Robert C. Stanton, M.D.
A normal result of cellular metabolism is the production of highly reactive forms of oxygen called oxidants. These oxidants under physiologic circumstances have important roles in many cellular activities. The normal balance of oxidants in cells is maintained by the interaction of processes that produce oxidants and processes that reduce oxidants, called antioxidants. The principal antioxidant in all cells is the compound NADPH. The principal source of NADPH for the antioxidant system is glucose 6-phosphate dehydrogenase (G6PD), which is the rate-limiting enzyme of the pentose phosphate pathway. Traditionally researchers have focused on the role of G6PD in lipid metabolism and the role of G6PD in G6PD deficient-associated hemolytic anemia. Moreover, scientists thought that G6PD was a classic “housekeeping gene” that was not highly regulated.
Discoveries from the laboratory of Robert C. Stanton, M.D., have shown that G6PD is a highly regulated enzyme. Research revealed that G6PD is regulated by growth factors, glucose level, aldosterone, and many other factors. Research from the laboratory has elucidated intracellular signaling molecules that regulate G6PD at the transcriptional and post-translational level. Dr. Stanton’s laboratory has also determined that G6PD is central to the health of all cells being essential for cell survival. Additionally, discoveries from Dr. Stanton’s laboratory have demonstrated that decreases in G6PD activity lead to impaired function of multiple cellular systems that depend on NADPH and ultimately cell death.
Diabetes is associated with increased levels of oxidants (oxidative stress). For patients with diabetes, complications associated with increased oxidant damage include diseases of the heart, eye, kidney, nerves, and blood vessels. The increase in oxidants in diabetes occurs due to both increased production of oxidants and decreased function of antioxidants. Studies in animals and in human tissue from Dr. Stanton’s laboratory have demonstrated that increased levels of glucose (as occurs in diabetes) leads to a decrease in the activity of G6PD in certain cell types and, as a consequence of lower G6PD activity, leads to decreased level of NADPH. This lack of sufficient NADPH is likely a significant cause of the increased oxidative stress (increased oxidants) seen in diabetes that leads to kidney disease, vascular disease and other complications. The lack of NADPH also leads to impaired function of other cellular systems that are dependent on NADPH. For example, the critical enzyme, nitric oxide synthase that produces nitric oxide, also is dependent on NADPH. Experiments with collaborators have determined that decreased G6PD activity leads to lower nitric oxide production and multiple cellular consequences as a result.
Recent publications have illustrated the central importance of G6PD to cell health and survival. G6PD deficient mice (no diabetes) had signs of kidney damage (increased urine albumin) and small pancreatic islets as compared to control mice. This experimental finding illustrates the critical role that G6PD plays in cellular function and cell survival. In further studies using isolated mouse islets and human islets, it was determined that G6PD was central to normal islet (pancreatic beta cell) function and to pancreatic beta cell survival. Hence, decrease G6PD activity may play an important role in beta cell death. Most recently, research from the laboratory has discovered that overexpression of G6PD in aortic endothelial cells that were exposed to high glucose, leads to a restoration of all cellular antioxidant pathways to normal levels and prevents the high glucose-mediated decrease in cell survival. These results demonstrate that increasing G6PD is a very promising goal for treatment of the complications of diabetes.
Dr. Stanton’s laboratory current projects are focused on continuing the elucidation of the basic cellular physiologic roles for G6PD and the mechanisms and consequences associated with the pathophysiologic alterations of G6PD. Projects in the laboratory are aimed at understanding the specific cellular and molecular mechanisms that lead to impaired G6PD enzyme activity and to determine how to prevent this impairment with a goal of developing treatments for the prevention and treatment of diabetic kidney disease, diabetic vascular disease, and for preserving pancreatic beta cell mass. To that end, Dr. Stanton’s laboratory also looks for specific drugs that restore G6PD activity and increase levels of NADPH.
Dr. Stanton’s laboratory also collaborates with multiple colleagues at the Joslin Diabetes Center, Harvard Medical School, and University of Minnesota in the USA. In addition, there are on-going collaborations on basic and clinical projects with scientists in China.
Dr. Stanton is a Principal Investigator in the Section on Vascular Cell Biology and the Chief of the Kidney and Hypertension Section at the Joslin Diabetes Center, as well as an Associate Professor of Medicine at Harvard Medical School. He received his medical degree from Hahnemann Medical College in Philadelphia and completed residency training at the Oregon Health Sciences University, where he was the Chief Resident in Internal Medicine. He completed his fellowship in Nephrology at Harvard Medical School and Brigham and Women’s Hospital and postdoctoral training in Physiology at Tufts University School of Medicine. In addition to his research activities, Dr. Stanton is very involved with teaching at all levels (student, resident, fellow, and faculty) at local, national, and international levels. He has worked with national and international medical faculty to educate them on how to organize medical courses and how to use various educational methods. Dr. Stanton has been invited to lecture throughout the United States and throughout the world (including China, India, the Middle East, Europe, and South America). He has received three Honorary Professorships from Universities in China. He serves on many Harvard Medical School Committees and is co-director of the Human Systems Pathophysiology Course for second-year medical students at Harvard Medical School. He also Chairs the Harvard Medical School Fundamentals of Medicine Year 2 Harvard Committee. Dr. Stanton is an author of many original articles and chapters, and has served both in reviewer and in editorial positions for academic journals.
Page last updated: November 01, 2014