U. Researchers Prevent Diabetes in Obese Rats
(03/07/2007)
University of Utah researchers have shown that inhibiting production of a fat molecule called ceramide prevented obese rats from developing type 2 diabetes.
Their finding, reported this week in Cell Metabolism, may open new doors to treatment or even prevention of type 2 diabetes. And it has some potential for type 1 diabetes, as well - something they have a grant to investigate, according to Scott A. Summers, Ph.D., associate professor of internal medicine and one of the study's authors. William L. Holland, a doctoral student in Summer's lab, is the study's lead author.
Ceramide is derived from saturated fats, says Summers, and it accumulates in people who have insulin resistance, a major risk factor for type 2 diabetes. With insulin resistance, the body does not effectively use insulin to convert blood sugar into energy for cells.
Summer had already demonstrated, in the petri dish, that ceramide affects insulin sensitivity. This research applies the findings to live animals, in this case fat lab rats who are predisposed to diabetes.
Type 1 diabetes occurs when the pancreas doesn't make the hormone insulin, while type 2 occurs when the body doesn't use it effectively, often as a result of insulin resistance. As many as 95 percent of cases are type 2 and the number has grown along with American waistlines.
They already knew that factors associated with metabolic diseases like diabetes induce ceramide synthesis and they could use it to cause insulin resistance. The question was whether ceramide would prove to be just one of 100 factors or very important.
To find out, they used "various drugs and genetic strategies to block synthesis of ceramide," including using a compound that interrupts ceramide production in the pre-diabetic rats. The rats typically develop diabetes around 10 weeks of age. They started giving them the compound, myriocin, when they were 8 weeks old and continued for six weeks.
By 16 weeks old, none of the rats had developed diabetes and they were using insulin better. Holland learned how to evaluate insulin sensitivity from experts in Australia, funded by a National Science Foundation grant.
They concluded regulation of the fat molecule is clearly important, but they're still learning the mechanisms of how ceramide production is regulated. And they don't know if the findings apply to a type of ceramide or to all of the molecules in its class, Summers says.
Unraveling that could lead to a "more druggable target" that could be used for treatment or prevention.
Because ceramide is important for health, Summers says, researchers must take care not to prevent its production outright. And any remedy that results is something patients will likely need for decades, so they have to make sure there are no side effects, he says.
They confirmed their conclusion by knocking out an enzyme needed to synthesize ceramide, using a genetic mouse model.
Summers says inhibiting ceramide production is as good as or better than drugs now being prescribed to improve insulin sensitivity.
They will next try to determine how ceramide production is regulated so they can develop a way to screen potential drugs. The compound they used, myriocin, has potential side effects that would preclude its use in humans. And any drug that's found, Summers warns, is years away from pharmacy shelves.
