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September 23, 2002

'Futile' Cycle Both Fights Diabetes and Causes Weight Gain

Penn Researchers Describe Paradox Underlying the Effectiveness of Anti-Diabetes Drugs

(Philadelphia, PA) - If obesity is the leading cause of type II diabetes, then why do thiazolidinediones (TZDs), the only available drugs that treats this form of diabetes, actually cause more weight gain? Today, in the online version of Nature Medicine, researchers at the University of Pennsylvania School of Medicine address the fundamental workings of TZDs (also known as glitazones or under brand names such as Actos® and Avandia®), and provide a potential new target for further study.

Their research describes how TZDs trigger the creation of glycerol kinase, an enzyme that causes fat cells to store fatty acids faster than it produces them.

"It is what researchers call a 'futile' cycle. Just as fat cells release their larder of fatty acids, glycerol kinase causes the fat cells to put them back in storage," said Mitchell A. Lazar, MD, PhD, Chief of the Division of Endocrinology, Diabetes, and Metabolism and Director of the Penn Diabetes Center. "The glycerol kinase is packing the pantry faster than fat cells can pull the cans off of the shelves. The net influx of fatty acids into fat tissue contributes to reduced fatty acids in the bloodstream that, in turn, leads to increased sensitivity to insulin."

Type II, or adult-onset diabetes, occurs as cells lose the ability to respond to insulin, a hormone which allows cells to absorb sugar for fuel. The disease affects millions, and has become an epidemic in the industrialized world. According to Lazar, two big mysteries remain concerning type II diabetes: how cells become insulin resistant and how TZDs cause them to lose resistance to insulin. By studying how the drug works, the researchers have uncovered a fundamental clue that may allow the development of better therapies.

"Right now, our findings suggest that weight gain is an inherent part of how TZDs function and diabetics should bear in mind the role of a healthy diet in combination with drug therapy," said Lazar. "TZDs actually lower insulin requirements in diabetics, and this is likely to be beneficial in terms of the risk of hypertension and heart disease associated with diabetes."

Despite their beneficial qualities, it seems that TZDs have little respect for medical textbooks. "According to conventional medical knowledge, fat cells do not produce glycerol kinase for precisely the reason that helps TZDs to be effective," said Lazar.

Fatty acids are stored in fat cells as triglycerides (TGs). When the body senses that it needs fuel, such as what happens when diabetic cells cannot absorb blood sugar, fat cells breakdown TGs to produce glycerol, which travels to the liver to make the sugar glucose, and fatty acids, which muscles use an emergency fuel source.

TZDs, however, reverse this process as it happens. When the drug binds to a receptor in fat cells called PPARgamma, TZD causes the cells to uncharacteristically produce glycerol kinases. These enzymes then recombine glycerol and fatty acids into TGs. They also open the cell's door to trap passing fatty acids, which lowers the amount of fatty acids in the bloodstream.

In addition, researchers have found that TZDs may also alter the chemical signals produced by fat cells, which may prove beneficial in producing the next generation of anti-diabetes drugs.

"We have come to understand that fat cells are more than just storage bins for excess fats," said Lazar. "They produce hormones and actively regulate how our bodies process and use fats. Future drug discovery may depend on the role of fat itself."

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