title: Hepatic glucose sensing is required to preserve β cell glucose competence.
abstract: Liver glucose metabolism plays a central role in glucose homeostasis and may also regulate feeding and energy expenditure. Here we assessed the impact of glucose transporter 2 (Glut2) gene inactivation in adult mouse liver (LG2KO mice). Loss of Glut2 suppressed hepatic glucose uptake but not glucose output. In the fasted state, expression of carbohydrate-responsive element-binding protein (ChREBP) and its glycolytic and lipogenic target genes was abnormally elevated. Feeding, energy expenditure, and insulin sensitivity were identical in LG2KO and control mice. Glucose tolerance was initially normal after Glut2 inactivation, but LG2KO mice exhibited progressive impairment of glucose-stimulated insulin secretion even though β cell mass and insulin content remained normal. Liver transcript profiling revealed a coordinated downregulation of cholesterol biosynthesis genes in LG2KO mice that was associated with reduced hepatic cholesterol in fasted mice and reduced bile acids (BAs) in feces, with a similar trend in plasma. We showed that chronic BAs or farnesoid X receptor (FXR) agonist treatment of primary islets increases glucose-stimulated insulin secretion, an effect not seen in islets from Fxr(-/-) mice. Collectively, our data show that glucose sensing by the liver controls β cell glucose competence and suggest BAs as a potential mechanistic link.
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Seyer
authors.forename: David
authors.initials: D
authors.lastname: Vallois
authors.forename: Carole
authors.initials: C
authors.lastname: Poitry-Yamate
authors.forename: Frédéric
authors.initials: F
authors.lastname: Schütz
authors.forename: Salima
authors.initials: S
authors.lastname: Metref
authors.forename: David
authors.initials: D
authors.lastname: Tarussio
authors.forename: Pierre
authors.initials: P
authors.lastname: Maechler
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Bernard
authors.initials: B
authors.lastname: Lanz
authors.forename: Rolf
authors.initials: R
authors.lastname: Grueter
authors.forename: Julie
authors.initials: J
authors.lastname: Decaris
authors.forename: Scott
authors.initials: S
authors.lastname: Turner
authors.forename: Anabela
authors.initials: A
authors.lastname: da Costa
authors.forename: Frédéric
authors.initials: F
authors.lastname: Preitner
authors.forename: Kaori
authors.initials: K
authors.lastname: Minehira
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
authors.forename: Bernard
authors.initials: B
authors.lastname: Thorens
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001647:Bile Acids and Salts / Q000378:metabolism; D001786:Blood Glucose; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D015536:Down-Regulation; D004734:Energy Metabolism; D005243:Feces / Q000737:chemistry; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D055786:Gene Knockout Techniques; D005947:Glucose / Q000378:metabolism* / Q000502:physiology; D018149:Glucose Intolerance / Q000097:blood / Q000235:genetics; D051273:Glucose Transporter Type 2 / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D050356:Lipid Metabolism; D008099:Liver / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001647:Bile Acids and Salts; D001786:Blood Glucose; D051273:Glucose Transporter Type 2; D007328:Insulin; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D019275:Radiopharmaceuticals; C495682:Slc2a2 protein, mouse; D014157:Transcription Factors; D019788:Fluorodeoxyglucose F18; D002784:Cholesterol; D005947:Glucose
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