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Hepatic glucose sensing is required to preserve β cell glucose competence

Seyer, Pascal
Vallois, David
Metref, Salima
Tarussio, David
Staels, Bart
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Published in Journal of Clinical Investigation. 2013, vol. 123, no. 4, p. 1662-76
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.
Keywords AnimalsBile Acids and Salts/metabolismBlood GlucoseCells, CulturedCholesterol/blood/metabolismDown-RegulationEnergy MetabolismFeces/chemistryFluorodeoxyglucose F18/metabolismGene Knockout TechniquesGlucose/metabolism/physiologyGlucose Intolerance/blood/geneticsGlucose Transporter Type 2/genetics/metabolismHomeostasisInsulin/secretionInsulin ResistanceInsulin-Secreting Cells/metabolism/secretionLipid MetabolismLiver/metabolism/physiopathology/radionuclide imagingMiceMice, 129 StrainMice, Inbred C57BLMice, KnockoutNuclear Proteins/genetics/metabolismRadiopharmaceuticals/metabolismTranscription Factors/genetics/metabolismTranscriptome
PMID: 23549084
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Article (Published version) (2 MB) - public document Free access
Research group Mitochondries et métabolisme énergétique (671)
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SEYER, Pascal et al. Hepatic glucose sensing is required to preserve β cell glucose competence. In: Journal of Clinical Investigation, 2013, vol. 123, n° 4, p. 1662-76. doi: 10.1172/JCI65538 https://archive-ouverte.unige.ch/unige:28233

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Deposited on : 2013-05-29

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