Researchers uncover why TZDs cause weight gain in type 2 diabetics

The class of type 2 diabetes medications known as thiazolidinediones, or TZDs, is very effective at lowering blood sugar levels in most people.

However, the medications also come with a long list of side effects, something that concerns doctors. A new study from the UT Southwestern Medical Center has shown that the key to these side effects may lie in people's fat.

One of the most serious side effects associated with TZDs is rapid weight gain. This is particularly concerning among individuals with type 2 diabetes because many are already overweight and at risk for developing heart disease. Adding more unnecessary weight could result in a dangerous situation.



The researchers reported in the journal Cell Metabolism that the reason TZDs cause weight gain is they remodel a person's fat cells, recruiting adipose stem cells to develop in adipocytes, which are primarily responsible for creating new fat tissue.



In testing on mice treated with one form of TZD known as rosiglitazone, the researchers observed that the fat stem cells were more likely to become adipocytes than the fat stem cells of untreated mice. Once the animals developed more adipocytes, the production of fat tissue kicked into overdrive.

However, the team did note that after two months of this rapid fat tissue production the new adipocytes slowed down and eventually stopped producing new fat tissue. The researchers said that it appeared the cells had become exhausted.

Jonathan Graff, MD, the leader of the study, said that the improved understanding of how TZDs alter fat stem cells could one day be used in new therapeutic approaches that turn the cells into other types of energy-burning fat.

Regardless, he said that the findings underscore the need to develop new medications that are as effective as TZDs at lowering blood sugar but do not carry the risk of side effects. This could enable individuals with type 2 diabetes to control their blood sugar without worrying about putting extra pounds, which may jeopardize their cardiovascular health.

"Although TZDs are effective at lowering blood glucose levels, side effects and concerns that TZDs increase cardiovascular risk have hastened the need to find alternative therapeutics," Graff said. "A better understanding of whether and how TZDs modulate the adipose lineage may shed light on their insulin-sensitizing efficacy, and may also help to develop the next generation insulin-sensitizers."

Heart disease is the leading cause of death among individuals with type 2 diabetes. While much research has been devoted to preventing cardiac symptoms among individuals with the condition, relatively little progress has been made.

It certainly does not help that many individuals with type 2 diabetes take medications that may increase their odds of developing heart disease. Anything that limits this risk could be a major boon to their health and well-being. This may include developing medications that do not contribute to the risk of heart disease.
 
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