Metabolic suppression

The key to understanding diabetic complications

 
 
Joseph R. Williamson, MD 58, retired professor of pathology, and his daughter Ca
Robert Boston

Study co-author Joseph R. Williamson, MD 58, retired professor of pathology, and his daughter Catherine, a nurse practitioner in the School of Medicine's Division of Infectious Diseases, attended his 55th medical school reunion in April.

BY Holly Edmiston

In people with diabetes, increased blood glucose levels set off a cascade of events that impair cell metabolism. Over time, the cells become damaged. In order for them to survive, they "shift their priorities" to maintain the most critical cellular functions. New research findings support the importane of this adaptive response. This novel concept of a "shift in priorities" is called metabolic suppression.

Joseph R. Williamson, MD, retired professor of pathology, has researched the causes of diabetic complications for more than 50 years. His first research article was published in 1959 in The American Journal of Pathology; his latest, and he says last, in the December 2012 issue of the Journal of Diabetes & Metabolism.

Williamson and his co-author of the recent study, Yasuo Ido, MD, PhD, of Boston University School of Medicine, say their findings should be of interest and importance not only to clinicians treating patients with diabetes, but also to researchers investigating metabolic imbalances that cause diabetic complications evoked by hyperglycemia.

In the study, the authors provide new evidence for the importance of metabolic suppression, which is an adaptive response of cells to minimize damage caused by oxidative stress. It enables cells to reduce cellular dysfunction and damage, and to prolong their survival despite persistent oxidative stress.

“Metabolic suppression is the cell’s ability to maximize its energy in the most effective way possible,” explains Williamson, “preferentially selecting the most critically essential cellular functions.”

In the study, the authors provide new evidence for the importance of metabolic suppression, which is an adaptive response of cells to minimize damage caused by oxidative stress. It enables cells to reduce cellular dysfunction and damage, and to prolong their survival despite persistent oxidative stress.

Metabolic suppression was first described by Hochachka, et al, as an adaptive response of cells to survive the adverse effects of hypoxia, says Williamson. Subsequently, he and Ido recognized the remarkable similarity of oxidative stress and metabolic suppression caused both by hypoxia and by hyperglycemia.

“The important role of metabolic suppression in people with diabetes, hypoxia or ischemia is supported by many well-known diabetes researchers cited in the article,” says Williamson. He notes, however, that the term “metabolic suppression” is not mentioned in those authors' interpretations of the observations, possibly because they were unaware of Hochachka's findings.

Williamson, who spent more than 40 years as a faculty member at Washington University after graduating from its School of Medicine in 1958, notes that the importance of increased sorbitol oxidation in the pathogenesis of diabetic complications has remained controversial since he and his co-authors first proposed it in a perspective article in the journal Diabetes in 1993. Although he officially retired in 1998, he has spent the last 15 years conducting an extensive review of the literature related to the concept of metabolic suppression.

It has long been recognized that high blood glucose levels (hyperglycemia) cause damage to numerous cells and tissues in the body. Hyperglycemia increases glucose metabolism in cells by two major pathways. The normal pathway produces energy required to support normal cell functions. In contrast, the second pathway, the sorbitol pathway, causes oxidative stress, which damges cells, impairing cell function and survival. This oxidative stress, says Williamson, plays a key role in causing the complications of diabetes. 

In the study, the authors also link metabolic imbalances caused by hyperglycemia to each other and explain how they mediate cellular dysfunction and damage in a wide spectrum of cells and tissues while, at the same time, rendering them more resistant to hypoxic/ischemic injury by evoking metabolic suppression. The cells survive but are damaged, causing complications of diabetes. They also draw attention to the fundamental importance of the balance of antioxidants in modulating signaling pathways and oxidative stress that regulate physiologic functions, such as blood flow, during diabetes or hypoxia.

Finally, the researchers draw attention to the importance of potent natural antioxidants for treatment and prevention of diabetic complications. These antioxidants, such as C-peptide and pyruvate, markedly decrease or normalize cellular dysfunction caused by oxidative stress without the side effects seen in some pharmacologic agents.

“Our findings are novel, exciting, and very important,” says Williamson.

He and Ido believe that the concept of metabolic suppression has significant implications for the design and optimization of future therapies for the prevention and treatment not only of diabetic complications, but also in other diseases.

Corresponding author: Joseph R. Williamson, MD, Department of Pathology, Washington University School of Medicine: jrw@pathology.wustl.edu

“Linking Diabetic Complications to Sorbitol Oxidation, Oxidative Stress and Metabolic Suppression” 
Journal of Diabetes & Metabolism:  
http://www.omicsonline.org/2155-6156/2155-6156-3-219.digital/2155-6156-3-219.html

 

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