title: Cholecystokinin-Induced Gallbladder Emptying and Metformin Elicit Additive Glucagon-Like Peptide-1 Responses.
abstract: Bile acids have been suggested to mediate glucagon-like peptide-1 (GLP-1) secretion. Metformin, too, has been shown to increase GLP-1 levels. The effect of gallbladder emptying, metformin, or a combination has, however, never been studied.
  
  
  
  We hypothesized that cholecystokinin (CCK)-8-induced gallbladder emptying stimulates human GLP-1 secretion and that metformin would potentiate this effect.
  
  
  
  A double-blinded, randomized study.
  
  
  
  The study was conducted at a specialized research unit.
  
  
  
  Ten healthy male subjects with no family history of diabetes (age, 22 [range, 20-32] years; body mass index, 21.7 [19.3-24.2] kg/m(2); fasting plasma glucose, 4.9 [4.7-5.3] mm; and glycosylated hemoglobin A1c, 5.1 [4.4-5.8] %).
  
  
  
  On 4 separate days, the subjects received metformin or placebo and a concomitant 60-minute intravenous infusion of saline or CCK. Blood was sampled for 4 hours, and gallbladder volume was measured by ultrasound.
  
  
  
  Plasma levels of GLP-1.
  
  
  
  CCK-induced gallbladder emptying and metformin alone (no observed effect on gallbladder emptying) both elicited significant and additive GLP-1 responses. Metformin alone or combined with gallbladder emptying elicited a significant peptide YY response. CCK-induced gallbladder emptying resulted in a short-lasting glucose-dependent insulinotropic polypeptide response independent of metformin. No effects were seen on plasma glucose, insulin, C-peptide, or gastrin.
  
  
  
  CCK-induced gallbladder emptying in healthy subjects elicits significant GLP-1 secretion, which can be potentiated by metformin.
authors.affiliation: Center for Diabetes Research (U.R., D.P.S., M.C., M.H., A.B., T.V., F.K.K.), Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences (U.R., M.H., S.T., J.J.H., F.K.K.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Clinical Pharmacology (M.C.), Bispebjerg Hospital, University of Copenhagen, 2400 Copenhagen, Denmark; and Department of Clinical Biochemistry (J.F.R.), Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Rohde
authors.affiliation: Center for Diabetes Research (U.R., D.P.S., M.C., M.H., A.B., T.V., F.K.K.), Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences (U.R., M.H., S.T., J.J.H., F.K.K.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Clinical Pharmacology (M.C.), Bispebjerg Hospital, University of Copenhagen, 2400 Copenhagen, Denmark; and Department of Clinical Biochemistry (J.F.R.), Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
authors.forename: David Peick
authors.initials: DP
authors.lastname: Sonne
authors.affiliation: Center for Diabetes Research (U.R., D.P.S., M.C., M.H., A.B., T.V., F.K.K.), Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences (U.R., M.H., S.T., J.J.H., F.K.K.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Clinical Pharmacology (M.C.), Bispebjerg Hospital, University of Copenhagen, 2400 Copenhagen, Denmark; and Department of Clinical Biochemistry (J.F.R.), Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
authors.forename: Mikkel
authors.initials: M
authors.lastname: Christensen
authors.affiliation: Center for Diabetes Research (U.R., D.P.S., M.C., M.H., A.B., T.V., F.K.K.), Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences (U.R., M.H., S.T., J.J.H., F.K.K.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Clinical Pharmacology (M.C.), Bispebjerg Hospital, University of Copenhagen, 2400 Copenhagen, Denmark; and Department of Clinical Biochemistry (J.F.R.), Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Hansen
authors.affiliation: Center for Diabetes Research (U.R., D.P.S., M.C., M.H., A.B., T.V., F.K.K.), Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences (U.R., M.H., S.T., J.J.H., F.K.K.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Clinical Pharmacology (M.C.), Bispebjerg Hospital, University of Copenhagen, 2400 Copenhagen, Denmark; and Department of Clinical Biochemistry (J.F.R.), Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
authors.forename: Andreas
authors.initials: A
authors.lastname: Brønden
authors.affiliation: Center for Diabetes Research (U.R., D.P.S., M.C., M.H., A.B., T.V., F.K.K.), Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences (U.R., M.H., S.T., J.J.H., F.K.K.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Clinical Pharmacology (M.C.), Bispebjerg Hospital, University of Copenhagen, 2400 Copenhagen, Denmark; and Department of Clinical Biochemistry (J.F.R.), Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
authors.forename: Signe
authors.initials: S
authors.lastname: Toräng
authors.affiliation: Center for Diabetes Research (U.R., D.P.S., M.C., M.H., A.B., T.V., F.K.K.), Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences (U.R., M.H., S.T., J.J.H., F.K.K.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Clinical Pharmacology (M.C.), Bispebjerg Hospital, University of Copenhagen, 2400 Copenhagen, Denmark; and Department of Clinical Biochemistry (J.F.R.), Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
authors.forename: Jens Frederik
authors.initials: JF
authors.lastname: Rehfeld
authors.affiliation: Center for Diabetes Research (U.R., D.P.S., M.C., M.H., A.B., T.V., F.K.K.), Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences (U.R., M.H., S.T., J.J.H., F.K.K.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Clinical Pharmacology (M.C.), Bispebjerg Hospital, University of Copenhagen, 2400 Copenhagen, Denmark; and Department of Clinical Biochemistry (J.F.R.), Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
authors.forename: Jens Juul
authors.initials: JJ
authors.lastname: Holst
authors.affiliation: Center for Diabetes Research (U.R., D.P.S., M.C., M.H., A.B., T.V., F.K.K.), Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences (U.R., M.H., S.T., J.J.H., F.K.K.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Clinical Pharmacology (M.C.), Bispebjerg Hospital, University of Copenhagen, 2400 Copenhagen, Denmark; and Department of Clinical Biochemistry (J.F.R.), Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
authors.forename: Tina
authors.initials: T
authors.lastname: Vilsbøll
authors.affiliation: Center for Diabetes Research (U.R., D.P.S., M.C., M.H., A.B., T.V., F.K.K.), Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences (U.R., M.H., S.T., J.J.H., F.K.K.), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Clinical Pharmacology (M.C.), Bispebjerg Hospital, University of Copenhagen, 2400 Copenhagen, Denmark; and Department of Clinical Biochemistry (J.F.R.), Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
authors.forename: Filip Krag
authors.initials: FK
authors.lastname: Knop
mesh_terms: D000328:Adult; D001786:Blood Glucose; D002096:C-Peptide / Q000097:blood; D002766:Cholecystokinin / Q000494:pharmacology*; D004311:Double-Blind Method; D005704:Gallbladder / Q000000981:diagnostic imaging / Q000187:drug effects*; D016473:Gallbladder Emptying / Q000187:drug effects*; D005755:Gastrins / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000097:blood*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D009929:Organ Size / Q000187:drug effects; D014463:Ultrasonography; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D005755:Gastrins; D007004:Hypoglycemic Agents; D007328:Insulin; D052216:Glucagon-Like Peptide 1; D002766:Cholecystokinin; D008687:Metformin