Navigation Links
The battle for CRTC2: How obesity increases the risk for diabetes
Date:6/21/2009

La Jolla, CAObesity is probably the most important factor in the development of insulin resistance, but science's understanding of the chain of events is still spotty. Now, researchers at the Salk Institute for Biological Studies have filled in the gap and identified the missing link between the two. Their findings, to be published in the June 21, 2009 advance online edition of the journal Nature, explain how obesity sets the stage for diabetes and why thin people can become insulin-resistant.

The Salk team, led by Marc Montminy, Ph.D., a professor in the Clayton Foundation Laboratories for Peptide Biology, discovered how a condition known as ER (endoplasmic reticulum) stress, which is induced by a high fat diet and is overly activated in obese people, triggers aberrant glucose production in the liver, an important step on the path to insulin resistance.

In healthy people, a "fasting switch" only flips on glucose production when blood glucose levels run low during fasting. "The existence of a second cellular signaling cascadelike an alternate route from A to Bthat can modulate glucose production, presents the potential to identify new classes of drugs that might help to lower blood sugar by disrupting this alternative pathway," says Montminy.

It had been well established that obesity promotes insulin resistance through the inappropriate inactivation of a process called gluconeogenesis, where the liver creates glucose for fuel and which ordinarily occurs only in times of fasting. Yet, not all obese people become insulin resistant, and insulin resistance occurs in non-obese individuals, leading Montminy and his colleagues to suspect that fasting-induced glucose production was only half the story.

"When a cell starts to sense stress a red light goes on, which slows down the production of proteins," explains Montminy. "This process, which is known as ER stress response, is abnormally active in livers of obese individuals, where it contributes to the development of hyperglycemia, or high blood glucose levels. We asked whether chronic ER stress in obesity leads to abnormal activation of the fasting switch that normally controls glucose production in the liver." The ER, short for endoplasmic reticulum, is a protein factory within the cell.

To test this hypothesis the Salk team asked whether ER stress can induce gluconeogenesis in lean mice. Glucose production is turned on by a transcriptional switch called CRTC2, which normally sits outside the nucleus waiting for the signal that allows it to slip inside and do its work. Once in the nucleus, it teams up with a protein called CREB and together they switch on the genes necessary to increase glucose output. In insulin-resistant mice, however, the CRTC2 switch seems to get stuck in the "on" position and the cells start churning out glucose like sugar factories in overdrive.

Surprisingly, when postdoctoral researcher and first author Yiguo Wang, Ph.D., mimicked the conditions of ER stress in mice, CRTC2 moved to the nucleus but failed to activate gluconeogenesis. Instead, it switched on genes important for combating stress and returning cells to health. On closer inspection, Wang found that in this scenario CRTC2 did not bind to CREB but instead joined forces with another factor, called ATF6a.

What's more, like jealous lovers CREB and ATF6a competing for CRTC2's affectionthe more ATF6a is bound to CRTC2, the less there is for CREB to bind to. "This clever mechanism ensures that a cell in survival mode automatically shuts down glucose production, thus saving energy," says Wang.

This observation led the researcher to ask what happens to ATF6a following the kind of persistent stress presented by obesity? They found that the levels of ATF6a go down when ER stress is chronically activated, compromising the cells' survival pathway and favoring the glucose production pathway; hyperglycemia wins in conditions of persistent stress.

Explains Wang, "Our study helps to explain why obese people have a stronger tendency to become diabetic. When ER stress signaling is abnormal glucose output is actually increased."

"It is possible that mutations in the highly conserved CRTC2 lead to a predisposition to inappropriate gluconeogenesis," says Montminy, who is now trying to identify natural mutations in CRTC2 that may lead to insulin resistance in carriers.


'/>"/>

Contact: Gina Kirchweger
Kirchweger@salk.edu
858-453-410-01340
Salk Institute
Source:Eurekalert  

Related biology news :

1. Queens scientists find new way to battle MRSA
2. Carbon sinks losing the battle with rising emissions
3. Researchers identify potential new weapon in battle against HIV infection
4. Color My Pyramid nutrition education program battles obesity in DC schools
5. In Vietnam, alongside progress, a battle for life
6. LSU and Ohio State battle on football field, collaborate in research field
7. In promiscuous antelopes, the battle of the sexes gets flipped
8. Amber specimen captures ancient chemical battle
9. Older climbers face uphill battle on Mount Everest
10. Researchers engineer metabolic pathway in mice to prevent diet-induced obesity
11. New guidelines to fight obesity in pregnancy issued
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
The battle for CRTC2: How obesity increases the risk for diabetes
(Date:1/20/2016)... Jan. 20, 2016  Synaptics Incorporated (NASDAQ: ... solutions, today announced sampling of S1423, its newest ... and small screen applications including smartwatches, fitness trackers, ... round and rectangular shapes, as well as thick ... with moisture on screen, while wearing gloves, and ...
(Date:1/13/2016)... New York , January 13, 2016 ... Market Research has published a new market report titled ... Growth, Trends, and Forecast, 2015 - 2023. According to the ... in 2014 and is anticipated to reach US$1,625.8 mn ... 2015 to 2023. In terms of volume, the biometric ...
(Date:1/11/2016)... , Jan. 11, 2016  higi, the leading ... 10,000 retail locations, web and mobile, today announced ... million from existing investors. --> ... devoted to further innovate higi,s health platform – ... web portal – including expanding services and programs ...
Breaking Biology News(10 mins):
(Date:2/4/2016)... EDISON, N.J. , Feb. 4, 2016 ... company focused on the development and commercialization of targeted ... BIO CEO & Investor Conference 2016, to be held ... and Source Capital Group,s 2016 Disruptive Growth & Healthcare ... on February 10-11, 2016. James Sapirstein ...
(Date:2/4/2016)... , February 4, 2016 ... Laboratories (ABL), Inc. --> Strasbourg, France ... --> PharmaVentures is pleased to announce that it ... its biopharmaceutical manufacturing unit in Strasbourg, France ... --> --> Transgene (Euronext: ...
(Date:2/3/2016)... -- With the growing need for better therapeutics, and ... such as monoclonal antibodies, recombinant protein therapeutics and ... are in high demand. Conventionally expression systems were ... of these therapeutics. However, due to issues with ... approaches and novel expression systems are currently being ...
(Date:2/3/2016)... ... February 03, 2016 , ... ... a new office dedicated to the North American healthcare market. , Aerocom Healthcare, ... healthcare facilities. The company will provide new pneumatic tube systems or expand ...
Breaking Biology Technology: