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
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
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
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."