Researchers discover why some type 2 diabetes medications cause weight gain

Thiazolidinedione (TZD) medications may be effective at lowering blood sugar levels in individuals with type 2 diabetes, but they have also been shown to cause significant weight gain. This can be a major health risk for individuals who are already more likely to suffer from cardiovascular disease.

Now, a new study from a group of University of Cincinnati researchers may help explain why these drugs cause weight gain, and it suggests modifying them to prevent this potentially dangerous side effect.

The researchers reported in the journal Nature Medicine that TZDs target peroxisome proliferator-activated receptor-gamma (PPAR-γ) proteins, which are molecules found in fat tissue in the body that regulate the production of fat cells. By working on this process, TZDs can control blood sugar levels, but it was also thought that they stimulated the tissue, leading to weight gain.

However, after examining the effect of TZDs on mice, the researchers found that the drugs activate PPAR-γ systems in the brain in addition to those in fat tissue. These systems have previously been associated with appetite. Therefore, the researchers concluded that TZDs can lead to an unregulated appetite, which may be the cause of weight gain among patients who take them.

"If you artificially turn on PPAR-γ, you can increase food intake in rats," said Randy Seeley, who led the investigation. "If you block these receptors in animals on high-fat diets that make animals obese, animals gain less weight."

He added that the prior assumption that TZDs stimulated fat tissue was illogical because simply having activated tissue does not necessarily result in more fat. An individual would still need to consume excess calories in order to gain weight. This proves the theory that the medications stimulate appetite regulators in the brain more consistently.

Seeley said that researchers should consider finding ways to design medications that reduce blood sugar levels in type 2 diabetics to the same degree that TZDs do, but that do not affect brain PPAR-γ systems.