MARYLAND HEIGHTS, Mo. — According to a report in the May issue of Cell Metabolism, while drugs known as thiazolidinediones, or TZDs, are widely used in diabetes treatment, they 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," stated George Seki of the University of Tokyo. "However, TZDs sometimes cause massive volume expansion, resulting in heart failure."
The findings may lead to the development of improved diabetes therapies.
TZDs act on a hormone receptor known as peroxisome proliferator-activated receptor γ. 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 reported.
The discovery helps to explain the speed with which side effects of TZDs sometimes can arise, and may lead to strategies to improve insulin resistance without the accompanying severe cardiovascular side effects, the researchers noted. "Massive volume expansion in human subjects usually occurs after weeks of use of TZDs," they wrote. "However, it can also occur as rapidly as four 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, the researchers added. In fact, several selective PPARγ modulators already have been developed and appear to induce less fluid retention, at least in animals. Whether that will prove to work in humans to prevent massive fluid retention remains to be seen.