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:6/1/2016)... , June 1, 2016 Favorable ... Election Administration and Criminal Identification to Boost Global Biometrics ... recently released TechSci Research report, " Global Biometrics Market ... Competition Forecast and Opportunities, 2011 - 2021", the global ... by 2021, on account of growing security concerns across ...
(Date:5/12/2016)... WearablesResearch.com , a brand of Troubadour ... from the Q1 wave of its quarterly wearables survey. ... receptivity to a program where they would receive discounts ... company. "We were surprised to see that ... LaColla , CEO of Troubadour Research, "primarily because there ...
(Date:4/28/2016)... -- First quarter 2016:   , Revenues ... first quarter of 2015 The gross margin was 49% ... and the operating margin was 40% (-13) Earnings per ... from operations was SEK 249.9 M (21.2) , Outlook ... 7,000-8,500 M. The operating margin for 2016 is estimated ...
Breaking Biology News(10 mins):
(Date:6/23/2016)... ... June 23, 2016 , ... Supplyframe, the ... the Supplyframe Design Lab . Located in Pasadena, Calif., the Design Lab’s ... how hardware projects are designed, built and brought to market. , The Design ...
(Date:6/23/2016)... , June 23, 2016 Apellis Pharmaceuticals, ... 1 clinical trials of its complement C3 inhibitor, ... and multiple ascending dose studies designed to assess ... of subcutaneous injection in healthy adult volunteers. ... either as a single dose (ranging from 45 ...
(Date:6/23/2016)... , June 23, 2016 On Wednesday, ... at 4,833.32, down 0.22%; the Dow Jones Industrial Average edged ... closed at 2,085.45, down 0.17%. Stock-Callers.com has initiated coverage on ... ), Nektar Therapeutics (NASDAQ: NKTR ), Aralez Pharmaceuticals ... (NASDAQ: BIND ). Learn more about these stocks ...
(Date:6/23/2016)... ... June 23, 2016 , ... Velocity Products, ... tools designed, tuned and optimized exclusively for Okuma CNC machining centers at The ... of a collaboration among several companies with expertise in toolholding, cutting tools, machining ...
Breaking Biology Technology: