Nitric
Oxide and Its Role in Health and Diabetes.
Thomas
Burke Ph.D.
Part 8.
Nitric Oxide(NO) and diabetic peripheral neuropathy (DPN)
Diabetic Peripheral
Neuropathy (DPN; peripheral nerve damage) is a common complication of
diabetes. Almost 70% of people with diabetes develop DPN within 5
years and after 5 years the incidence rate increases to almost 100%.
DPN most often begins as a tingling feeling and insidiously progresses
to loss of sensation to hot and cold and to pressure. Additionally,
DPN sometimes manifests itself as diffuse pain in the extremities. DPN
is uncomfortable, may lead to poor balance and higher risks of falls,
and is dangerous to those who have it.
We have all come in contact with people with insensate feet who
have developed ulcers because they did not sense poorly fitting shoes
or unexpected foreign objects.
Recently, the
Centers for Medicare and Medicaid Services
(formerly HCFA) in Decision Memorandum CAG 00059 characterized
DPN with loss of protective sensation (LOPS) as a localized illness of
the foot and the
most important factor leading to amputation in people with
diabetes. Diagnostically,
this Decision Memorandum states that DPN with LOPS is determined by
insensitivity to a Semmes Weinstein 5.07 Monofilament at 2 sites on
the bottom of the foot.
Just how does DPN
occur in people with diabetes? The
causation is debated among researchers and clinicians in the field.
One theory is that progressive loss of circulation to the peripheral
nerves is the cause of DPN. Another
theory is that DPN is due to nerve dysfunction possibly due to
accumulation of sorbitol on peripheral nerves.
According to the NIDDK (Peripheral Neuropathy: The Nerve Damage
of Diabetes), other researchers believe that lack of nitric oxide or
poor nitric oxide metabolism may be the culprit. The debate and
research goes on and hopefully one day we will have the answer.
While the pain
associated with DPN may respond to drug therapy (for instance,
Neurontin) or to topicals (lidocaine or capsaicin), clinicians have
had little in their armamentarium to reverse the progressive loss of
sensation observed with DPN. Clinical trials for a class of drugs
known as aldose reductase inhibitors have been unsuccessful.
However, Dellon has reported success with a surgical
intervention similar to that employed in carpal tunnel release.
Additionally, alpha lipoic acid is under investigation in
Europe as having potential to increase sensation in cases of DPN.
The American
Diabetes Association, based on the 10-year study of 1,441 patients
with IDDM, recommends, that tight glucose control is one of the best
ways to delay the onset or progression of DPN. Tight glucose control
may delay the onset of LOPS in DPN, by decreasing the accumulation of
sugar molecules called sorbitol within the nerves themselves. Reducing
serum glucose levels also lowers the concentration of glycosylated
hemoglobin (HbA1c). We have already mentioned in an earlier article
that people with diabetes produce lower than normal levels of nitric
oxide that may account for decreases in blood flow and a decreased
capacity of blood vessels to dilate. Now we know that even the low
amounts of NO produced are tightly bound to glycosylated hemoglobin.
Not surprisingly, when HbA1c is elevated, the NO that is present in
red blood cells is not easily released to promote vasodilation.
This may account, in part, for very low blood flow to the
nerves of the feet and, thus to the symptoms of DPN.
In view of the
risks associated with DPN, either slowing its progression or,
hopefully, reversing its course, is a worthwhile clinical goal. A
promising new approach involves the use of an FDA cleared,
non-invasive, medical device which may increase local levels of NO,
thereby restoring circulation to the feet of people with DPN. It is
hypothesized that that this device may promote a NO-mediated increase
in circulation to help to regrow nerves that were lost to DPN or it
may reestablish normal function in those nerves that still remain in
the feet, or both. The first report (A Kochman, et. al., JAPMA 2002,
in press) of the effect of this drug-free technology on patients with
DPN is very encouraging. After only one month of treatment (3X/week
for 30 min/day), 42/42 patients who were insensate to a Semmes
Weinstein 5.07 Monofilament when they entered the study were able to
feel this 5.07 Monofilament at the conclusion of the study. In other
words, loss
of protective sensation was no longer clinically present.
The next article
will detail why this device, the Anodyne Ò
Therapy System, may be able to alter local levels of nitric oxide so
as to restore sensation lost with diabetes.
Dr. Tom Burke
received his PhD in Physiology from University of Houston, Post
Doctoral Training at Duke Medical School, He was an Associate
Professor of Medicine and Physiology at the University of Colorado
Medical School. He has authored more than 70 published scientific
clinical articles and has been a visiting scientist at the Mayo
Clinic, Yale University, University of Alabama, and University of
Florida. He is a recognized international lecturer on cell injury and
nephrology.
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