Article, 2024

Colesevelam has no acute effect on postprandial GLP-1 levels but abolishes gallbladder refilling

European Journal of Endocrinology, ISSN 1479-683X, 0804-4643, Volume 190, 4, Pages 314-326, 10.1093/ejendo/lvae033

Contributors

Gether, Ida Marie [1] Bahne, Emilie [1] Nerild, Henriette Holst [1] Rehfeld, Jens Frederik 0000-0002-4718-9571 [2] [3] Hartmann, Bolette 0000-0001-8509-2036 [3] Holst, Jens-Juul 0000-0001-6853-3805 [3] Vilsbøll, Tina 0000-0002-0456-6787 [1] [3] [4] Sonne, David Peick 0000-0002-4898-2256 [1] [5] Knop, Filip Krag K 0000-0002-2495-5034 (Corresponding author) [1] [3] [4]

Affiliations

  1. [1] Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
    2. [NORA names: Denmark; Europe, EU; Nordic; OECD];
  2. [2] Rigshospitalet
    3. [NORA names: Capital Region of Denmark; Hospital; Denmark; Europe, EU; Nordic; OECD];
  3. [3] University of Copenhagen
    4. [NORA names: KU University of Copenhagen; University; Denmark; Europe, EU; Nordic; OECD];
  4. [4] Steno Diabetes Center
    5. [NORA names: Steno Diabetes Centers; Hospital; Denmark; Europe, EU; Nordic; OECD];
  5. [5] Bispebjerg and Frederiksberg Hospital
    6. [NORA names: Capital Region of Denmark; Hospital; Denmark; Europe, EU; Nordic; OECD]

Abstract

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.

Keywords

C-peptide, CCK secretion, FGF19, GLP-1, GLP-1 levels, GLP-1 response, GLP-1 secretion, GLP-1-mediated effects, absorption, acid, action, acute effects, administration, antidiabetic action, bile, bile acid sequestrants, bile acids, cholecystokinin, circulating factors, colesevelam, concentrations of FGF19, concentrations of glucose, control, crossover study, days, double-blind, effect, effects of colesevelam, emptying, excursion, exendin(9-39)NH2, factors, fibroblast growth factor 19, findings, gallbladder, gallbladder emptying, gallbladder motility, gallbladder refilling, glucose, glucose excursions, glucose tolerance, glycaemic control, hypercholesterolaemia, improve glycaemic control, increasing CCK secretion, individuals, infusion, intravenous infusion, levels, meal test, mixed meal test, motility, no effect, orally, paracetamol, paracetamol absorption, placebo, placebo-controlled crossover study, postprandial GLP-1 levels, postprandial GLP-1 response, postprandial GLP-1 secretion, postprandial cholecystokinin, postprandial concentrations, postprandial concentrations of glucose, postprandial gallbladder, postprandial gallbladder motility, postprandial glucose excursions, reduced circulating concentrations, reducing postprandial glucose excursions, refill, response, saline, secretion, sequestration, study, test, tolerance, treatment, treatment of hypercholesterolaemia, type, type 2 diabetes

Funders

  • Danish Medical Association
  • A.P. Møller og Hustru Chastine Mc-Kinney Møllers Fond
  • Novo Nordisk Foundation

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