Inactivation by oxidative stress of specific transcription factors essential for pancreatic islet beta cell function is a key event in the development of type 2 diabetes, Vanderbilt University researchers and their colleagues have found.
The findings, reported recently in The Journal of Clinical Investigation, suggest that identification of small, drug-like molecules to “reactivate” these transcription factors could provide a new way to treat type 2 diabetes, and possibly type 1 diabetes as well.
Insulin is a hormone released by the beta cells of the pancreas that enables the body’s tissues to absorb glucose from the bloodstream. In type 2 diabetes, the tissues become resistant to insulin, and the beta cells can’t release enough insulin to overcome that resistance.
Obesity is a risk factor for type 2 diabetes, and also for increased oxidative stress, the accumulation of reactive oxygen species, including hydrogen peroxide, that can damage proteins, lipids and DNA.
A team of scientists led by Shuangli Guo, Ph.D., and Chunhua Dai, M.D., found that the beta cells are particularly vulnerable to oxidative stress. In particular, four transcription factors, proteins that transcribe and help turn on genes essential for beta cell development and function, were inactivated under oxidative stress conditions.
Their inactivation is an early warning sign of beta cell dysfunction caused by oxidative stress. Another piece of evidence was the finding in a mouse model that Gpx1, a gene which can detoxify hydrogen peroxide, “rescued” beta cell function.
These findings help explain why antioxidants can improve beta cell function in animal and human cell culture models of type 2 diabetes, and why bariatric surgery can lead to improved beta cell function and blood glucose control, presumably by reducing oxidative stress.
Guo is a former postdoctoral fellow in Molecular Physiology and Biophysics and Dai is a research assistant professor of Medicine. Their co-authors included Vanderbilt’s Min Guo and scientists at the University of California at San Diego, the University of Washington and the Pacific Northwest Diabetes Research Institute in Seattle.
Vanderbilt’s Roland Stein, Ph.D., Mark Collie Professor of Diabetes Research, and Alvin Powers, M.D., Joe C. Davis Professor of Biomedical Science and director of the Vanderbilt Diabetes Research and Training Center (DRTC), were the paper’s senior authors.
National Institutes of Health grants supporting the research included DK050203, DK090570, DK066636, DK068854, DK072473, DK089572 and DK089538.
