Getting rid of old, dysfunctional cells in human fat also alleviates signs of diabetes, researchers at UConn Health report. The discovery could lead to new treatments for type 2 diabetes and other metabolic diseases.
The cells in your body are constantly renewing themselves, with older cells aging and dying when new ones are born. But sometimes this process goes wrong. Occasionally, damaged cells are left behind. They are called senescent cells and they hang around and have a negative effect on other cells nearby. Their bad influence changes the way neighboring cells deal with sugar or proteins and thus causes metabolic problems.
Type 2 diabetes is the most common metabolic disease in the United States. According to the Centers for Disease Control and Prevention (CDC), approximately 34 million people, or one in 10 people in the United States, have it. Most people with diabetes have insulin resistance, which is associated with obesity, sedentary lifestyle, and poor diet. But it also has a lot to do with aging cells in people’s body fat, according to new findings from Ming Xu and colleagues at the UConn Health School of Medicine.
And getting rid of these aging cells appears to stop diabetic behavior in obese mice, they report in the November 22nd issue of Cell Metabolism. Ming Xu, Assistant Professor at the UConn Center on Aging and the Department of Genetics and Genomic Sciences at UConn Health, led the research along with UConn Health researchers Lichao Wang and Binsheng Wang as key contributors.
Reducing the negative effects of fat on metabolism is a dramatic result, the researchers said. If therapy worked this well in humans, it would be a breakthrough treatment for diabetes.
Xu and his colleagues tested the effectiveness of a combination of experimental drugs, dasatinib and quercetin. Dasatinib and quercetin have been shown to extend lifespan and health in old mice. In this study, they found that these drugs can kill senescent cells from cultures of human adipose tissue. The tissue was donated by people with obesity who were known to have metabolic problems. If left untreated, human adipose tissue caused metabolic problems in immunodeficient mice. After treatment with dasatinib and quercetin, the harmful effects of adipose tissue were nearly eliminated.
These drugs can make human fat healthy, and that could be great. The results were very impressive and paved the way for potential clinical trials. “
Ming Xu, Assistant Professor, UConn Center on Aging
Xu and his colleagues at UConn Health and the Mayo Clinic are now tracking the use of the dasatinib and quercetin combination in clinical trials to see if the drugs can improve type 2 diabetes in human patients. “While these preclinical results have been very promising, large-scale clinical trials are absolutely critical to evaluating the efficacy and safety of these drugs in humans prior to clinical use,” said Xu.
The research team is also focusing on a previously unexplored senescent cell population. These senescent cells express high levels of p21, a cyclin-dependent kinase inhibitor and one of the key markers for cellular senescence. Using a newly developed mouse model, Xu’s team showed that getting rid of these senescent cells once a month can both slow the development of diabetes and relieve the diabetic symptoms that have developed in obese mice. Xu says that previous research has focused on various cell markers, but that the effects of eliminating cells that express p21 high levels on the relief of diabetes have been so pronounced that this marker deserves more attention.
Research was funded primarily by the National Institutes on Aging, the Mayo Clinic’s Regenerative Medicine Initiative for Diabetes-Career Development Award, the Esperance Fellowship in Personalized Nutrition, and the American Federation for Aging Research.
University of Connecticut
Wang, L., et al. (2021) The targeting of p21Cip1-strongly expressing cells in adipose tissue alleviates insulin resistance in obesity. Cell metabolism. doi.org/10.1016/j.cmet.2021.11.002.