Thiazolidinediones (TZDs) are a class of drugs that can be used to treat type 2 diabetes by reversing insulin resistance, one of the main characteristics of type 2 diabetes. Although TZDs were very popular in the 1990s and early 2000s, they have become more popular in recent decades as they have been found to cause undesirable side effects such as weight gain and the accumulation of excess fluid in body tissues. No longer used by doctors.

Now, researchers at the University of California, San Diego School of Medicine are studying ways to isolate the positive effects of these drugs, which could help create new treatments without the old side effects. In a new study published in natural metabolismResearchers discovered how one of the best-known TZD drugs works at a molecular level and were able to reproduce its positive effects without giving mice the drug itself.

For decades, TZDs were the only drugs that could reverse insulin resistance, but they are now rarely used because of their side effects. Impaired insulin sensitivity is the root cause of type 2 diabetes, so developing treatments to safely reverse it would be a major step forward for patients. ”

Jerrold Olefsky, MD, Professor of Medicine and Assistant Vice President for Integrative Research, University of California, San Diego Health School

Obesity is the main cause of insulin resistance in type 2 diabetes. Currently, over 40% of Americans suffer from obesity, resulting in nearly $173 billion in annual health care costs in 2021. Obesity not only causes expansion of adipose tissue (fat), but also low-level inflammation. This inflammation causes immune cells called macrophages to accumulate in fatty tissue and can account for up to 40 percent of the total number of cells in the tissue.

When fatty tissue becomes inflamed, these macrophages release tiny nanoparticles that contain instructions for surrounding cells in the form of microRNAs, tiny pieces of genetic material that help control gene expression. These microRNA-containing capsules, called exosomes, are released into the circulation and travel through the bloodstream to be absorbed by other tissues such as the liver and muscles. This can lead to various metabolic changes associated with obesity, including insulin resistance. In this study, researchers wanted to understand how TZD drugs that reverse insulin resistance affect this exosome system.

The researchers treated a group of obese mice with rosiglitazone, a type of TZD drug. These mice became more sensitive to insulin, but they also gained weight and retained excess fluid, a known side effect of rosiglitazone. But by isolating exosomes from adipose tissue macrophages in mice that had been given the drug and injecting them into a separate group of obese mice that had not been given the drug, the researchers were able to transfer rosiglitazone’s negative effects without transferring them. was able to bring about the effect of

“Exosomes were as effective at reversing insulin resistance as the drug itself, but without the same side effects,” Olefsky said. “This indicates that exosomes may ultimately link obesity-related inflammation and insulin resistance to diabetes. It may also be possible to harness this system to increase insulin sensitivity. It also shows that.

The researchers were also able to identify specific microRNAs within the exosomes that are responsible for rosiglitazone’s beneficial metabolic effects. The molecule, called miR-690, could eventually be harnessed for new treatments for type 2 diabetes.

“Developing exosomes themselves as a therapy is probably not practical due to the difficulties in their production and administration. However, by knowing the factors that drive the beneficial effects of exosomes at the molecular level, we can improve the effectiveness of these effects. “It will allow us to develop drugs that can be mimicked,” he said. Olefsky. “There is also a lot of precedent for using microRNAs themselves as medicines, so that is what excites us most about the future exploration of miR-690.”