Diabetes is a state of insulin resistance resulting from many known factors, such as poor diet, sedentary lifestyle, and obesity, but there are likely unknown causes, too. Researchers from the University of Connecticut (UConn) are exploring some of these lesser known influences, including the physiologic impact of cellular senescence, which describes the outcome of stress on cells, leading to an irreversible proliferative arrest and causing proinflammatory secretions.
According to research conducted by Ming Xu, assistant professor and corresponding author and colleagues from the UConn School of Medicine, the identification of a previously unexamined cellular senescent population (p21Cip1 highly expressing [p21high] cells) that accumulates in adipose tissue in obese individuals and removal of those offending cells from adipose tissue in mice prevents insulin resistance in mice. The authors believe that clearing these senescent cells from body fat in humans may improve insulin sensitivity in obese individuals.
Dr. Xu and colleagues at the UConn School of Medicine and the Mayo Clinic investigated whether a combination of senolytic investigational drugs, dasatinib and quercetin, improves type 2 diabetes (T2D) in humans. These agents had previously demonstrated efficacy in mitigating insulin resistance (IR) following xenotransplantation into immunodeficient mice. The authors note that IR and impaired tissue response are among the earliest hallmark signs of prediabetes, resulting in pancreatic beta-cell dysfunction and abnormal insulin secretion.
According to Dr. Xu, "These drugs can make human fat healthy, and that could be great. The results were very impressive and cleared the route for potential clinical trials." He added, "Although these preclinical results were very promising, large scale clinical trials are absolutely critical to examine the efficacy and safety of these drugs in humans before clinical use."
The team indicated that more than 93 million U.S. adults are obese, and obesity is among the most significant risk factor for developing T2D, which is a leading cause of death, especially in the older population.
The authors conclude that their findings lay the foundation for pursuing the targeting of cells as a new therapy to alleviate insulin resistance. The authors write, "Our study implicates p21high cells as a new and potentially translatable target for T2D interventions. Monthly clearance of p21high cells can provide long-term protective effects on IR in obese mice."
The research was funded primarily by the National Institutes on Aging, the Regenerative Medicine Initiative for Diabetes Career Development Award from Mayo Clinic, the Esperance Fellowship in Personalized Nutrition, and the American Federation for Aging Research.
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