Contact: Michael Smart, (801) 378-7320 [email protected]
BYU researcher mimics the beneficial effects of exercise by activating key enzyme
Finding opens doors to new treatment for type II diabetes
Embargoed until release of journal article Nov. 12
PROVO, Utah -- The 15 million Americans who suffer from type II diabetes all share the same problem: their muscles have difficulty absorbing glucose -- a sugar that provides energy -- from their bloodstreams. For years, scientists have known that physical exercise helps muscles take in glucose, but they haven't fully understood why -- until now.
Brigham Young University's Will Winder has now identified the key enzyme involved in triggering this absorption process and has repeatedly stimulated it with a drug in rats, resulting in some of the same beneficial results that exercise provides, including increased glucose uptake.
Winder's discovery opens up possibilities for scientists to now try to find a drug that will safely achieve the same effect in humans and also puts researchers one step closer to discovering what causes type II diabetes.
"We believe this to be a step forward in the effort to provide more effective treatments for patients with type II diabetes," said Winder, a professor of zoology. "There is still much work to be done before we can apply these findings to humans, but these results give us a good springboard."
Winder's research will be published this week as the "Highlighted Topic" in the Journal of Applied Physiology. The November issue of the journal goes online Nov. 12 at: http://jap.physiology.org
His findings help fill in a missing link to understanding one of the body's key chain reactions, the one ignited by exercise that results in better absorption of glucose into muscles. In this reaction, glucose is transported into muscle cells by proteins called "GLUT4." These transporter proteins act like buses that carry their passengers, glucose molecules, to muscles. Type II diabetics have just as many "buses" as healthy people do. But recent studies indicate that without regular exercise, many of type II diabetics' buses may sit stalled in the parking garage and don't carry the passengers into the muscle. Regular exercise stimulates the creation of more buses, and those extra reinforcements are thought to enable diabetics to absorb enough glucose to stay healthy. The ability to help type II diabetics manufacture more of those buses -- the GLUT4 transporter proteins -- is a key in combating their disease.
What scientists didn't know until Winder's study was how exercise "turned on" the gene that tells the body to make more transporters. He found that the spark plug of that process is an enzyme called AMP-activated kinase (AMPK). This enzyme is normally activated when muscles contract.
"The discovery that activation of AMPK can turn on the synthesis of GLUT4 provides a link between the events that occur during exercise and the increase in GLUT4 protein," explained Lynis Dohm, a GLUT4 researcher and professor of biochemistry at the East Carolina University School of Medicine.
"The discovery that activation of (this enzyme) increases transporter protein is a major finding because it give us both an explanation for how exercise increases glucose uptake in muscle and also a possible pharmacological treatment for diabetes," Dohm said. "Any treatment that will increase the rate of glucose transport into muscle will be a useful treatment for diabetes."
Winder emphasizes that there is more to the AMPK story than these new findings. Building on the work of previous researchers, his team -- including Grahame Hardie of Dundee, Scotland and Gary Merrill of Rutgers -- published a paper in late 1997 that was the first to report the key triggering effect of AMPK in the glucose absorption process. Collaborating with Laurie Goodyear's team at Harvard's Joslin Diabetes Center, Winder developed more evidence for the short-term effects of AMPK.
Then he wanted to see if there could be a long-term positive effect of activating the enzyme. His recent experiments show that there is. Repeated activation of the enzyme over a five-day period results in long-term increases in the transporter proteins. Rats who had repeated injections of the drug, AICAR, that triggered the enzyme had higher counts of transporters even after the initial effects of the drug wore off.
That means that drugs that activate AMPK could mimic the long-term beneficial effects of exercise for diabetics. It also brings to mind the tempting but counterintuitive prospect of losing weight without exercising. In fact, Winder's work could lead to a possible drug to treat obesity because he has found that the AMPK enzyme stimulates the fat burning process at the same time it triggers glucose absorption.
He emphasizes, however, that a good, old-fashioned work-out will still be better in the long run. First of all, artificial activation of AMPK doesn't increase the metabolism like exercise does. Also, when muscles contract they use the glucose they have stored away in a form called glycogen. Triggering AMPK with a drug causes the transporters to bring more glucose into the muscle, but it doesn't use up the glycogen that's already there, so there might not be room for the new glucose. Researchers will have to figure out a way to artificially deplete glycogen as part of their effort to find a drug for type II diabetics.
"It is possible that activating the AMPK system with drugs may prove useful for treatment of obesity and in stimulating glucose uptake in those who are unable to exercise," Winder said. "But exercise will always be a better solution for the rest of us. There is already good evidence that those who exercise regularly are less apt to develop type II diabetes."
Winder plans to test different compounds for their effects on AMPK in an effort to find a drug that can activate the fat-burning and glucose uptake processes in humans. He's also collaborating with East Carolina's Dohm to determine exactly how AMPK signals the gene that makes GLUT4 transporter proteins.
"Despite a considerable amount of effort and resources allocated to determining the origins of the disease, the basic cellular defect for the vast majority of patients remains unknown," Winder said. "Finding a cause is essential to finding a cure."
Winder's coauthors on the Journal of Applied Physiology study are Burton Holmes and Emily Kurth-Kraczek, both BYU graduate students in zoology. The BYU research into the effects of AMPK is funded by a five-year, $750,000 grant from the National Institute of Arthritis
and Musculoskeletal and Skin Diseases, a part of the National Institutes of Health (NIH).
As Winder concludes the third year of the grant period, he is guardedly optimistic about the achievements of his team so far.
"One always hopes that work funded by the NIH will yield something that will benefit the people paying the bill," Winder said, referring to the taxpayer-supported nature of the NIH. "It's really quite gratifying to see our work go in this direction, where it might be applied to the treatment of diabetes."
Contact: William Winder, (801) 378-3093
Lynis Dohm, (252) 816-2682
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