Stress-signaling Fat Is A Culprit Behind Insulin Resistance

Moreover, the researchers show, a treatment that blocks ceramide's synthesis markedly improves insulin response and prevents the onset of diabetes in obese rodents. The findings therefore identify ceramide as a target for therapies aimed at improving insulin response and blood sugar control, the researchers said.

"A collision of genetic and environmental factors has produced an epidemic growth of obesity and insulin-resistance rates during the last decade," said Scott Summers of the University of Utah. As a result, he noted, some have even suggested that life expectancies may soon start to decline.

"We've found that ceramide has a big effect on insulin resistance," Summers continued. "In some animal models, ceramide inhibition led to an almost complete restoration of insulin sensitivity."

Insulin hormone stimulates the uptake and storage of blood sugar and other nutrients in skeletal muscle and fat tissue while simultaneously blocking the release of blood sugar stored in the liver, he explained. Insulin resistance occurs when a normal dose of the hormone becomes incapable of eliciting those responses.

The condition is a characteristic of or risk factor for many metabolic diseases, including diabetes, hypertension, atherosclerosis, and cancer.

In humans, the development of insulin resistance is likely caused by a diverse range of factors, including an excess of nutrients, inflammation, and glucocorticoids, all of which can be influenced by obesity and a sedentary lifestyle. Glucocorticoids are a class of steroid hormone involved in many important body functions. Synthetic glucocorticoids are also used as drugs to treat conditions including asthma and inflammation. However, the drugs can also impair blood sugar control in some patients.

The researchers had previously found in cultured cells that ceramide leads to insulin resistance. Ceramides are a type of lipid found in cell membranes, and they also serve as signals in the body's stress response, Summers explained.

However, others subsequently examined animals infused with unsaturated oils and found that they became insulin resistant without any rise in ceramide, Summers said. That finding led to some doubt that ceramide played a significant role in insulin resistance.

The Summers team suspected that unsaturated fats like soy or olive oil might differ from saturated fats, which are generally linked to more adverse health effects. To find out whether ceramide "really matters," the researchers examined the effects of manipulating ceramide levels on insulin response.

They found that increased ceramide levels are a requirement of impaired insulin response in mice given a glucocorticoid used to treat rheumatoid arthritis. Animals genetically altered in a way that limited their synthesis of ceramide didn't become insulin resistant when taking the drug as normal animals did.

The team also found that infusion of lard oil, a saturated fat, caused the mice to become less responsive to insulin, as expected. However, when the animals were treated with a drug that blocks ceramide synthesis, the effects of the lard oil were virtually eliminated.

In contrast, the effects of an infusion of soy oil on insulin response were not erased by the ceramide blocker, evidence that saturated and unsaturated fats induce insulin resistance by different means.

"Unsaturated fat operates in a ceramide-independent way," Summers said. "This shows that saturated and unsaturated fats travel through different pathways [in the body]."

Finally, the researchers found, obese mice, which were insulin resistant, became less so when treated with the ceramide-blocking drug.

"Collectively, these studies identify enzymes involved in ceramide biosynthesis as therapeutic targets for combating insulin resistance caused by glucocorticoid therapy or obesity," the researchers concluded.

The researchers include William L. Holland, Li-Ping Wang, Katherine M. Sargent, Yanqi Liu, Krishna Narra, Kyle L. Hoehn, Trina A. Knotts, Don H. Nelson, and Scott A. Summers of University of Utah in Salt Lake City, UT; Joseph T. Brozinick, Eric D. Hawkins, Angel Siesky, and Sotirios K. Karathanasis of Eli Lilly and Company in Indianapolis, IN; Greg K. Fontenot of Lexicon Genetics Incorporated in The Woodlands, TX; Morris J. Birnbaum of Howard Hughes Medical Institute and University of Pennsylvania of Philadelphia, PA.

This work was supported by National Institutes of Health grants R01-DK58784 and R21-DK073181 to S.A.S. and F31-DK070565-03 to W.L.H., an American Diabetes Association Research Award to S.A.S., and American Heart Association postdoctoral and predoctoral fellowships to T.A.K. and K.L.H., respectively.

Holland et al.: "Inhibition of Ceramide Synthesis Ameliorates Glucocorticoid-, Saturated-Fat-, and Obesity-Induced Insulin Resistance." Cell Metabolism 5, 167--179, March 2007 DOI 10.1016/j.cmet.2007.01.002 http://www.cellmetabolism.org