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Preventing Type 2 Diabetes

Can drugs prevent the onset of type 2 diabetes? One class of drugs shows promise, but it has its drawbacks.

TZDs and the TRIPOD Study continued...

Buchanan believes that TZDs might prevent beta cells from becoming overloaded and wearing out. By averting this, insulin resistance wouldn't worsen and, by extension, the development of type 2 diabetes could be stopped.

In the TRIPOD study, 235 Hispanic women who previously had gestational diabetes -- diabetes that develops during pregnancy -- and were at high risk of developing type 2 diabetes were treated with the TZD Rezulin (troglitazone), then another TZD, Actos. Buchanan and his colleagues found that the TZDs stabilized beta-cell function and led to a 55% reduction in diabetes compared with a placebo group. Startlingly, the benefits of the drugs seemed to last even after use was stopped.

"That was one of the most striking results," Buchanan tells WebMD. "We found that in people who didn't have diabetes, the preventative effect of the drug persisted eight months after it was stopped."

The Technical Details: How TZDs Work

The exact mechanism of how TZDs improve beta-cell function isn't entirely understood. The most widely accepted theory is that TZDs activate a receptor common in fat cells called the nuclear peroxisomal proliferator-activated receptors-gamma, or PPAR-gamma. These receptors affect how glucose and fats are metabolized, and once they are activated, the uptake or absorption of fat cells is increased; this also stimulates the metabolism of glucose and lessens the liver's production of new glucose.

What's particularly interesting is that TZDs may actually increase the total amount of fat on a person, but they appear to cause a redistribution of fat in ways that may help increase insulin sensitivity. Visceral fat -- fat surrounding the organs of the abdomen -- seems to be connected to the development of insulin resistance while subcutaneous fat -- fat beneath the skin in other parts of the body -- is not. TZDs appear to decrease the amount of visceral fat and increase the amounts of subcutaneous fat.

Other Benefits

Unrelated to its effects on beta cells, TZDs may lower the cardiovascular risks of diabetes. Given that heart problems and strokes are among the most deadly complications of diabetes, this may prove an important effect of the drugs.

While TZDs also have the ability to lower glucose, their abilities to do so are modest compared with other medications.

"TZDs are not very potent when used as monotherapy," says David Nathan, director of the diabetes center at Massachusetts General Hospital and a professor of medicine at Harvard Medical School. "In fact, they are considerably less potent than the sulfonylureas or metformin [standard diabetes drugs]." Nathan tells WebMD the greatest benefit may come by combining TZDs with other drugs, although he cautions that the results of doing so are not yet fully understood.

Another potentially significant benefit of TZDs is that they appear to lower the levels of free fatty acids in the bloodstream, a new focus of attention for diabetes experts because of their connection to diabetic complications. "I think that's an important aspect of TZDs," says Paul Jellinger, MD, past president of the American Association of Clinical Endocrinologists. "It's one of the apparent benefits of TZDs that hasn't been widely appreciated yet."

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