Diabetic patients, their physicians and health care providers, including certified diabetic educators, all recognize that diabetes is a disease in which blood flow slowly and insidiously decreases over time. The heart, kidneys, eyes, skin, and nerves all exhibit signs of reduced blood flow. One organ may show symptoms earlier than another, but all organs eventually demonstrate reduced function associated with the progressive decrease in blood flow. The key to slowing this progressive deterioration of organ function is to delay the decrease in blood flow, or if possible, to restore it back toward normal levels.
Thomas Burke, Ph.D.
The body’s natural vasodilator is nitric oxide (NO) but its production by diabetic patients is often 50% or more below normal levels. In addition, any NO that is formed is very tightly bound to hemoglobin within RBCs (and possibly to other heme proteins in other cells) so that it cannot be easily released to cause a needed increase in blood flow.
The past articles in this series have shown that there are several ways to increase the production or the local release of NO. Oxygen is critical to NO production but with poor circulation to sites such as nerves and skin, not enough oxygen is available to fully activate the enzyme that generates NO from the amino acid L-arginine. In addition, as blood flow decreases, the generation of ATP (from oxygen and glucose) diminishes and high amounts of acid molecules are formed. Acidosis also diminishes the production of NO. Since production is diminished, the only readily useful source of NO is that already stored in cells, such as RBCs. The problem is how to release the stored NO so that local vasodilation can occur. The Anodyne Therapy System™ (ATS), mentioned several times in this series, turns out to be an easy to use, efficacious, non-invasive, drug free way to accomplish the local release of NO from RBCs. The ATS uses near infrared light (NIR) that penetrates far deeper into tissues than do shorter wavelengths such as ultraviolet (UV).
Why is a wavelength of light so effective in releasing NO from RBCs? To answer this question one must acknowledge the important contributions of physicians/scientists who have studied NO for so many years. The 1998 Noble Prize in Medicine or Physiology was awarded to three Americans, one of whom, Dr. R.F. Furchgott, noted that NO could be made available acutely when he shined white light on tissues and that, as a result, blood flow increased. Since light is made up of several different wavelengths (or colors), subsequent research studies explored the beneficial effects of individual colors to determine which might be better at causing NO production or release and the accompanying vasodilation. Studies with visible colors were followed by experiments with single wavelengths (monochromatic) of non-visible light such as ultraviolet (UV) and near infrared (NIR).
Once NO is made available following the ATS’s effect on RBCs, and local blood flow (both arterial perfusion and venous return) is increased, skin ulcers heal faster and sensory and other nerve functions improve toward normal. (All these events occur through the effect of nitric oxide to elevate cGMP and the phosphorylation events that follow.)
Loss of sensation, especially in the feet of diabetic patients, has always been a progressive and irreversible side effect of diabetes; there was, until the ATS became available for clinical use in 1994, no known treatment for diabetic peripheral neuropathy. Since Loss Of Protective Sensation (LOPS) is the leading cause of diabetic foot ulcers and amputations, saving the foot has become a goal of all agencies (Federal, for-profit, and not-for-profit) interested in diabetes foot care. One important recommendation to diabetic patients is to exercise. Exercise is much easier to engage in if blood flow is restored to near normal levels. In addition, exercise itself produces NO in blood vessels (by a process known as “shear stress”) so that once circulation is restored toward normal levels, exercise helps to sustain the improvement in blood flow. However, it is quite difficult for a diabetic patient, with poor baseline blood flow and little or no sensation in their feet, to engage in this needed exercise.
Use of the ATS now appears to be a simple way to reverse LOPS (i.e., to restore protective sensation). Restoration of protective sensation is the leading way to dramatically decrease the incidence of ulceration and reduce the number of diabetes-related amputations performed each year. Associated costs of simply just treating diabetic ulcers, rather than healing them, should also decrease since the ATS also helps to heal (not just treat) diabetic ulcers. Importantly, the ATS mediated increase in local NO, besides just increasing blood flow, oxygen, and nutrient delivery, has other secondary effects. The ATS mediated increase in circulation restores the ability of cells such as fibroblasts to secrete growth factors, and NO enhances cell division so that new cells are formed faster than in the absence of NO. In addition, the increase in circulation delivers more white blood cells to the area so that healing and infection control can be achieved naturally. If needed, antibiotics are also delivered more effectively to the site of an infection when localized blood flow is increased. This is a remarkable series of outcomes, all attributed to increasing local NO at the treatment site.
It is highly unlikely that we would have been able to draft this series of articles on diabetic peripheral neuropathy and wound healing if Dr. Furchgott had not been curious about the effects of light in his laboratory experiments so many years ago. In fact, even he recognized the importance of NO to diabetic patients. Dr. Furchgott wrote a lengthy article in 1998 entitled “Nitric oxide: from basic research on isolated blood vessels to clinical relevance in diabetes”, An R Acad Nac Med (Madrid) 115: 317-331. The Anodyne Therapy System capitalizes on these Nobel Prize winning laboratory experiments and appears to lead, non-invasively, to a biologic correction of diabetic circulatory problems that previously defied any consistent mechanical or pharmaceutical treatment.
Patients with serious diseases, and even their physicians, are often frustrated with the slow pace by which basic research is translated into treatments or cures. This series of articles highlights that such results do occur, and we encourage everyone to continue to support basic research conducted by the National Institutes for Health. One never knows where the next breakthrough will occur. We hope that the information on NO and diabetes, provided in this series of articles over the last 12 weeks for patients and their healthcare providers, will stimulate discussion about the importance of NO in ameliorating some of the symptoms of diabetes.
In conclusion, we recognize that research continues in the field of nitric oxide every day and that, in the future, targeted pharmaceutical drugs might be developed to locally increase nitric oxide. In the meantime, the Anodyne Therapy System™ is a currently available, viable approach to locally stimulating NO release so as to increase circulation and reduce pain, two outcomes that may be of particular advantage to diabetic patients.
Dr. Tom Burke received his PhD in Physiology from University of Houston and 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.
If you’ve missed any of this series of articles, just click below for Parts 1-10.