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The Science Behind the Diabetes/Obesity Connection

By Bonnie Prescott
Beth Israel Deaconess Medical Center Staff

By now, it's a well-accepted fact that extra body weight is a risk factor for Type 2 diabetes. According to the American Diabetes Association, at least one of five overweight individuals has more than one metabolic problem, including diabetes, high blood pressure and high cholesterol. Collectively these are often referred to as "the metabolic syndrome."

Ongoing laboratory research at Beth Israel Deaconess Medical Center (BIDMC) is helping to explain some of the underlying molecular factors that link excess weight and Type 2 diabetes. The following three studies by BIDMC scientists have been published in medical journals during the past year, and all provide important discoveries that could eventually lead to new therapies and diagnostic tests for this widespread problem.

Why abdominal fat is dangerous. All body fat is not created equal. Abdominal fat not only creates unsightly "beer bellies," but is also associated with the development of insulin resistance, Type 2 diabetes and cardiovascular disease. Earlier this year, Dr. Barbara Kahn, Chief of BIDMC's Department of Endocrinology, Diabetes and Metabolism, and colleagues discovered that a molecule called RBP4 - retinol binding protein 4 - is produced in very high amounts by the "visceral fat" that lies deep within the abdomen. In earlier studies, Dr. Kahn and her colleagues showed that RBP4 is closely linked to insulin resistance and cardiovascular risk factors. The new findings are important because, in the future, by measuring RBP4 levels in the blood, doctors might be able to identify patients who are at risk for developing Type 2 diabetes and cardiovascular disease before symptoms appear.

"Being able to determine diabetes risk well before the onset of symptoms could provide an important opportunity for patients to take preventive measures and avoid complications," says Dr. Kahn. "For example, for those who are overweight or inactive, this could mean making changes to their diet and fitness routines. Ultimately, these findings could help clinicians to better manage the growing diabetes epidemic worldwide."

How ketogenic diets work. Over the past several years, studies in animals have found that high-fat, low-carbohydrate "ketogenic" diets lead to weight loss. Now a study by BIDMC endocrinologist Dr. Eleftheria Maratos-Flier helps to explain why.

Her research has found that a hormone produced in the liver - known as FGF21 - is required by the body to oxidize fatty acids and thereby burn calories. "When the diet is extremely low in starches and sugars, blood-sugar levels drop substantially so that muscle and brain have to turn to alternative fuels," she explains. To compensate, the body breaks down fatty acids in the liver and converts them to "ketones," which then serve as the alternative fuel source. Known as ketosis, this process occurs during periods of fasting and starvation, or while consuming a low-carb diet, such as the Atkins diet.

By identifying FGF21 as one of the key genes behind this course of events, Dr. Maratos-Flier and colleagues have shown that in order for animals on a carbohydrate-restricted diet to switch gears and begin burning fat, they need increased blood levels of this molecule. She plans to study human subjects to find out if the same applies. In the meantime, she adds, "Diets that limit carbohydrates and eliminate transfats, and at the same time emphasize fiber and good fats, appear to be healthiest. And this is especially important for individuals who are predisposed to developing diabetes."

The role of the brain. A third laboratory study has discovered an abnormality that could play an important role in the development of obesity-induced Type 2 diabetes. And, says BIDMC endocrinology researcher Dr. Bradford Lowell, this aspect of diabetes really is "all in your head."

"For many years we've known that there are some neurons in the brain that become 'excited' by glucose [blood sugar]," explains Dr. Lowell. "But we haven't understood exactly how or why this is significant. With our new study, we show that these brain cells sense increases in glucose [as would occur after eating a meal] and then initiate responses that are aimed at returning blood-glucose levels to normal."

Consequently, he adds, when these glucose-sensing neurons are defective, blood sugar accumulates and, as the experiments showed in animals, the risk of developing obesity-induced diabetes increases.

"These new findings add to our understanding of Type 2 diabetes at a critically important time," says Dr. Lowell. "The discovery that defects in glucose-sensing by the brain may also be contributing to Type 2 diabetes could help lead to new therapeutic strategies for this widespread problem."

Above content provided by Beth Israel Deaconess Medical Center. For advice about your medical care, consult your doctor.

Posted January 2010

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Beth Israel Deaconess Medical Center
Shapiro Clinical Center, 3rd Floor
330 Brookline Avenue
Boston, MA 02215
617-667-5100

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