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Hepatic glucose sensing is required to preserve β cell glucose competence
Pascal Seyer, … , Marc Foretz, Bernard Thorens
Pascal Seyer, … , Marc Foretz, Bernard Thorens
Published March 15, 2013
Citation Information: J Clin Invest. 2013;123(4):1662-1676. https://doi.org/10.1172/JCI65538.
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Research Article Metabolism Article has an altmetric score of 17

Hepatic glucose sensing is required to preserve β cell glucose competence

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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

Pascal Seyer, David Vallois, Carole Poitry-Yamate, Frédéric Schütz, Salima Metref, David Tarussio, Pierre Maechler, Bart Staels, Bernard Lanz, Rolf Grueter, Julie Decaris, Scott Turner, Anabela da Costa, Frédéric Preitner, Kaori Minehira, Marc Foretz, Bernard Thorens

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Figure 2

Absence of liver GLUT2 expression suppresses hepatic glucose uptake but does not impair endogenous glucose production.

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Absence of liver GLUT2 expression suppresses hepatic glucose uptake but ...
(A) PET imaging of 18FDG uptake by the liver and kidneys of control and LG2KO mice during the first 15 minutes after injection (dorsal view; red, high uptake; green, low uptake). (B) Kinetics of 18FDG uptake by the liver of control (white squares, n = 6) and LG2KO (black circles, n = 8) mice. Note the suppression of 18FDG uptake between 1 minute and 9 minutes after injection in the liver of LG2KO mice. **P < 0.01 versus control mice. (C) Time-activity curve of 18FDG uptake in the blood of control (white squares, n = 6) and LG2KO (black circles, n = 8) mice acquired by imaging the inferior vena cava. Inset shows expanded view of the same graph from 0 to 3 minutes after tracer injection. (D) Endogenous glucose production by control and LG2KO mice (n = 10). (E) Evolution of blood glucose levels in fasted control and LG2KO mice (n = 9). ***P < 0.001 versus control mice. (F) Evolution of hepatic glycogen content in control and LG2KO mice in the indicated states (n = 5). **P < 0.01. Rd, rate of glucose disappearance; HGO, hepatic glucose output.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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