|Lipoic Acid: A blessing for Diabetics Part II
An Interview with Dr. Hans Tritschler
Part II: Clinical Studies
By Richard A. Passwater, Ph.D.
This is the second of two parts describing the benefits of lipoic acid supplementation, and especially, the blessing of lipoic acid means for diabetics. In Part I, Dr. Hans Tritschler and I discussed background information about the functions of lipoic acid. Now we will discuss some of the recent studies that make it obvious that every diabetic should take lipoic acid supplements.
Diabetes strikes one of every twenty Americans. Not only is it the third leading cause of death in the U. S., it inflicts serious suffering in the form of blindness, nerve damage, heart disease, gangrene, and amputated limbs. In little more than a generation, the incidence of diabetes has increased over 600 percent, accounting for 300,000 to 350,000 deaths each year during the early 1990's. About half of those with coronary artery disease and three-fourths of those suffering strokes developed their circulatory problems prematurely as a result of diabetes.
Diabetes is a group of diseases in which the body cannot properly metabolize food into energy. The result is a build-up of blood sugar that causes long-term "glycation" damage and even more immediate problems. The high sugar level in the blood results in osmotic changes and reduced blood volume, shock acidosis, coma and death. Insulin-dependent diabetes mellitus (type I) normally results from the body not producing enough insulin. This is normally the result of damage to the beta-cells of the pancreas. This form of diabetes usually, but not always, begins in childhood and was often called "juvenile diabetes."
Non-insulin diabetes (type II) accounts for about 85 percent of diabetes cases and is usually associated with age and/or obesity. It is still sometimes called adult- onset diabetes. This form of diabetes is caused "insulin resistance" of peripheral cells or the inability of insulin receptors to utilize insulin efficiently. Normally diet and oral medication can keep blood sugar levels near the normal range, but insulin is generally of no value. Type II diabetics generally have high levels of insulin in the blood but it is ineffective because of the insulin resistance of the tissues.
The bad news is that even when blood sugar levels are reduced below a critical level, they still fluctuate widely and are still above the level that leads to glycation. Glycation damage and free radical damage lead to the complications such as cataract, retinopathy, stiffened arteries and heart tissue, damaged lipoproteins (Ox-LDL) and nerve destruction.
Blood sugar (glucose) and other sugars called "reducing" sugars, such as fructose and ribose, react spontaneously -- without the need for enzymes -- with collagen, a major protein found in skin, blood vessels and connective tissue -- and other proteins to form cross-linked sugar-damaged proteins.
The rate of sugar modification of proteins is proportional to the blood sugar level. The process of forming these sugar-damaged proteins is called "glycation." The actual sugar-damaged proteins and complex derivatives of glucose themselves are called "advanced glycosylation end products," or "AGEs" for short. That's not a bad acronym as "AGEs" lead to an "aged" body at an early age. AGEs are yellowish-brown fluorescent structures. The process can be compared to the browning reaction in toast and sliced apples. The formation rate of AGEs increases as the blood sugar level increases and the length of time the level is raised increases.
The spontaneous reaction of sugar with tissue proteins such as collagen and myelin is responsible for accelerated tissue aging in diabetics, and is believed responsible for kidney damage and is also involved in the atherosclerosis process, which are both common complications of diabetes. Glycation reactions also play a role in the normal aging of tissue. This observation has led to the "Glycation Hypothesis of Aging." Recent studies show that diabetics as well as aging animals do indeed have increased concentrations of AGEs in their collagen. Of related interest is the fact that average blood sugar levels tend to rise with increasing age owing to the fact that the tissues becomes less sensitive to the actions of insulin as we age. It is not just a loss of reserve due to aging and the loss of tissue, but it directly involves the interaction of insulin and the tissues themselves.
The roles of oxygen-damaged protein and sugar-damaged protein definitely explain much of the secondary aging effects and some of the primary aging process. It appears likely that, other factors being equal, high blood sugar levels, and also wide fluctuations in blood sugar levels, increase the cross-linking of collagen and other important proteins. Conversely, maintaining precise blood sugar control at the optimal level throughout life should result in tissues that are "young for their age."
Passwater: Dr. Tritschler, please tell us more about the role of glycation in diabetes.
Tritschler: Professor Lester Packer from the University of California at Berkeley and Professor Peter Nawroth from Heidelberg University have shown that lipoic acid can reduce glycation. This observation is of pivotal importance, since the glycation process represents the initial pathological event leading to the diabetic complications such as nephropathy (kidney damage), polyneuropathy (nerve damage), microangiopathy (heart damage) and others. Since lipoic acid can prevent glycation, it can prevent or retard the development of these devastating and deadly complications of diabetes.
Passwater: Does Lipoic acid improve glucose transport and help regulate blood sugar levels?
Tritschler: The antidiabetic property of lipoic acid was first hypothesized three years ago. At that time we had received several case reports that lipoic acid enhances the action of insulin and antidiabetic drugs for lowering blood glucose (blood sugar) levels. We have since then obtained preclinical evidence that lipoic acid enhances glucose utilization which is decreased in diabetes. From these experimental studies, we learned that lipoic acid has a positive effect on the glucose transporters that regulate the uptake of glucose from the blood stream into the cell. As a result of this very interesting finding, we conducted three clinical pilot studies. These pilot studies verified this positive effect of lipoic acid, so we then conducted a large multicenter study. The large clinical study confirmed that 600 milligrams of lipoic acid daily improves glucose utilization in type-II (adult onset or non insulin- dependent) diabetic patients. This is an extremely interesting finding because in type-II diabetes, there is impaired glucose utilization despite the fact that these patients have sufficient levels of insulin.
Since increased glucose utilization leads to reduced blood glucose levels, we expect to see decreased blood glucose levels during 600 milligrams of lipoic acid supplementation. We have just completed a small pilot study in Frankfurt showing a very nice antidiabetic effect from 1,200 milligrams of lipoic acid daily. The biochemical abnormalities associated with type-II diabetes were markedly improved by lipoic acid. We are now planning a large placebo-controlled, double-blind study to confirm these results.
Passwater: I remember that during the 1995 Munich Conference on Diabetic Neuropathy it was reported that lipoic acid acts to increases glucose transport by stimulating the glucose transporters GLUT-1 and GLUT-4 to move from the cell interior to the membrane. This action is independent of insulin transport. It is believed that the sulfur atoms of lipoic acid are responsible for the translocation action. This restoration of normal blood sugar level in turn increases the number of glucose transporters in the membranes of muscle cells. This is a very desirable cycle. I also remember that your name was included in the research group that reported at the Munich meeting on how lipoic acid increases glucose uptake by muscle cells and decreases glucose uptake by fat cells. Did you make any other presentations?
Tritschler: Actually, I didn't present any of the papers personally. I was too busy handling organizational details along with two German opinion leaders.
Passwater: What other interesting research or clinical trials were reported there?
Tritschler: During the Munich conference, the investigators presented consistent clinical and preclinical results showing improvement of type II diabetes and diabetic polyneuropathy by supplementation with lipoic acid. They provided sufficient experimental and clinical evidence that lipoic acid is a very useful metabolic antioxidant for the treatment of these disorders and most likely in the prevention of diabetic complications. Moreover, the safety aspects were discussed in detail.
Passwater: I have only the abstract from the conference, but the information would be useful to many health professionals. Will the full papers be published?
Tritschler: Yes, the full scientific program will be published later this year.
Passwater: Would you recommend that U. S. physicians look into the research on lipoic acid and diabetes?
Tritschler: Definitely. AS we have discussed, the most recent lipoic acid studies have been presented at International Diabetic Congresses and many studies have been published in international journals. Our goal is that the international and particularly the American medical community becomes familiar with the actual status of lipoic acid research and deepen their interest in the new opportunities provided by the clinical applications of lipoic acid.
Passwater: How much lipoic acid is required to help diabetics significantly reduce their risk of the adverse effects of diabetes such as diabetic neuropathy, diabetic retinopathy, cataracts and diabetic cardiopathy?
Tritschler: The answer is very simple. Clinical studies have shown that 600 milligrams per day of oral lipoic acid are required to improve diabetic polyneuropathy. This dose is the daily dose recommended in Germany by opinion leaders.
Passwater: Why do diabetics suffer nerve damage?
Tritschler: As I mentioned before, the glycation process is the initial step of a cascade leading to diabetic complications and therefore also to diabetic polyneuropathy. The so-called advanced glycation end-products (AGEs) cause a reduced blood flow in the peripheral nerve, which in turn leads to oxidative stress. There is indisputable evidence that chronic oxidative stress damages the peripheral nerve fibers leading to their degradation. If this process is not promptly interrupted by strict glucose control and therapeutical intervention, the nerve fibers will die. This degenerating process is accompanied clinically by the loss of sensation in the lower limbs.
Passwater: Can lipoic acid reverse this nerve damage if it helps keep blood sugar less than the level that causes damage?
Tritschler: Lipoic acid can reduce the glycation process and consequently improve the nerve blood flow that is impaired in diabetic polyneuropathy. Furthermore, lipoic acid reduces the oxidative stress in the diabetic nerve and concomitantly enhances the levels of the antioxidant, reduced glutathione, which is depleted in diabetic polyneuropathy. This process is ultimately responsible for the improvement of nerve function. On these bases, we may conclude that lipoic acid interferes with the pathogenetic mechanism of diabetic polyneuropathy.
Passwater: Why does lipoic acid help protect diabetics against cataracts or retinopathy?
Tritschler: The vicious metabolic circle of high glucose blood levels, increased glycation products, reduced blood flow and enhanced oxidative stress is the mechanism common to most diabetic complications including diabetic retinopathy. It is also interesting to note that laboratory experiments have demonstrated that lipoic acid prevents cataract formation, most likely as result of interrupting this vicious circle.
Passwater: Does lipoic acid improve the sorbitol pathway in diabetics?
Tritschler: We have not investigated the effects of lipoic acid on the sorbitol pathway -- neither in diabetic patients nor in healthy individuals. The reason for this lies in the recently doubted relevance of the sorbitol pathway to the development of diabetic neuropathy. There is now a large body of evidence demonstrating clinical and experimental inefficacy of substances able to improve the sorbitol pathway.
Passwater: Now, your finding that I find most interesting. Do Advanced Glycosylated End products (AGEs) cause the release of oxygen free radicals when the AGEs are taken up into receptors?
Tritschler: Yes, we have reported evidence of free radical-related damage provided by AGEs locked into the system. The experimental design and the technologies used to demonstrate these phenomena are very complicated to explain, however they provide data highly reliable and relevant to the diabetes clinical setting.
Passwater: What is the significance of your research showing that lipoic acid affects NF-kB interaction with DNA?
Tritschler: This is a very important question. I think that modern medicine is going into a new direction searching for the gene abnormalities that may underlie complex biochemical abnormalities as diabetic complications or HIV-induced cell death. Concerning the diabetic complications, there is a considerable amount of evidence that the activation of one transcription factor leads to all diabetic complications. If this hypothesis is true, the therapeutic aim should be to inactivate this transcription factor in order to reverse all diabetic complications. Based on the studies from Professor Peter Nawroth, lipoic acid is a good potential candidate. We are at the cutting edge of science and we will need several years to prove this intriguing theory scientifically. Nevertheless, we are very interested in the field to influence the transcription factor NF-kB and hope to achieve a scientific break through in the upcoming years.
Passwater: In part I, I referred to you as a human dynamo in reference to your energy level. Is your secret genetic or do you take extra supplements. Give us a clue -- what supplements do you take?
Tritschler: I have no clue about my genetic contribution. Concerning antioxidants, I take 400 IU of natural vitamin E and 50 milligrams of lipoic acid daily. I take the German standardized formula, with which all of the studies have been done. Since I am concerned about my cholesterol level, I follow a low-fat diet. Since vitamin E is a fat-soluble vitamin present in the fatty-regions of foods, I take supplements of natural vitamin E to increase my vitamin E level.
The Cambridge Heart Antioxidant Study (CHAOS) has recently shown a 77 percent reduction in the heart infarct rate in those people who took 400 IU of natural vitamin E daily. With this study I feel very confident with the 400 IU level of intake of vitamin E, but in addition, I also take 50 milligrams of lipoic acid to keep the vitamin E in my body activated. As Dr. Packer has said in a previous interview, lipoic acid acts to reactivate the vitamin E that has been deactivated by free radicals.
This is achieved via lipoic acid recycling vitamin C to its active form which in turn recycles vitamin E to its active form. Since I eat many fruits and vegetables, I'm not concerned about my vitamin C levels. Therefore, I take no extra vitamin C supplements, but lipoic acid to complete the antioxidant cycle or network which is composed of the antioxidants vitamin E, vitamin C, lipoic acid and glutathione.
Passwater: Your research covers so many different and interesting areas. Is there a possibility that there could be even other areas of lipoic acid research that you could possibly be investigating?
Tritschler: My research is strongly focused on the effects of lipoic acid in diabetes and diabetic polyneuropathy. Another very exciting area is HIV. Recent clinical studies have shown an almost complete depletion of the antioxidant glutathione in patients with HIV. As you remember from your December 1995 interview with Dr. Lester Packer, he showed that lipoic acid restores the reduced glutathione levels. Dr. Jurgen Fuchs has clinically tested this antioxidant ability of lipoic acid and found positive results using 600 milligrams of lipoic acid per day orally. Dr. Luc Montagnier, as you mentioned in your September 1995 interview with him, first identified the HIV virus. He is planning to test antioxidants including lipoic acid in AIDS patients. A field that remains for me of highest interest and yet remains unexplored except for my first report, is the use of lipoic acid treatment in mitochondrial cytopathies, which brings me back to the beginning of our interview and shows an old unforgotten love.
Passwater: Thank you for sharing your research with our readers.
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