Scientists Identify New Mechanism of Insulin Resistance
DURHAM, NC – Resistance to insulin that precedes type 2
diabetes may stem from a "metabolic traffic jam" that blocks
the body's ability to switch between glucose and fat as energy
sources, say researchers at Duke University Medical Center.
Normal blood glucose (sugar) control depends on insulin, a
hormone that's released after eating that stimulates sugar
uptake in muscles and other parts of the body. Insulin
resistance arises when the body no longer responds to insulin's
signals. It's a serious condition that often accompanies
obesity and increases risk of developing type 2 diabetes, a
disease marked by dangerously high blood sugar levels.
Scientists have been studying the disorder for years, but have
not been able to agree upon its root cause.
But Debbie Muoio, an assistant professor of medicine in
Duke's Sarah W. Stedman Nutrition and Metabolism Center thinks
she may have a pretty good idea. She and her colleagues trace
the development of insulin resistance to overworked
mitochondria – the tiny power plants inside each cell – that
simply get worn down and worn out trying to burn excess
The study appears in the current issue of Cell
Normally, the body switches fuel sources during the day,
says Muoio, a phenomenon known as "metabolic flexibility."
"For example, overnight and during periods of fasting or
exercise, muscles and other organs in the body burn fat as
fuel. That's because there is usually more fat available at
that time. But during the day, and especially after a meal,
mitochondria switch to glucose," she says. This makes sense,
because food makes more glucose available and healthy
individuals increase glucose use when it's on hand. But there's
the hitch: If the diet is consistently too rich in fat and
calories, the switchover does not occur. The mitochondria just
keep working harder and harder to burn all the fat, and the
effort eventually fails.
This is what leads to a "metabolic traffic jam," – a
mitochondrial gridlock where fat accumulates and blocks the
use, or metabolism, of glucose. Muoio believes that chronically
stressed mitochondria send out a distress signal that prevents
insulin from doing its job, allowing sugar to build up in the
"We think this is what leads to insulin resistance," says
Muoio, who acknowledges that the idea is not entirely new. "The
first seeds of this hypothesis were actually planted fifty
years ago, but it died out because researchers lacked the
investigative tools to prove it."
Now, they have them. Muoio's team used a mass spectrometer
to identify mitochondrial metabolites – by-products of
fat-burning – that were found to be associated with obesity and
the onset of insulin resistance.
They also developed cell and animal models that showed that
when deprived of a fat-importing enzyme, mitochondria were
protected and muscles continued to respond to insulin's
signals, suggesting that fat overload was indeed the
There is some good news in all of this, though, says Muoio.
"There are two very easy ways to prevent insulin resistance:
Exercise more – you'll help mitochondria burn fat more
effectively, or eat less fat in your diet. That's always easier
said than done, of course."
Several other investigators from the Stedman Center
contributed to the research, including lead author Timothy
Koves, Robert Noland, Dorothy Slentz, Merrie Mosedale, Olga
Ilkayeva, James Bain, Robert Stevens and Christopher Newgard.
Additional co-authors include Gary Lopaschuk, John Ussher and
Jason Dyck, from the University of Alberta. Lopaschuk and Dyck
investment in a company interested in developing inhibitors to
an enzyme central to the mitochondrial activity described in
Funding for the study came from the National Institutes of
Health, the American Diabetes Association, the Canadian
Institutes of Health Research and the Canadian Diabetes