Interviewee: Ron Evans, Salk Institute
How Overeating Leads to Diabetes
The current obesity epidemic has in its shadow a growing diabetes epidemic, since obesity is a major risk factor for diabetes. That’s because obesity leads to the insulin resistance that causes Type-II diabetes. But exactly why it occurs has not been completely clear on a molecular level.
Now researchers at the Salk Institute in La Jolla, CA, have discovered a new piece to the molecular puzzle, and think they have an important new target for treating insulin resistance, and diabetes.
“We discovered a way that we can reactivate the process of insulin action and therefore defeat the mechanisms that are associated with increased eating and obesity and hopefully develop a new treatment for diabetes,” says Ron Evans, molecular biologist and professor at the Salk Institute.
When we eat, our bodies produce insulin to turn sugar into energy. In obese people, that process somehow goes awry, and the body’s cells reject sugar as an energy source and the sugar instead enters the bloodstream.
Evans says until recently most scientists thought the process of pumping insulin into cells was like stepping on the accelerator pedal of a car.
“When you push down that would be insulin. And when you take your foot off the accelerator, that was what most people thought stops the action of insulin,” he says. “But that’s different than having a brake, and taking your foot off the accelerator is not he same as putting on the brake. And a car would not work well if you could only take your foot off the accelerator.”
But when observing individual cells in the lab, he and his colleagues discovered a molecule, an enzyme called OGT (short for O-linked Beta-N-acetylglucosamine transferase), that actually serves as a brake that turns insulin off. They wrote in the journal Nature that in obese people, this brake probably works too well, and leads to diabetes.
“It’s like trying to drive [a car] with the brake on,” says Evans, who is also an investigator at the Howard Hughes Medical Institute. “Not a very efficient process.”
He says the reason no one noticed it before could be that this brake was located in an unexpected place, the cell nucleus, whereas the insulin signaling is known to happen on the surface of the cell.
“So it starts on the outside, it triggers a response on the inside, that helps turn the system down,” he explains. “And we were very surprised by, first, the nature of the switch from the inside to the outside. And this is an idea of location is everything. The insulin causes a change of location of our switch that allows the entire process to be turned off.”
Evans thinks that treatments that target the brake might be more effective than today’s diabetes treatments, which are aimed at the accelerator, because the brake exerts control over everything else: “If you can control the brake, you can either increase the braking activity or you can let it go. And improve insulin action or you can slow it down. So we now have a key control.”
Controlling the Brake
After discovering the enzyme, Evans and postdoctoral student Xiaoyong Yang bred mice and fed them a high fat, high calorie diet, equivalent to a fast food diet in people. The mice became obese and diabetic.
“Then we genetically triggered the switch to be either on or off and asked what happened,” explains Evans. “And just as we predicted, when the switch was on, it slammed the breaks on insulin action and when the switch was off, it increased the accelerator and allowed insulin to perform more effectively than normal.”
While fine-tuning how to precisely control this switch, just how “on” or “off” to turn it, will take some time, Evans says the switch itself is an exciting new target for a new generation of diabetes drugs. He says it could lead to a pill that replaces insulin injections for diabetics.
“Our view is that we can develop a drug that is a pill that people with diabetes or some type of problem in responding to insulin could take on a daily basis,” he says. “And that pill would help take that foot off the break all the time and allow the entire system to be more in balance so that you accelerate when you need it, and you break when you need it. And so you wont be fighting yourself the entire time.”
And since insulin resistance is just the beginning of a long line of related health problems, including high blood pressure, heart disease and nerve damage, the pill could be considered much more than a diabetes drug.
“We think this will be another way to give general body healthfulness that goes beyond just diabetes, but will help many of the problems associated with overweight and excess calories,” he says.
Evans is now in the process of creating such a drug. He hopes to license it to a pharmaceutical company for large scale testing and development, a process that could take five to six years.
The research was published in the February 12 issue of Nature, and was funded by the Howard Hughes Medical Institute, National Institutes of Health, University of California Discovery BioStar grant with matching funds from Pfizer Incorporated, Burroughs Wellcome Fund, and the V Foundation.
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