Research & Development World

  • Home Page
  • Topics
    • Aerospace
    • Archeology
    • Automotive
    • Biotech
    • Chemistry
    • COVID-19
    • Environment
    • Energy
    • Life Science
    • Material Science
    • R&D Market Pulse
    • R&D Management
    • Physics
  • Technology
    • 3D Printing
    • A.I./Robotics
    • Battery Technology
    • Controlled Environments
      • Cleanrooms
      • Graphene
      • Lasers
      • Regulations/Standards
      • Sensors
    • Imaging
    • Nanotechnology
    • Scientific Computing
      • Big Data
      • HPC/Supercomputing
      • Informatics
      • Security
      • Software
    • Semiconductors
  • 2021 R&D 100 Award Winners
    • R&D 100 Awards
    • 2020 Winners
    • Winner Archive
  • Resources
    • Digital Issues
    • Podcasts
    • Subscribe
  • Global Funding Forecast
  • Webinars

Potential Enzyme as Therapeutic Target for Diabetes

By Kanazawa University | January 29, 2018

Proposed model for HGU regulation by Sirt2. NAD+/Sirt2 deacetylates K126 of GKRP, an inhibitor protein of glucokinase, thereby inducing glucose-dependent GKRP dissociation from glucokinase and enhancing HGU. However, in obesity and diabetes, impeded NAD+/Sirt2-dependent GKRP deacetylation inhibits glucokinase-GKRP dissociation and reduces HGU. Photo: Kanazawa University

Abnormalities in glucose uptake by the liver (or hepatic glucose uptake; HGU) cause elevations in blood glucose levels following meals, a state that is known as postprandial hyperglycemia. Such abnormalities are observed in obesity and type 2 diabetes and result in an increased risk of cardiovascular complications. Although the exact mechanism of HGU impairment is unknown, there is evidence that it is mediated by abnormal regulation of the enzyme hepatic glucokinase and the glucokinase regulatory protein (GKRP).

Now, a team of Japanese researchers led by Hiroshi Inoue from Kanazawa University, Ishikawa, and collaborators from the National Centre for Global Health and Medicine, Tokyo, have identified a sirtuin enzyme (Sirt2) as a key player in regulating hepatic glucokinase through modifying GKRP, suggesting that this mechanism offers a potential therapeutic target for type 2 diabetes.

Previous reports show that the signaling molecule nicotinamide adenine dinucleotide (NAD+) governs glucose metabolism. In this paper, Inoue and colleagues used in vitro knockdown experiments to identify Sirt2 as a mediator of NAD+-dependent HGU. However, Sirt2, did not influence the gene expression levels of glucokinase and glucose-6-phosphatase, thereby implying that Sirt2 affected HGU through post-translational modifications.

In normal cells, glucokinase binds to GKRP in low glucose conditions, while the two proteins dissociate in response to elevation of glucose levels. In cells derived from diabetic mice, however, this desolation does not take place even under high glucose concentrations. In the current study, the researchers were able to reverse this perturbation by overexpressing Sirt2 and showed that Sirt2 can regulate the dissociation by directly binding to GKRP and deacetylating it (at residue K126) in a NAD+-dependent manner.

The researchers also performed experiments in mice and found that expressing a form of GKRP that could not be acetylated perturbs HGU, suggesting that acetylation of GKRP is involved in HGU and the maintenance of normal glucose levels. Furthermore, the researchers found that a decrease in NAD+-dependent Sirt2 activity and defective Sirt2-dependent deacetylation of GKRP were responsible, at least in part, for the HGU abnormality observed in obese diabetic mice.

Overall, the results indicate that NAD+ and Sirt2 regulate HGU and that Sirt2 acts through deacetylating GKRP. The authors conclude that “these findings suggest that NAD +/Sirt2-dependent GKRP deacetylation regulation plays an important role in HGU control and that this regulation is a novel therapeutic target in type 2 diabetes and obesity and is responsible for HGU impairment.”

Related Articles Read More >

New onesource concierge service streamlines flow cytometry management for labs
Amyloid Mass Spectrometry supports Alzheimer’s drug discovery and development
Exothera to develop and manufacture COVID vaccine based on proprietary technology
New dangers in the woods — and the hope that research offers us
2021 R&D Global Funding Forecast

Need R&D World news in a minute?

We Deliver!
R&D World Enewsletters get you caught up on all the mission critical news you need in research and development. Sign up today.
Enews Signup

R&D World Digital Issues

February 2020 issue

Browse the most current issue of R&D World and back issues in an easy to use high quality format. Clip, share and download with the leading R& magazine today.

Research & Development World
  • Subscribe to R&D World Magazine
  • Enews Sign Up
  • Contact Us
  • About Us
  • Drug Discovery & Development
  • Pharmaceutical Processing
  • 2022 Global Funding Forecast

Copyright © 2022 WTWH Media LLC. All Rights Reserved. The material on this site may not be reproduced, distributed, transmitted, cached or otherwise used, except with the prior written permission of WTWH Media
Privacy Policy | Advertising | About Us

Search R&D World

  • Home Page
  • Topics
    • Aerospace
    • Archeology
    • Automotive
    • Biotech
    • Chemistry
    • COVID-19
    • Environment
    • Energy
    • Life Science
    • Material Science
    • R&D Market Pulse
    • R&D Management
    • Physics
  • Technology
    • 3D Printing
    • A.I./Robotics
    • Battery Technology
    • Controlled Environments
      • Cleanrooms
      • Graphene
      • Lasers
      • Regulations/Standards
      • Sensors
    • Imaging
    • Nanotechnology
    • Scientific Computing
      • Big Data
      • HPC/Supercomputing
      • Informatics
      • Security
      • Software
    • Semiconductors
  • 2021 R&D 100 Award Winners
    • R&D 100 Awards
    • 2020 Winners
    • Winner Archive
  • Resources
    • Digital Issues
    • Podcasts
    • Subscribe
  • Global Funding Forecast
  • Webinars