Popular diabetes drugs' cardiovascular side effects explained

May 3, 2011

Drugs known as thiazolidinediones, or TZDs for short, are widely used in diabetes treatment, but they come with a downside. The drugs have effects on the kidneys that lead to fluid retention as the volume of plasma in the bloodstream expands.

"TZDs usually increase body weight by several kilograms," said George Seki of the University of Tokyo. "However, TZDs sometimes cause massive volume expansion, resulting in ."

Now his team reports in the May issue of , a Cell Press publication, that those negative consequences arise in more than one way. The findings may lead to the development of improved therapies.

TZDs act on a hormone receptor known as peroxisome proliferator-activated receptor γ (PPARγ). PPARγ is a master gene of fat cell biology and differentiation, Seki explained, making it an ideal target for diabetes treatment.

However, TZDs also lead to changes in gene expression that enhance the sodium transport system of the kidney and lead to the reabsorption of water and salt, as scientists knew. But, Seki said, that mechanism alone didn't seem to be enough to explain the volume expansion.

Seki's team has found that TZDs also have direct effects on channels in the kidney known as the proximal tubules. TZDs rapidly stimulate sodium-coupled bicarbonate absorption from renal proximal tubules. Inhibitors of PPARγ or other players in the pathway suppress that stimulation, they report.

The researchers confirm that those effects occur regardless of whether PPARγ can bind DNA to influence the activity of other genes.

The discovery helps to explain the speed with which side effects of TZDs can sometimes arise and may lead to strategies to improve insulin resistance without the accompanying severe cardiovascular side effects, the researchers say.

"Massive volume expansion in human subjects usually occurs after weeks of use of TZDs," they wrote. "However, it can also occur as rapidly as 4 days after use of TZDs, supporting the involvement of multiple mechanisms. Thus, combination therapy with different diuretics targeting both renal proximal tubules and the distal nephrons could be a therapeutic option in case of TZD-induced massive volume expansion."

The findings also raise the possibility that other small molecules might bind PPARγ in slightly different ways, leading to different biological responses, they added. In fact, several selective PPARγ modulators have already been developed and appear to induce less fluid retention, at least in animals. Whether that will prove to work in humans to prevent massive remains to be seen.

More information: Endo et al.: “Thiazolidinediones Enhance Sodium-Coupled Bicarbonate Absorption from Renal Proximal Tubules via PPARγ-Dependent Nongenomic Signaling.” Cell Metabolism May 4, 2011

Related Stories

Recommended for you

Synthetic 3D-printed material helps bones regrow

September 28, 2016

A cheap and easy to make synthetic bone material has been shown to stimulate new bone growth when implanted in the spines of rats and a monkey's skull, researchers said Wednesday.

Epigenetic clock predicts life expectancy

September 28, 2016

UCLA geneticist Steve Horvath led a team of 65 scientists in seven countries to record age-related changes to human DNA, calculate biological age and estimate a person's lifespan. A higher biological age—regardless of chronological ...

Engineered blood vessels grow in lambs

September 27, 2016

In a hopeful development for children born with congenital heart defects, scientists said Tuesday they had built artificial blood vessels which grew unaided when implanted into lambs, right into adulthood.

Fighting the aging process at a cellular level

September 22, 2016

It was about 400 BC when Hippocrates astutely observed that gluttony and early death seemed to go hand in hand. Too much food appeared to 'extinguish' life in much the same way as putting too much wood on a fire smothers ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.