Cellular 'stress sensor' that also modulates metabolism could offer therapeutic target for diabetes

July 31, 2013
Cell biology: Cellular damage control’s link with diabetes
Experiments in a fruit fly model offer useful insights into a potentially important clinical target in human obesity and diabetes. Credit: 2013 European Molecular Biology Laboratory

An organelle called the endoplasmic reticulum (ER) helps to process newly synthesized proteins destined for delivery to the cell membrane. When the ER becomes overloaded and begins to accumulate poorly folded proteins, an 'ER stress' response ensues. ER stress tends to occur in obesity and other metabolic disorders. Now, research from Stephen Cohen and colleagues at the A*STAR Institute of Molecular and Cell Biology has revealed a potential therapeutic target linking ER stress to the onset of diabetes.

Cohen's team initially set out to identify components of the . "We were screening for genes involved in tissue growth control in the fly," he says (see image). "Growth is regulated in part by the insulin pathway, so such screens can also pick up genes that function as metabolic regulators." Their screen focused on FOXO, a protein that acts as a regulator of other genes. Insulin signaling causes FOXO to segregate in the cytoplasm, so that it can no longer bind its in the nucleus. The researchers therefore searched for other genes that modulate FOXO activity.

They uncovered a link between PERK, a protein that disseminates signals involved in ER stress, and FOXO. When they genetically modified fruit flies to produce excess FOXO, this protein suppressed insulin-induced growth and the flies matured with small, underdeveloped eyes. However, when the researchers also reduced PERK levels in these flies, returned to normal, indicating that PERK helps amplify the effects of FOXO.

Follow-up experiments demonstrated that PERK introduces chemical modifications to FOXO that help direct this protein to the nucleus where it executes its gene regulatory functions. Cohen and colleagues demonstrated that PERK also boosts FOXO function in , and found that lowering PERK activity increased these cells' sensitivity to insulin signaling. FOXO also helps to promote in cells by increasing production of the insulin receptor—which in turn inactivates FOXO. Thus, PERK contributes significantly to an important metabolic feedback loop.

This system could be susceptible to break down if PERK activity were to intersect with other ER stress-induced signaling pathways. This could accelerate the onset of metabolic disease by promoting insulin resistance, a disruption of insulin signaling that is also a critical step towards onset of diabetes. "We are very interested in the potential that PERK could be used to modulate insulin responsiveness," says Cohen. "We are now exploring the biological functions of PERK to better understand its potential usefulness as a ."

Explore further: Joslin researchers discover new effect for insulin

More information: Zhang, W., Hietakangas, V., Wee, S., Lim, S. C., Gunaratne, J. & Cohen, S. M. ER stress potentiates insulin resistance through PERK-mediated FOXO phosphorylation. Genes & Development 27, 441–449 (2013). www.genesdev.org/cgi/doi/10.1101/gad.201731.112

Related Stories

Joslin researchers discover new effect for insulin

March 20, 2008

Researchers at the Joslin Diabetes Center have shown that insulin has a previously unknown effect that plays a role in aging and lifespan, a finding that could ultimately provide a mechanism for gene manipulations that could ...

A new strategy normalizes blood sugars in diabetes

March 28, 2010

Researchers at Children's Hospital Boston have identified a new strategy for treating type 2 diabetes, identifying a cellular pathway that fails when people become obese. By activating this pathway artificially, they were ...

Treatment target for diabetes, Wolfram syndrome

August 7, 2012

Inflammation and cell stress play important roles in the death of insulin-secreting cells and are major factors in diabetes. Cell stress also plays a role in Wolfram syndrome, a rare, genetic disorder that afflicts children ...

Protecting the body in good times and bad

July 16, 2013

The nasty side effects of radiation and chemotherapy are well known: fatigue, hair loss and nausea, to name a few. Cancer treatment can seem as harsh as the disease because it can't differentiate healthy cells from cancerous ...

Recommended for you

Researchers discover otulipenia, a new inflammatory disease

August 22, 2016

National Institutes of Health researchers have discovered a rare and sometimes lethal inflammatory disease - otulipenia - that primarily affects young children. They have also identified anti-inflammatory treatments that ...

Solving the mystery of meningiomas reveals a surprise twist

August 23, 2016

In solving one mystery—the genetic roots of benign brain tumors called meningiomas—a team of scientists led by Yale researchers stumbled upon an even greater one: How is it possible that two of the mutations linked to ...

Two key proteins preserve vital genetic information

August 22, 2016

Cancer is often driven by various genetic mutations that are acquired through changes to a person's DNA over time. These alterations can occur at the chromosome level if the proteins are not properly organized and segregated ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.