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
dysfunction? Authors:
Evans,
JL;Goldfine, ID;Maddux, BA;Grodsky, GM
Figure 1:
Proposed general theory of how elevated glucose
and possibly FFA levels contribute to the
pathophysiology of diabetes via the generation
of ROS and consequent activation of numerous
stress-sensitive pathways. The causative link
among hyperglycemia, mitochondrial ROS
generation, oxidative stress, and the
development of diabetic complications has been
previously suggested (10,11,22). ROS (and RNS),
by inflicting macromolecular damage, may play a
key direct role in the pathogenesis of
diabetes. ROS also function as signaling
molecules (analogous to second messengers) to
activate several stress-sensitive pathways
(indirect role). In addition, in type 2
diabetes, there is growing evidence that
activation of stress-sensitive pathways, such
as NF-kB, p38 MAPK, JNK/SAPK, and hexosamine,
by elevations in glucose and possibly FFA
levels leads to both insulin resistance and
impaired insulin secretion. Thus ROS and
oxidative stress, induced by elevations in
glucose and possibly FFA levels, may play a key
role in causing insulin resistance and
ß-cell dysfunction by their ability to
activate stress-sensitive signaling pathways.
The proposed sequence of events may also
include other stress pathways, such as the
increased production of AGE, sorbitol,
cytokines, and prostanoids along with PKC
activation. DAG, diacylglycerol.
Figure 2:
Figure 2:
a-Lipoic acid (LA) is an eight-carbon fatty
acid that is synthesized in trace quantities in
organisms ranging from bacteria to man. LA
functions naturally as a cofactor in several
mitochondrial enzyme complexes responsible for
oxidative glucose metabolism and cellular
energy production. LA has been prescribed as
pharmacotherapy in Germany for over thirty
years for the treatment of diabetes-induced
neuropathy. Both pre-clinical and clinical
studies have established that LA suppresses the
activation of NF-kB, a transcription factor
that is a major mediator of the inflammatory
response. The ability of LA to block the
activation of NF-kB is clearly linked to its
ability to protect cells from oxidative
stress-induced insulin resistance. In animal
studies, oral treatment with LA results in the
activation of AMP-activated protein kinase
(AMPK), the major cellular fuel sensor and an
enzyme that is activated by the predominant
anti-diabetic interventions of exercise,
metformin, and thiazolidinediones. Activation
of AMPK yields many beneficial effects on
metabolism, especially the mobilization of
lipid stores in skeletal muscle and liver.
Reduced intracellular lipid reduces cellular
inflammation, and increase the response of
these tissues to insulin, i.e. LA increases
insulin sensitivity. As a consequence of
increasing insulin sensitivity, LA improves
glucose utilization in patients with type 2
diabetes.