Hepatic glucose sensing is required to preserve β cell glucose competence

J Clin Invest. 2013 Apr;123(4):1662-76. doi: 10.1172/JCI65538. Epub 2013 Mar 15.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bile Acids and Salts / metabolism
  • Blood Glucose
  • Cells, Cultured
  • Cholesterol / blood
  • Cholesterol / metabolism
  • Down-Regulation
  • Energy Metabolism
  • Feces / chemistry
  • Fluorodeoxyglucose F18 / metabolism
  • Gene Knockout Techniques
  • Glucose / metabolism*
  • Glucose / physiology
  • Glucose Intolerance / blood
  • Glucose Intolerance / genetics
  • Glucose Transporter Type 2 / genetics
  • Glucose Transporter Type 2 / metabolism
  • Homeostasis
  • Insulin / metabolism
  • Insulin Resistance
  • Insulin Secretion
  • Insulin-Secreting Cells / metabolism*
  • Lipid Metabolism
  • Liver / diagnostic imaging
  • Liver / metabolism*
  • Liver / physiopathology
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Radionuclide Imaging
  • Radiopharmaceuticals / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcriptome

Substances

  • Bile Acids and Salts
  • Blood Glucose
  • Glucose Transporter Type 2
  • Insulin
  • Mlxipl protein, mouse
  • Nuclear Proteins
  • Radiopharmaceuticals
  • Slc2a2 protein, mouse
  • Transcription Factors
  • Fluorodeoxyglucose F18
  • Cholesterol
  • Glucose

Associated data

  • GEO/GSE43581