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U Of U Researchers Block Fat Molecule Production in Rats, Improve Sensitivity to Insulin

By blocking production of a fat molecule that plays an important role in resistance, University of Utah School of Medicine researchers improved insulin sensitivity in obese rats, ultimately preventing the rodents from developing type two diabetes.

Reported in the March 6 issue of Cell Metabolism, the finding opens the possibility of developing drugs to treat or prevent type two diabetes, a disease directly linked with obesity, indicated Scott Summers, associate professor of internal medicine and corresponding author on the study.

William Holland, a doctoral student in Summers' lab, is the study's first author.

The molecule, ceramide, accumulates in cells when people take in too much saturated fat.

Although ceramide plays a number of roles to keep people healthy, it also causes insulin resistance, which interferes with the body's ability to use insulin to convert blood glucose into energy for cells. Insulin resistance is a major risk factor for type two diabetes.

In prior research, Summers had shown that ceramide modulates insulin sensitivity in laboratory cultured cells.

But until the latest study, it had not been shown whether synthesis of the lipid was important for insulin sensitivity in live animals.

"Taking this from cultured cells to animals was a major challenge," said Summers. "This really proves that aberrant ceramide accumulation is an important component of insulin resistance in animals."

Diabetes is a metabolic disease in which the body does not produce insulin or properly use the hormone produced in the pancreas to convert blood glucose into energy.

An estimated 21 million Americans have type one or type two diabetes.

Type one diabetes results when the pancreas cannot make insulin.

Type two diabetes often results from insulin resistance.

As Americans have put on pounds in recent decades, the occurrence of type two diabetes has soared. The American Diabetes Association estimates that up to 95 percent of people with diabetes have type two.

The same metabolic factors that produce insulin resistance also generate ceramide.

To test whether ceramide contributes to insulin resistance and type two diabetes, Holland and Summers administered a compound to interrupt ceramide production in rats genetically predisposed to the disease.

The rats typically develop diabetes at 10 to 11 weeks old, and were given the compound, myriocin, starting at 8 weeks old, for a period of six weeks. By the age of 16 weeks, none of the rats had developed diabetes.

In fact, insulin sensitivity in the animals improved and insulin levels dropped.

Holland used a National Science Foundation grant to learn how to evaluate insulin sensitivity from a group in Australia.

To verify ceramide's role in insulin resistance, Holland and Summers also used a genetic model of mice in which they knocked out, or disabled, an enzyme required for ceramide synthesis.

The results confirmed ceramide's role in insulin resistance and also raised the potential for gene therapy in preventing type two diabetes.

"Insulin sensitizers are some of the most commonly prescribed drugs on the market," said Holland . "The effect of inhibiting ceramide production is on par with or better than the best of them."

Next, Holland and Summers want to understand more about how ceramide synthesis is regulated and develop a screening mechanism for potential drugs.

Although myriocin stops ceramide production in mice, its potential side effects would preclude its use in people. Therefore, researchers would have to find another drug that interrupts ceramide production in humans to prevent or treat type two diabetes.

If researchers, including private sector companies, find a drug, it could take up to 10 years to bring it to market, according to Summers and Holland.

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