In rare cases, someone who is thin could still end up with type 2 diabetes while an obese person may be surprisingly healthy. Some Asian countries have a higher diabetes rate than the United States even though the obesity rate is relatively low. New research points toward an answer to the riddle of the obesity paradox: An accumulation of a toxic class of fat metabolites, known as ceramides, may increase the risk for type 2 diabetes.
Among patients in Singapore receiving gastric bypass surgery, ceramide levels predicted who had diabetes better than obesity did. Even though all of the patients were obese, those who did not have type 2 diabetes had less ceramide in their adipose tissue than those who were diagnosed with the condition.
"Ceramides impact the way the body handles nutrients," says the study's senior author Scott Summers, Ph.D., chairman of the University of Utah Department of Nutrition and Integrative Physiology. "They impair the way the body responds to insulin, and also how it burns calories."
the researchers also show that a buildup of ceramides prevents the normal function of fat (adipose) tissue in mice.
When people overeat, they produce an excess of fatty acids. Those can be stored in the body as triglycerides or burned for energy. However in some people, fatty acids are turned into ceramides.
"It's like a tipping point," Summers said.
At that point, when ceramides accrue, the adipose tissue stops working appropriately, and fat spills out into the vasculature or heart and does damage to other peripheral tissues. Until now, scientists didn't know how ceramides were damaging the body.
The three-year project found that adding excess ceramides to human fat cells, or mice, caused them to become unresponsive to insulin and develop impairments in their ability to burn calories. The mice were also more suceptible to diabetes as well as fatty liver disease.
Conversely, they also found that mice with fewer ceramides in their adipose tissue were protected from insulin resistance, a first sign of diabetes. Using genetic engineering, researchers had deleted the gene that converts saturated fats into ceramides.
The findings indicate that high ceramides levels may increase diabetes risk and low levels could protect against the disease.
The scientists think this could mean that some people are more likely to convert calories into ceramides than others. "That suggests some skinny people will get diabetes or fatty liver disease if something such as genetics triggers ceramide accumulation," said Bhagirath Chaurasia, Ph.D., assistant professor at the University of Utah and the lead author of the study.
Adipose tissue exists as three types. White adipose tissue is considered the "bad" kind, because it predominately stores fat. Brown adipose tissue burns fat to generate heat. Beige adipose tissue is a variety of white fat that can change to brown when the body needs to produce heat or create energy. Based on their research, the scientists propose that as ceramides build up, the tissue loses the characteristics of brown fat, effectively becoming more white. This sets off a sequence of events that can lead to disease.
"By blocking ceramide production, we might be able to prevent the development of type 2 diabetes or other metabolic conditions, at least in some people," Chaurasia said. Knowing how problematic ceramide accumulation is inside adipose tissue will help researchers focus on that specific problem.
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