SALT LAKE CITY — Using mice, researchers from the University of Utah have discovered a treatment that could potentially prevent Type 2 diabetes in humans, according to a new study.
"We know that there's a link between obesity and diabetes and heart disease. We think that the real problem, the real driver of disease, is not necessarily how much fat you have, but how much fat you store in the wrong place," said Scott Summers, chairman of Nutrition and Integrative Physiology at U. Health.
By targeting ceramides — a type of fat molecule — in the mice, researchers were able to keep obese mice healthy, long-living and free from diabetes. They say the research could be translated into a future drug to help prevent diabetes in people.
Summers served as co-senior author on the study published last week in "Science." When we eat too much, he said, our bodies stores nutrients as triglycerides in fat cells. That's a safe way to store fat, but those stores eventually get full and the nutrients move into other places like the heart, liver and pancreatic cells, which aren't designed to store fat.
More than 150,000 people in Utah have been diagnosed with diabetes, according to the Utah Department of Health. Meanwhile, about 80 million Americans ages 20 and older are said to have pre-diabetes, putting them at risk for getting the disease. The state spends more than a billion dollars every year on direct and indirect costs of diabetes.
The key to preventing pre-diabetes lies in ceramides, Summers said.
Scientists think ceramides are designed to protect cells from too much fat, Summers explained, but if they build up too much, they drive diabetes and heart disease.
During the study, the researchers generated some mice so that they could remove the ceramide gene completely from their bodies. In other mice, the researchers edited their DNA to remove the gene from different organs.
When the gene was taken out of the whole animal, they lived without the gene for over a year, "which was surprising to us," Summers said.
"Because if you got rid of that gene before they were born, it's really harmful and the animals were quite sick. But if we got rid of it after they were born, the animals were fine. So that was pretty amazing to us," the doctor explained.
The control group of mice kept the gene containing ceramides and received treatment with a drug that helps remove them.
Researchers used two methods to make the mice obese — some were fed a high fat diet of cookie dough.
"And they get quite heavy, and they sort of become pre-diabetic, and (have) fatty liver disease," Summers said.
Others were obese because they lacked a gene called leptin. Humans and animals that lack leptin eat insatiably and become morbidly obese, Summers said, unless they're given leptin. Without leptin, those mice were genetically engineered to be obese, even on a normal diet.
When ceramides were taken out of the leptin-deficient mice, they remained "incredibly obese" but "completely healthy," according to Summers.
Results were consistent among all of the mice groups.
Summers said one of his students refers to the mice as "fat, happy, and feeling fine."
Impaired glucose tolerance, which is a measure of pre-diabetes, was resolved in all of the mice. Obese animals usually don't clear glucose very quickly, but the researchers' treatment made the "fat mice" handle glucose like skinny mice, according to Summers. Results were the same for both male and female mice.
The mice have been treated — and survived — for more than a year. Researchers continue to watch them to see how long they'll live.
The findings mark a milestone in diabetes research.
U. scientists have been trying to find a way to lower ceramides for several years. Since 2007, scientists have known that lowering ceramides could prevent diabetes. But the approach they were using — which included inhibiting another enzyme — didn't work, Summers said. A drug that was in development ended up causing toxicity.
But the new findings could lead to a drug treatment for people at risk or in the early stages of diabetes and even heart disease.
"We think this enzyme, this approach, one might make a drug against it and ceramides, and prevent diabetes and heart disease," Summers said.
Merck researchers also worked on the project. Both groups saw the same results in their joint efforts. The gene-editing method isn't likely to work in humans, though, according to Summers.
He and colleagues formed a company called Centaurus Therapeutics to develop the findings into a drug for humans. "And so we think this might be a real pharmacological approach to treat the disease."
In recent years, the evidence on ceramides has become "so strong" that Mayo Clinic has started to measure them in blood as markers of diabetes and heart disease, Summers said.
One in four people in Utah have a mutation in their gene that scientists think causes them to make more ceramides. People with the mutation have a higher rate of diabetes, according to Summers.
The researchers believe they're a year or two away from the treatment becoming available to humans. They're still going through safety screenings with drugs and hoping a pharmaceutical company will move forward with clinical trials.
The U. researchers also received a grant from the Juvenile Diabetes Research Foundation to test whether they might be able to reverse the effects of Type 1 diabetes.
Summers said patients sometimes call him and tell him their ceramides are high, asking for advice.
"And we don't have a lot to tell them right now. But I think we may in the future be able to start looking at their, sort of, ceramide score, and we might be able to also look at the genes that control ceramides and do some gene profiling," Summers explained.
"And then we can start to develop targeted diet interventions or exercise interventions to lower the ceramides. Then we wouldn't need a drug, right?"