 15 pregnant women with normal glucose tolerance (NGT) (baseline median age 31 (interquartile range 29;33) versus 32 (28;33) years, body mass index (BMI) 27.2 (24.7;30.7) versus 28.4 (26.2;31.0) kg/m 2 , HbA 1c 30 (29;32) versus 30 (28;31) mmol/mol) were included. No differences in postprandial gallbladder emptying or GLP-1 responses were observed between women with and without GDM, neither during pregnancy nor postpartum. Pregnancy increased fasting gallbladder volumes by 69 (30;122)% and 103 (59;156)% and postprandial gallbladder emptying by 77 (28;236)% and 99 (37;190)% compared with postpartum in women with and without GDM, respectively. Postprandial GLP-1 responses were reduced by 60 (3;82)% and 81 (11;90)% during pregnancy compared with postpartum in women with and without GDM, respectively., Conclusion: Pregnancy-induced changes in gallbladder motility seem to play no or a limited role in previously reported GDM-associated reduced postprandial GLP-1 responses as gallbladder emptying was greater and postprandial GLP-1 response was lower in pregnancy than postpartum regardless of GDM status., (© 2024 John Wiley & Sons Ltd.)

Oxytocin has been proposed to possess glucose-stabilizing effects through the release of insulin and glucagon from the pancreas. Also, exogenous oxytocin has been shown to stimulate extrapancreatic glucagon secretion in depancreatized dogs. Here, we investigated the effect of exogenous oxytocin on circulating levels of pancreatic and gut-derived glucose-stabilizing hormones (insulin [measured as C-peptide], glucagon, glucagon-like peptide 1 [GLP-1], and glucose-dependent insulinotropic polypeptide). We studied nine pancreatectomized (PX) patients and nine healthy controls (CTRLs) (matched on age and body mass index) before, during, and after an intravenous infusion of 10 IU of oxytocin administered over 12 min. Oxytocin did not increase plasma glucagon levels, nor induce any changes in plasma glucose, C-peptide, or GIP in any of the groups. Oxytocin decreased plasma glucagon levels by 19 ± 10 % in CTRLs (from 2.0 ± 0.5 [mean ± SEM] to 1.3 ± 0.2 pmol/l, P = 0.0025) and increased GLP-1 by 42 ± 22 % in PX patients (from 9.0 ± 1.0-12.7 ± 1.0 pmol/l, P = 0.0003). Fasting plasma glucose levels were higher in PX patients compared with CTRLs (13.1 ± 1.1 vs. 5.1 ± 0.1 mmol/l, P < 0.0001). In conclusion, the present findings do not support pancreas-mediated glucose-stabilizing effects of acute oxytocin administration in humans and warrant further investigation of oxytocin's gluco-metabolic effects., Competing Interests: Declaration of Competing Interest None of the authors declare conflicts of interests in relation to the present manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Colesevelam, a bile acid sequestrant approved for the treatment of hypercholesterolaemia, improves glycaemic control in type 2 diabetes. We hypothesised that single-dose colesevelam increases postprandial GLP-1 secretion, thus, reducing postprandial glucose excursions in individuals with type 2 diabetes. Further, we explored the effects of single-dose colesevelam on ultrasonography-assessed postprandial gallbladder motility, paracetamol absorption (proxy for gastric emptying), and circulating factors known to affect gallbladder motility., Methods: In a randomised, double-blind, placebo-controlled crossover study, 12 individuals with type 2 diabetes (mean ± SD: age 61 ± 8.8 years; body mass index 29.8 ± 3.0 kg/m2) were subjected to 4 mixed meal tests on separate days; 2 with orally administered colesevelam (3.75 g) and 2 with placebo, with intravenous infusion of the GLP-1 receptor antagonist exendin(9-39)NH2 or saline., Results: Single-dose colesevelam had no effect on postprandial concentrations of glucose (P = .786), C-peptide (P = .440), or GLP-1 (P = .729), and exendin(9-39)NH2 administration revealed no GLP-1-mediated effects of colesevelam. Colesevelam did not affect gallbladder emptying but abolished gallbladder refilling (P = .001), increased postprandial cholecystokinin (CCK) secretion (P = .010), and decreased postprandial serum concentrations of fibroblast growth factor 19 (FGF19) (P = .035) and bile acids (P = .043)., Conclusion: Single-dose colesevelam had no effect on postprandial GLP-1 responses or glucose tolerance but disrupted postprandial gallbladder refilling by increasing CCK secretion and reducing circulating concentrations of FGF19 and bile acids. These findings leave the antidiabetic actions of colesevelam unresolved but provide mechanistic insights into its effect on gallbladder motility., Competing Interests: Conflict of interest: J.J.H. is part of the advisory boards and has given paid lectures for Novo Nordisk and is co-founder, shareholder, and board member of Bainan Pharmaceuticals and Antag Therapeutics. T.V. has served on scientific advisory panels, been part of speaker's bureaus, served as a consultant to, and/or received research support from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, GSK, Mundipharma, MSD/Merck, Novo Nordisk, Sanofi, and Sun Pharmaceuticals. F.K.K. has served on scientific advisory panels and/or been part of speaker's bureaus for, served as a consultant to, and/or received research support from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, Gubra, MedImmune, MSD/Merck, Mundipharma, Norgine, Novo Nordisk, Sanofi, ShouTi, Zealand Pharma, and Zucara, and is co-founder of and minority shareholder in Antag Therapeutics. The remaining authors have nothing to disclose. F.K.K. is on the editorial board of European Journal of Endocrinology. F.K.K. was not involved in the review or editorial process for this paper, on which F.K.K. is listed as author. All authors declare that the present study was conducted without any conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

As cases of gallbladder-related adverse events have been reported in patients treated with glucagon-like peptide (GLP)-1 receptor agonists and GLP-2 receptor agonists, studies have investigated the effects of these hormones on the enterohepatic circulation of bile acids and gallbladder motility. Results suggest, that bile acids and GLP-2 counteract postprandial cholecystokinin-mediated gallbladder contraction, while GLP-1 may delay gallbladder refilling. This provides important information on the effect and safety of drugs based on GLP-1 and GLP-2, respectively.