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U researchers make tiny change in metabolism of mice, successfully reverse prediabetes

U researchers make tiny change in metabolism of mice, successfully reverse prediabetes

(Bhagirath Chaurasia, Ph.D, Scott Summers, Ph.D.; Credit: Charlie Ehlert, University of Utah Health)


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SALT LAKE CITY — University of Utah scientists published a study this week which may revolutionize the treatment and prevention of diabetes and heart disease.

Researchers at the University of Utah have developed a way to prevent the onset of prediabetes in mice fed a fat-heavy diet, according to a University of Utah press release. It also has been shown to reverse prediabetes in mice which are already obese.

“I’m neither diabetic or prediabetic, but having relatives who are makes this exciting news for me,” Tina Hudson, a Utah resident, told KSL.com.

The small chemical change, which involves simply shifting the position of two hydrogen atoms, may make a huge difference in preventing major risk factors for diabetes and heart disease, the press release said. The study was published by scientists from the University of Utah Health and Merck Research Laboratories in Science on July 4.

The effect was achieved through limiting an enzyme (a catalyst for a reaction within the human body), the press release said. This resulted in the prevention of the final bonded hydrogens in a fatty lipid called ceramide from being removed, lowering the amount of total ceramides in the body.

The study

“Obesity predisposes people to diabetes and heart disease,” Scott Summers, co-senior author on the study and chairman of Nutrition and Integrative Physiology at the University of Utah, told KSL.com in an email.

The main reason for obesity causing diabetes and heart disease is the spillover of fat into places where it doesn't belong, like the liver, heart and vasculature, according to Summers. Ordinarily, fat is stored in adipose tissue (fat cells).

The researchers on the study: Bhagirath Chaurasia, Ph.D, Scott Summers, Ph.D., and Trevor Tippetts; Credit: Charlie Ehlert, University of Utah Health
The researchers on the study: Bhagirath Chaurasia, Ph.D, Scott Summers, Ph.D., and Trevor Tippetts; Credit: Charlie Ehlert, University of Utah Health

“The fat normally gets stored as triglyceride, but when those safe storage depots get full, the fat spills over into another pathway to produce ceramides,” he continued. “Ceramides change cellular metabolism. In particular, we have found that they inhibit glucose utilization (e.g. cause insulin resistance), induce triglyceride production and cause apoptosis (cell death). These actions are the key components of diabetes and heart disease.”

Summers and his team found that a certain double-bond in the ceramide backbone was essential for these actions, Summers said. The revelation was new and exciting and, shockingly, animals could live quite well without the double bond as long as it was removed after they were born rather than before.

In addition to that, the mice were protected from insulin resistance (which can cause diabetes) and fatty liver disease, Summers said. “In an animal that already had steatosis or insulin resistance, getting rid of the double bond reversed the pathologies.”

(Left) Fatty liver from an obese mouse. (Right) Fat is cleared from liver in mice in which ceramides were lowered by inactivating an enzyme, dihydroceramide desaturase 1 (DES1) ; Credit: Trevor Tippetts
(Left) Fatty liver from an obese mouse. (Right) Fat is cleared from liver in mice in which ceramides were lowered by inactivating an enzyme, dihydroceramide desaturase 1 (DES1) ; Credit: Trevor Tippetts

This was exciting for two reasons, according to Summers. First, inhibiting the enzyme which inserts this double bond may prove to be a safe strategy for treating the disorders. Second, they were able to create a hypothesis about why humans evolved to create a molecule which causes diabetes and heart disease.

Why do ceramides exist?

The study begs the question — if ceramides cause diabetes and heart disease, then why have humans evolved to create them? Scientists aren’t certain, but the study has shed more light on the question.

“In the paper, we speculated that organisms evolved to create ceramides in order to protect themselves from excessive fatty acids, (the main components of fatty foods),” Summers said. “Fatty acids are able to dissolve cell membranes. Ceramides rigidify membranes to protect the cell from these detergent-like fatty acids.”

When ceramide levels get too high, they tell the cell to kill itself, which is a way of protecting the person from this dying individual cell, Summers explained. These actions were probably once useful when an organism was swimming around in too much fat. Now, however, because humans are in a constant state of overnutrition, they lead to diabetes and heart disease.

Why past studies on ceramides haven’t worked

Summers and his team attempted altering ceramides in the past, but their results weren’t as effective, according to the press release. The mice developed serious side effects. This new study appeared to have gotten the process just right.

It would be possible to create drugs inhibiting several of the different enzymes acting in the ceramide management process, according to Summers. Research has been done in the past by Eli Lilly Pharmaceuticals, which found that inhibiting the first enzyme (serine palmitoyltransferase) worked but caused gut toxicity.

By inhibiting the enzyme featured in the study (dihydroceramide desaturase-1 or DES1), such problems aren’t created in the intestine, according to Summers.

“Indeed, in the paper, we got rid of the enzyme in the intestine, and the animals were fine,” he said. “We think this is because this enzyme introduces just a subtle change, (i.e. one double bond).”

Due to these effects in the study, as well as other information backing the reasoning, Summers believes this particular process won’t have major side effects.

What’s next for the researchers?

Summers and his team intend to continue their work on the project and are looking forward to developing further results.

“People with high ceramides are greatly at risk for diabetes and heart disease, and clinics have recently started measuring them as a measure of cardiovascular risk,” Summers explained. “There are indications that people lacking one copy of the DES1 gene are very healthy, and perhaps even protected from disease.”

They have created a company called Centaurus Therapeutics which is developing drugs to target the enzyme, according to Summers. They also plan to explore controlling ceramide levels through food and diet habits as well as medication, though that field remains underexplored.

Will it make a difference for the diabetic community?

“I’m grateful (the researchers) decided to reaccess the approach instead of throwing out the whole idea,” Hudson said.

She does have some concerns about the "initial side effects," shown in the study.

"It does make me wonder if some of those same side effects can arise in the long-term. Hopefully, the long-term monitoring of the mice will prove to be just as beneficial as the initial response to the treatment."

The researchers still have a long way to go, but they are hopeful their work will help prevent diabetes in humans as well as mice in the future.

“Medical advancements like this bring a great deal of hope to many people,” Hudson added.

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Cara MacDonald enjoys both engaging in outdoor recreation and writing about it. Born and raised in Utah, Cara enjoys skiing, rock climbing, hiking and camping. She is passionate about both learning about and experiencing the outdoors, and helping others to learn about and explore nature. She primarily writes Outdoors articles centering around wildlife and nature, highlighting adventure opportunities, and sharing tips and tricks for outdoor recreation.

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