title: Bile acids acutely stimulate insulin secretion of mouse β-cells via farnesoid X receptor activation and K(ATP) channel inhibition.
abstract: Type 2 diabetes mellitus is associated with alterations in bile acid (BA) signaling. The aim of our study was to test whether pancreatic β-cells contribute to BA-dependent regulation of glucose homeostasis. Experiments were performed with islets from wild-type, farnesoid X receptor (FXR) knockout (KO), and β-cell ATP-dependent K(+) (K(ATP)) channel gene SUR1 (ABCC8) KO mice, respectively. Sodium taurochenodeoxycholate (TCDC) increased glucose-induced insulin secretion. This effect was mimicked by the FXR agonist GW4064 and suppressed by the FXR antagonist guggulsterone. TCDC and GW4064 stimulated the electrical activity of β-cells and enhanced cytosolic Ca(2+) concentration ([Ca(2+)](c)). These effects were blunted by guggulsterone. Sodium ursodeoxycholate, which has a much lower affinity to FXR than TCDC, had no effect on [Ca(2+)](c) and insulin secretion. FXR activation by TCDC is suggested to inhibit K(ATP) current. The decline in K(ATP) channel activity by TCDC was only observed in β-cells with intact metabolism and was reversed by guggulsterone. TCDC did not alter insulin secretion in islets of SUR1-KO or FXR-KO mice. TCDC did not change islet cell apoptosis. This is the first study showing an acute action of BA on β-cell function. The effect is mediated by FXR by nongenomic elements, suggesting a novel link between FXR activation and K(ATP) channel inhibition.
authors.affiliation: Department of Pharmacology, Institute of Pharmacy, University of Tübingen, Tübingen, Germany. martina.duefer@uni-tuebingen.de
authors.forename: Martina
authors.initials: M
authors.lastname: Düfer
authors.forename: Katrin
authors.initials: K
authors.lastname: Hörth
authors.forename: Rebecca
authors.initials: R
authors.lastname: Wagner
authors.forename: Björn
authors.initials: B
authors.lastname: Schittenhelm
authors.forename: Susanne
authors.initials: S
authors.lastname: Prowald
authors.forename: Thomas F J
authors.initials: TF
authors.lastname: Wagner
authors.forename: Johannes
authors.initials: J
authors.lastname: Oberwinkler
authors.forename: Robert
authors.initials: R
authors.lastname: Lukowski
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Peter
authors.initials: P
authors.lastname: Krippeit-Drews
authors.forename: Gisela
authors.initials: G
authors.lastname: Drews
mesh_terms: D000818:Animals; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D011282:Pregnenediones / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D013657:Taurodeoxycholic Acid / Q000494:pharmacology*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D005947:Glucose; D007328:Insulin; D024661:Potassium Channels, Inwardly Rectifying; D011282:Pregnenediones; D018160:Receptors, Cytoplasmic and Nuclear; D013657:Taurodeoxycholic Acid; D000099150:Receptor, Farnesoid X-Activated; C023617:pregna-4,17-diene-3,16-dione