Histidine Augments the Suppression of Hepatic Glucose Production by Central Insulin Action

  1. Hiroshi Inoue1
  1. 1Department of Physiology and Metabolism, Brain/Liver Interface Medicine Research Center, Kanazawa University, Kanazawa, Japan
  2. 2Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
  3. 3Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan
  4. 4Division of Analytical Biomedical Sciences, Kobe University Graduate School of Health Sciences, Kobe, Japan
  5. 5BRAND’S Brain Research Centre, Cerebos Pacific Limited, Singapore, Singapore
  6. 6Division of Pharmaceutical Sciences, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
  7. 7Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Japan
  8. 8Laboratory of Host Defense, Immunology Frontier Research Center, Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Japan
  9. 9Department of Cell Metabolism and Nutrition, Brain/Liver Interface Medicine Research Center, Kanazawa University, Kanazawa, Japan
  10. 10Health Science Service Center, Kanazawa University, Kanazawa, Japan
  11. 11Department of Disease Control and Homeostasis, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
  12. 12Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
  1. Corresponding author: Hiroshi Inoue, inoue-h{at}staff.kanazawa-u.ac.jp.

Abstract

Glucose intolerance in type 2 diabetes is related to enhanced hepatic glucose production (HGP) due to the increased expression of hepatic gluconeogenic enzymes. Previously, we revealed that hepatic STAT3 decreases the expression of hepatic gluconeogenic enzymes and suppresses HGP. Here, we show that increased plasma histidine results in hepatic STAT3 activation. Intravenous and intracerebroventricular (ICV) administration of histidine-activated hepatic STAT3 reduced G6Pase protein and mRNA levels and augmented HGP suppression by insulin. This suppression of hepatic gluconeogenesis by histidine was abolished by hepatic STAT3 deficiency or hepatic Kupffer cell depletion. Inhibition of HGP by histidine was also blocked by ICV administration of a histamine H1 receptor antagonist. Therefore, histidine activates hepatic STAT3 and suppresses HGP via central histamine action. Hepatic STAT3 phosphorylation after histidine ICV administration was attenuated in histamine H1 receptor knockout (Hrh1KO) mice but not in neuron-specific insulin receptor knockout (NIRKO) mice. Conversely, hepatic STAT3 phosphorylation after insulin ICV administration was attenuated in NIRKO but not in Hrh1KO mice. These findings suggest that central histidine action is independent of central insulin action, while both have additive effects on HGP suppression. Our results indicate that central histidine/histamine-mediated suppression of HGP is a potential target for the treatment of type 2 diabetes.

Footnotes

  • Received December 7, 2012.
  • Accepted March 4, 2013.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

| Table of Contents

This Article

  1. Diabetes vol. 62 no. 7 2266-2277
  1. Supplementary Data
  2. All Versions of this Article:
    1. db12-1701v1
    2. 62/7/2266 most recent