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Joseph L. Evans talks with and answers a few questions about this month's Emerging Research Front Paper in the field of Biology & Biochemistry. The author has also sent along images of his work.
Evans Article: Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction?
Authors: Evans, JL;Goldfine, ID;Maddux, BA;Grodsky, GM
Journal: DIABETES, 52 (1): 1-8 JAN 2003
Addresses: Med Res Inst, 444 De Haro St,Suite 209, San Francisco, CA 94107 USA.
Med Res Inst, San Francisco, CA 94107 USA.
Univ Calif San Francisco, San Francisco, CA 94143 USA.

Why do you think your paper is highly cited?

Oxidative stress is a type of cellular inflammation that stems from chronic hyperglycemia. Oxidative stress had long been linked to the development of complications in type 1 and type 2 diabetic patients. Our paper, however, was the first to present evidence that oxidative stress, caused by hyperglycemia and previously unappreciated agents such as elevated free fatty acids, plays a major role in the development of insulin resistance and impaired insulin secretion—the major causes of type 2 diabetes (See Figure 1 to the right).

Does it describe a new discovery, methodology, or synthesis of knowledge?

Our paper offers a concise, complete, synthesis of a large body of work authored by many of the leading experts in the field. The paper presents a unifying hypothesis that ties together data from several diverse areas.

Would you summarize the significance of your paper in layman's terms?

Figure 1: +details
Click figure to enlarge and read description.
Figure 2:
Click figure to enlarge and read description.

Both the early and late stages of type 2 diabetes are worsened and most likely caused by increased cellular inflammation due to oxidative stress. Treatments that reduce the oxidative stress and/or suppress the responses stimulated by oxidative stress can offer new therapeutic opportunities. These treatments should delay the onset and/or even prevent the development of diabetes and its complications.

How did you become involved in this research and were any particular problems encountered along the way?

I first became involved in diabetes research in 1986 as a post-doctoral fellow at Dartmouth Medical School, under the expert guidance of Professor Lee Witters. Since that time, my research efforts moved from academia to industry, but have continually and unwaveringly focused on identifying and developing new potential treatment approaches for type 2 diabetes and other metabolic disorders.

Success in this endeavor involves not only a thorough understanding of the drug development process, but also a comprehensive knowledge of the pathophysiology of the disease. This challenge has driven me towards a holistic viewpoint of both disease etiology and treatment, and ultimately resulted in some of the ideas put forth in this paper.

As for problems, there are always problems; it is the job of the scientist to find solutions. However, it has been an ongoing struggle for my collaborators and I to secure adequate funding for research described in this paper, as is often the case with new ideas.

Where do you see your research leading in the future?

I firmly believe that this area of research will ultimately lead to safer and more efficacious treatments for type 2 diabetes than are currently available today. By targeting the cellular inflammation, these treatments will have a direct effect at improving insulin sensitivity, and reducing the deterioration of the insulin-producing beta cells.

One compound, in particular, that has shown great promise in this regard is alpha-lipoic acid. Although commonly thought of as an anti-oxidant, lipoic acid is a highly effective inhibitor of NF-kB activation (a primary inflammatory pathway) in humans. In addition, animal studies have shown that lipoic acid activates AMP-activated protein kinase in peripheral tissues, leading to reduced inflammation, reduced hepatic and muscle lipid accumulation, and increased glucose utilization and insulin sensitivity (See Figure 2 to the right above).

Do you foresee any social or political implications for your research?

Absolutely. The US, along with the rest of the world, is experiencing an epidemic in diabetes and other metabolic diseases, especially the metabolic syndrome and obesity. There is not a country in the world that possesses a healthcare budget with sufficient funding to care for all the affected individuals after they develop the disease. The drain on the limited available health care resources is already being felt, and will only get worse.

The long-term solution is prevention and early intervention, before the debilitating complications of the disease arise. It is imperative for us as scientists and as citizens to convince our elected officials at both the state and federal levels to allocate significantly more resources to address the obvious need for improved therapy. These additional resources should be used to support academic research and development, along with providing increased support for small private business entities that are seeking to develop and commercialize these new treatments.

Joseph L. Evans, Ph.D.
Founder and President
P & N Development Ventures
Redwood City, CA, USA


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2009 : April 2009 - Emerging Research Fronts : Joseph L. Evans
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