Yale Researchers Identify Why Diabetes Risk Increases as We Age

Type 2 diabetes, which is an outgrowth of insulin resistance, affects around 40 percent of the American population over age 65. But the underlying mechanism for the increased prevalence as we age has been unknown until now.

The Yale team found that overexpression of the human catalase gene prevented mitochondrial damage and an excessive buildup of muscle lipids, and preserved mitochondrial function in aging mice. This in turn protected the aging mice from developing muscle insulin resistance, which is the major underlying factor that leads to type 2 diabetes.

Previous studies by the Yale group had shown that elderly individuals, even when healthy, had a 35% reduction in muscle mitochondrial activity, associated with a 30% increase in the fat content in muscle cells and severe muscle insulin resistance. According to senior author Gerald I. Shulman, M.D., Ph.D., a Howard Hughes Medical Institute investigator, the George R. Cowgill Professor of Physiological Chemistry, and professor of medicine and cellular and molecular physiology, “This transgenic mouse study builds on our previous human studies and allowed us to directly test the hypothesis that age-associated reductions in muscle mitochondrial function can lead to intramuscular fat accumulation and insulin resistance — something that would be virtually impossible to do in human studies. These results also suggest that reducing mitochondrial oxidative stress may be a novel therapeutic target to prevent age-associated insulin resistance and type 2 diabetes, which is now reaching epidemic proportions in this country and abroad.”

Other authors are Hui-Young Lee, Michael J. Jurczak and Dongyan Zhang of the Howard Hughes Medical Institute and Yale School of Medicine; Cheol Soo Choi of Yale School of Medicine and Gachon University of Medicine and Science; Andreas L. Birkenfeld, Tiago C. Alves, Francois R. Jornayvaz, Dong Kyun Woo, Gerald S. Shadel, Kitt F. Petersen and Varman T. Samuel of Yale School of Medicine; Warren Ladiges and Peter S. Rabinovitch of the University of Washington; Janine H. Santos of UMDNH-New Jersey Medical School.

This study was supported by the United States Public Health Service, German Research Foundation, a VA Merit Grant, and by the Yale Clinical and Translational Science Award (CTSA) grant from the National Center for Research Resources at the National Institutes of Health.



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