Joseph L. Evans talks with
ScienceWatch.com 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.
Article: Are oxidative stress-activated signaling
pathways mediators of insulin resistance and beta-cell
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
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
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
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
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
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
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
KEYWORDS: KAPPA-B ACTIVATION; ALPHA-LIPOIC ACID; RAT
PANCREATIC-ISLETS; JUN NH2-TERMINAL KINASE; II DIABETES-MELLITUS;
LONG-TERM EXPOSURE; L6 MUSCLE-CELLS; PROTEIN-KINASE; FATTY-ACID;