U of U Discovery Raises Possibility of Drugs to Prevent Disease in Humans
SALT LAKE CITY -- By blocking production of a fat molecule that plays an important role in insulin resistance, University of Utah School of Medicine researchers improved insulin sensitivity in obese rats, ultimately preventing them from developing type 2 diabetes.
The finding, reported in the March 6 issue of Cell Metabolism, opens the possibility of developing drugs to treat or prevent type 2 diabetes, a disease directly linked with obesity, according to Scott A. Summers, Ph.D., associate professor of internal medicine and corresponding author on the study. William L. Holland, a doctoral student in Summers' lab, is the study's first author.
The fat 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 2 diabetes. In earlier research, Summers had shown that ceramide modulates insulin sensitivity in laboratory-cultured cells; but until now it hadn't 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," Summers said. "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 either doesn't make insulin, a hormone produced in the pancreas, or doesn't properly use it to convert blood glucose into energy. An estimated 21 million Americans have either type 1 or type 2 diabetes. Type 1 diabetes results when the pancreas cannot make insulin; type 2 often results from insulin resistance.
As Americans have put on pounds in recent decades, the occurrence of type 2 diabetes has soared. The American Diabetes Association estimates that up to 95 percent of people with diabetes have type 2.
The same metabolic factors that produce insulin resistance also generate ceramide. To test whether ceramide contributes to insulin resistance and type 2 diabetes, Holland and Summers administered a compound to interrupt ceramide production in rats genetically predisposed to diabetes. 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, meaning their bodies were better able to use the hormone, and insulin levels dropped as well. 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 2 diabetes.
"Insulin-sensitizers are some of the most commonly prescribed drugs on the market," Holland said. "The effect of inhibiting ceramide production is on par with or better than the best of them."
Holland and Summers next 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, meaning researchers would have to find another drug that interrupts ceramide production in humans to prevent or treat type 2 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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Contact Information:
Scott A. Summers, Ph.D., associate professor of internal medicine, (801) 585-0950 (office); Scott.Summers@hsc.utah.edu
Phil Sahm, Office of Public Affairs, 801-581-2517