Robert C. Stanton, M.D.
Diabetes is associated with increased levels of oxidants (toxic forms of oxygen that cause cells to die). For patients with diabetes, complications associated with increased oxidant damage include diseases of the heart, eye, kidney and blood vessels. The principal antioxidant, or reducing agent, in cells is the compound NADPH, which is produced by the pentose phosphate pathway. Traditionally researchers have not appreciated the unique importance of this pathway other than being one of the “housekeeping metabolic pathways” that all cells utilize. Discoveries in the laboratory of Robert C. Stanton, M.D., though has shown that this is a highly regulated pathway that is central to the health of all cells being essential for cell survival. Recent discoveries have demonstrated that alterations in this pathway lead to cell damage and cell death.
Specifically, Dr. Stanton’s research showed that glucose 6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway is regulated by growth factors, glucose level, aldosterone, and others. Research from the laboratory has also elucidated intracellular signaling molecules that regulate G6PD at the transcriptional and post-translational level. Furthermore studies in animals and using human tissue have demonstrated that diabetes causes a decrease in the activity of the enzyme G6PD. G6PD is the main source of NADPH. Decreased G6PD activity leads to decreased NADPH. This lack of sufficient NADPH is likely a significant cause of the increased oxidative stress seen in diabetes that causes kidney disease, vascular disease and other complications. NADPH is also required by the critical enzyme, nitric oxide synthase that produces nitric oxide. Nitric oxide acts as a vasodilator and leads to lowering of blood pressure. Thus, lack of NADPH also likely plays an important role in the development of hypertension in patients with diabetes. Moreover, NADPH is required by a number of other cellular reactions including the white blood cell enzyme NADPH oxidase, which is required for proper bacterial killing. Thus lack of NADPH leads to impaired antioxidant function, making cells susceptible to damage; decreased nitric oxide, leading to hypertension; and decreased white blood cell function, increasing susceptibility to infections.
Recent publications in 2010 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. In further studies with 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. The website, Diabete-in-Control selected the paper on beta cells and G6PD as one of the best articles of 2010 (FASEB J. 24:1497, 2010).
Dr. Stanton’s laboratory currenly focuses on understanding the causes of impaired G6PD enzyme activity to see whether prevention of this impairment helps prevent diabetic kidney disease, diabetic vascular disease, and preserve pancreatic beta cell mass. Dr. Stanton’s laboratory also looks for specific drugs that restore G6PD activity and increase levels of NADPH. Such drugs might play a major role in preventing the development and worsening of diabetic complications.
Dr. Stanton’s laboratory also collaborates with multiple colleagues at the Joslin Diabetes Center and Harvard Medical School. In addition, there are on-going collaborations on basic and clinical projects with scientists in China. And international clinical/translational projects are starting with international collaborators in different parts of the world to study the association of G6PD deficiency (the most common gene mutation in the world) with diabetes and diabetic complications.
Dr. Stanton is a Principal Investigator in the Section on Vascular Cell Biology and the Chief of the Nephrology Section at Joslin Clinic, 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. Dr. Stanton is involved with teaching at all levels (student, resident, fellow, and faculty) including serving on many Harvard Medical School Committees and serving in leadership positions at Harvard Medical School. Dr. Stanton also receives many invitations to lecture on research, clinical, and educational topics nationally and internationally (including China, India, Middle East, South America and elsewhere).