Featured Research

from universities, journals, and other organizations

Sugar production switch in liver may offer target for new diabetes therapies

Date:
April 8, 2012
Source:
Salk Institute for Biological Studies
Summary:
A newly discovered molecular switch controls liver glucose production and may represent a new avenue for treating insulin-resistant type II diabetes.

This is Marc R. Montminy, professor, Clayton Foundation Laboratories for Peptide Biology and Yiguo Wang, a research associate.
Credit: Image: Courtesy of the Salk Institute for Biological Studies

In their extraordinary quest to decode human metabolism, researchers at the Salk Institute for Biological Studies have discovered a pair of molecules that regulates the liver's production of glucose -- -- the simple sugar that is the source of energy in human cells and the central player in diabetes.

In a paper published April 8 in Nature, the scientists say that controlling the activity of these two molecules -- -- which work together to allow more or less glucose production -- -- could potentially offer a new way to lower blood sugar to treat insulin-resistant type II diabetes. They showed, through an experimental technique, that this was possible in diabetic mice.

"If you control these switches, you can control the production of glucose, which is really at the heart of the problem of type 2 diabetes," says Professor Marc Montminy, head of Salk's Clayton Foundation Laboratories for Peptide Biology.

The need for new drugs is accelerating, says Montminy, as almost 26 million Americans have type II diabetes, and an estimated 79 million people are at risk of developing the condition. Diabetes is the sixth leading cause of death in the United States, and treatment costs are estimated at $116 billion annually.

In order to develop new and effective treatments for diabetes, researchers need to understand the complex and delicate biology behind human metabolism as well as the disorders that develop when this finely tuned system is out of balance, Montminy says.

During the day, humans burn glucose, derived from the food we eat. This is the fuel that supplies the muscles and other parts of the body expending energy. At night, when we sleep, we revert to stored fat as a source of very dependable but slowly released energy. But certain parts of the body, most notably the brain, require glucose as a source of energy, even when we fast.

Pancreatic islet cells control both sides of this energy equation. Located in the pancreas, they produce glucagon, a hormone released during fasting, to tell the liver to make glucose for use by the brain. This process is reversed when we feed, and when the pancreatic islets release insulin, which tells the liver to stop making glucose.

Thus glucagon and insulin are part of a feedback system designed to keep blood glucose at a stable level.

Montminy's lab has for years focused on the central switches that control glucose production in the liver and others that control glucose sensing and insulin production in the pancreas. Among his key findings is that glucagon -- -- the fasting hormone -- -- turns on a genetic switch (CRTC2) that ramps up production of glucose in the blood. In turn, when insulin is increased in the blood, activity of CRTC2 is inhibited, and the liver produces less glucose.

"But in insulin-resistant type II diabetic individuals, the CRTC2 switch is turned on too strongly because the insulin signal is not getting through," Montminy says. "As a result, the liver produces too much glucose and the level of glucose in the blood stream is too high. Over a period of 10 to 20 years, the abnormal elevation of glucose leads to chronic complications including heart disease, blindness and kidney failure."

The new findings in the Nature study identify a relay system that explains how glucagon activates the CRTC2 switch during fasting, and how that system is compromised during diabetes.

The scientists say this relay system involves a molecular receptor (IP3) on the outside of liver cells that they call a "molecular spigot." Glucagon opens the IP3 spigot during fasting, allowing an increase in calcium, a common signaling molecule in the cell. This stimulates a molecular gas pedal, of sorts, known as calcineurin, which revs up CRTC2, activating genes that allow the liver to drive the metabolic engine by producing more glucose.

This is important, Montminy says, because the team also discovered that activity of the IP3 receptor and calcineurin in the liver are increased in diabetic insulin resistance, resulting in more blood sugar.

The findings therefore suggest that agents that can selectively damp down activity of the IP3 spigot and the calcineurin accelerator might help to shut down the CRTC2 switch and to lower blood sugar in type II diabetic patients, he says. That is precisely what happened when the researchers used these compounds on liver cells.

"We obviously have a lot of work to do to find out whether such a strategy might work in humans," he says.

The research team includes investigators from Salk Institute, Columbia University, University of California San Diego and University of Ottawa. In addition to Montminy, the coauthors on the paper are Yiguo Wang, Gang Li, Jason Goode, Jose Paz, Kunfu Ouyang, Robert Screaton, Wolfgang Fischer, Ju Chen and Ira Tabas.

The study was funded by grants from the National Institutes of Health, the Kieckhefer Foundation, the Clayton Foundation for Medical Research and the Leona M. and Harry B. Helmsley Charitable Trust.


Story Source:

The above story is based on materials provided by Salk Institute for Biological Studies. Note: Materials may be edited for content and length.


Journal Reference:

  1. Yiguo Wang, Gang Li, Jason Goode, Jose C. Paz, Kunfu Ouyang, Robert Screaton, Wolfgang H. Fischer, Ju Chen, Ira Tabas, Marc Montminy. Inositol-1,4,5-trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes. Nature, 2012; DOI: 10.1038/nature10988

Cite This Page:

Salk Institute for Biological Studies. "Sugar production switch in liver may offer target for new diabetes therapies." ScienceDaily. ScienceDaily, 8 April 2012. <www.sciencedaily.com/releases/2012/04/120408150618.htm>.
Salk Institute for Biological Studies. (2012, April 8). Sugar production switch in liver may offer target for new diabetes therapies. ScienceDaily. Retrieved July 31, 2014 from www.sciencedaily.com/releases/2012/04/120408150618.htm
Salk Institute for Biological Studies. "Sugar production switch in liver may offer target for new diabetes therapies." ScienceDaily. www.sciencedaily.com/releases/2012/04/120408150618.htm (accessed July 31, 2014).

Share This




More Health & Medicine News

Thursday, July 31, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

House Republicans Vote to Sue Obama Over Healthcare Law

House Republicans Vote to Sue Obama Over Healthcare Law

Reuters - US Online Video (July 31, 2014) The Republican-led House of Representatives votes to sue President Obama, accusing him of overstepping his executive authority in making changes to the Affordable Care Act. Mana Rabiee reports. Video provided by Reuters
Powered by NewsLook.com
Despite Health Questions, E-Cigs Are Beneficial: Study

Despite Health Questions, E-Cigs Are Beneficial: Study

Newsy (July 31, 2014) Citing 81 previous studies, new research out of London suggests the benefits of smoking e-cigarettes instead of regular ones outweighs the risks. Video provided by Newsy
Powered by NewsLook.com
Dangerous Bacteria Kills One in Florida

Dangerous Bacteria Kills One in Florida

AP (July 31, 2014) Sarasota County, Florida health officials have issued a warning against eating raw oysters and exposing open wounds to coastal and inland waters after a dangerous bacteria killed one person and made another sick. (July 31) Video provided by AP
Powered by NewsLook.com
Health Insurers' Profits Slide

Health Insurers' Profits Slide

Reuters - Business Video Online (July 30, 2014) Obamacare-related costs were said to be behind the profit plunge at Wellpoint and Humana, but Wellpoint sees the new exchanges boosting its earnings for the full year. Fred Katayama reports. Video provided by Reuters
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins