Scientists have figured out how an old diabetes drug works on a biochemical level and are using that knowledge to create new, safer alternatives. Thiazolidinediones (TZDs) were once widely used to treat type 2 diabetes by reversing insulin resistance. However, they were found to have negative side effects such as weight gain and fluid retention, leading to a decline in their use by doctors. But now, researchers are exploring ways to build on the benefits of TZDs while avoiding these drawbacks.The University of California San Diego School of Medicine is researching ways to identify the beneficial effects of these drugs to develop new treatments without the traditional side effects. In a recent study published in Nature Metabolism, the researchers uncovered how one of the most well-known TZD drugs operates at the molecular level and were able to reproduce its positive effects in mice without actually administering the drug to them. “For decades, TZDs have been the only drugs we have that can reverse insulin resistance, but we seldom use them anymore because of their side effects profile,” said Jerrold Olefsky, M.D., a professor.The professor of medicine and assistant vice chancellor for integrative research at UC San Diego Health Sciences stated, “The main issue in type 2 diabetes is impaired insulin sensitivity, and developing a treatment to safely restore this would be a significant advancement for patients.” Obesity is the primary cause of insulin resistance in type 2 diabetes, affecting over 40% of Americans and costing nearly $173 billion in medical expenses in 2021. In addition to expanding fat tissue, obesity also leads to inflammation and accumulation of immune cells called macrophages.adipose tissue can contain up to 40 percent of macrophages. When this tissue is inflamed, the macrophages release tiny nanoparticles with microRNAs, which are genetic material fragments that regulate gene expression. These capsules, known as exosomes, travel through the bloodstream and can be absorbed by other tissues, leading to metabolic changes associated with obesity, including insulin resistance. The current study focuses on this process.The scientists aimed to study the impact of TZD drugs, which help with insulin resistance, on the exosome system.
They gave rosiglitazone, a type of TZD drug, to a group of obese mice. These mice showed increased insulin sensitivity, but also experienced weight gain and fluid retention, known side effects of the drug. However, the researchers were able to extract exosomes from the adipose tissue macrophages of the drug-treated mice and inject them into another group of obese mice that had not received the drug. This resulted in the transfer of the positive effects of rosiglitazone without the negative effects.”The exosomes proved to be just as effective in reversing insulin resistance as the drug itself but without the same side effects,” stated Olefsky. “This suggests that exosomes could potentially connect obesity-related inflammation and insulin resistance to diabetes. It also suggests that we might be able to utilize this system to enhance insulin sensitivity.”
The researchers also managed to pinpoint the specific microRNA found within the exosomes that was responsible for the beneficial metabolic effects of rosiglitazone. This microRNA, known as miR-690, could potentially be used in new therapies for type 2 diabetes.
“It’s probably not feasible to directly use exosomes as a therapy,” Olefsky explained.Olefsky stated that developing exosomes as a treatment would be challenging due to the difficulties in producing and administering them. However, understanding the molecular mechanisms behind the beneficial effects of exosomes opens up the possibility of creating drugs that can replicate these effects. There is also a precedent for using microRNAs as drugs, which is the potential avenue for further exploration with miR-690.
