Life Extension Magazine October 2008
Unique form of Vitamin B6 Protects Against Complications Related To Diabetes and Aging
by Laurie Barclay, MD, introduction by William Faloon
By Laurie Barclay, MD
Every second, a destructive process called glycation occurs throughout our bodies.
Glycation occurs when sugars react with the body’s proteins, resulting in the formation of non-functioning glycation end products. While glycation is a normal consequence of aging, it is far from desirable.
Cataracts that blur vision in the eye lens are an example of glycation reactions. More ominous, glycation is associated with the development of atherosclerosis and kidney failure. Glycation end products have been isolated from Alzheimer’s lesions in the brain.
Collagen accounts for about a third of our total body proteins. Glycation causes the collagen in our skin and tissues throughout our bodies to cross-link, leading to unsightly characteristics of aging.
When meat is cooked, rapid glycation (or “browning”) reactions occur as proteins combine with the sugars present. This same glycation process also happens at a slower rate to our living proteins!
The alarming phenomenon of our aging body slowly being cooked to death has motivated scientists to develop ways to block pathological glycation reactions.
Life Extension members gained access to the first validated anti-glycation nutrient when high-dose carnosine became available. Additional protection against glycation was shown in response to benfotiamine, a fat-soluble form of vitamin B1.
For over a decade, however, governmental regulatory issues blocked access to one of the most important anti-glycation agents...a unique form of vitamin B6 called pyridoxamine.
You may wonder why supplementing with more than one anti-glycating agent is desirable. The answer is that there are many chemical processes involved in the formation of advanced glycation end products in the body. By blocking multiple chemical pathways involved in glycation reactions, one can optimally slow this devastating degradation of our living proteins.
Pyridoxamine has been extensively studied and its multiple anti-glycation properties make it important to include in a science-based daily supplement program.
In this article, Dr. Laurie Barclay describes the unique ability that pyridoxamine has shown in preventing the formation of damaging glycation end products while averting common diabetic complications such as neuropathy, retinopathy, and kidney failure.
Protein degradation is a major contributor to aging and disease. Proteins are the substances most responsible for the daily functioning of living organisms. Once too many proteins lose their functional ability, the body becomes prone to degenerative diseases and premature aging.
Destruction to proteins can be caused by oxidation (as by free radicals) and protein-sugar reactions (glycation). Glycation occurs when sugars react with proteins in the body to form damaged, non-functioning structures. Many age-related diseases such as arterial stiffening, cataract, and neurological impairment are at least partially attributable to glycation.
Unique Form of Vitamin B6
Vitamin B6 is involved in hundreds of beneficial enzymatic reactions in the body. It may even help protect against certain cancers.1
While the benefits of conventional vitamin B6 (pyridoxine) are well documented, scientists have discovered a unique form of vitamin B6 called pyridoxamine that specifically interferes with toxic glycation reactions. This unique form of vitamin B6 offers hope in combating the ravages of protein degradation involved in normal aging and the accelerated glycation reactions suffered by diabetics.
It is well known that diabetics suffer premature vascular disease along with a host of other disorders related to blood glucose imbalances. One reason is that excess blood glucose creates more glycation reactions in the body. It is thus imperative for diabetics to take extraordinary steps to protect against the formation of glycated end products (known technically as advanced glycation end products or AGEs).
Glycation end products are linked to a range of diabetes-related conditions, particularly kidney disease (nephropathy), visual loss (retinopathy), and nerve damage (neuropathy).2 One prominent anti-aging doctor described pyridoxamine as “the most potent natural substance for inhibiting AGE formation.”3
Paul Voziyan, PhD, a research associate professor of medicine and biochemistry at Vanderbilt University Medical Center tells Life Extension, “Pyridoxamine can inhibit glycation reactions and formation of AGEs, known culprits that cause damage in diabetes.”
The Biochemistry of Glycation
Glycation occurs in a series of several slow biochemical reactions, some, but not all, of which are reversible. The first step entails reactions of sugar molecules with amino acids or lipids to form “early” glycation products known as Amadori products.4 Unlike most body processes, this initial step does not involve enzymatic reactions and can be readily reversed.
Preventing this crucial first step in glycation therefore seems like a reasonable target in controlling or preventing the pathological processes that can result in advanced glycation end product (AGE) formation. Once the Amadori product is oxidized, this step is not reversible. At this point, glycation end products are as difficult to reverse as it would be to turn rusted metal back to its shiny, new condition, once the iron has oxidized.
AGEs do their dirty work by binding to receptors on the cell surface known as receptors for advanced glycation end products (RAGEs). When AGEs bind to RAGEs, more free radicals are produced, and other damaging processes associated with chronic inflammation are unleashed.5
Although we think of inflammation as being important primarily in conditions such as infection and arthritis, it is also a key process underlying aging and chronic diseases including diabetes and atherosclerosis.
Pyridoxamine Fights Glycation
Over a decade ago, a group of researchers confirmed that pyridoxamine can inhibit glycation reactions and AGE formation, awakening interest in further, more extensive investigation of the mechanism of action of this form of vitamin B6.27
“We now know that pyridoxamine can inhibit three processes critical in development of diabetic complications,” Prof. Voziyan says.” Firstly, pyridoxamine can sequester glucose and reactive products of glucose and lipid degradation, thus inhibiting formation of advanced glycation and advanced lipoxidation end products.”
“Secondly, pyridoxamine can scavenge catalytic metal ions, thus inhibiting toxic oxidative reactions; and thirdly, pyridoxamine can react with free oxygen radicals, thus preventing them from damaging biologically important macromolecules such as proteins and DNA,” Prof. Voziyan explains. “Since these mechanistic studies were performed either in [the laboratory] or in animal models, we do not yet know which of these mechanisms are responsible for the therapeutic effects of pyridoxamine in humans. It is likely that all three are important.”4,6-8
Sushil K. Jain, PhD, professor of pediatrics, physiology, biochemistry and molecular biology and chief of pediatric research at Louisiana State University Health Sciences Center in Shreveport, tells Life Extension that “pyridoxamine can scavenge toxic free radicals being produced in excess by high glucose and ketone levels in diabetic patients, and pyridoxamine can increase the utilization of glucose.”
In essence, pyridoxamine utilizes a two-pronged approach: it causes glucose to be metabolized more quickly, effectively reducing high glucose levels, while it consumes toxic free radicals produced by high levels of glucose and ketones (chemicals produced when fat is burned for energy) accompanying diabetes.
In addition to its role in preventing formation of advanced glycation (AGE) and advanced lipoxidation end products (ALE),9,10 pyridoxamine performs many vital functions of theoretical and practical benefit in both conditions.
“It is claimed that the benefits of pyridoxamine are due to prevention of protein damage by glycation,” Professor Paul J. Thornalley, from the Protein Damage and Systems Biology Research Group, Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, University Hospital, Coventry, UK, tells Life Extension.
“Pyridoxamine is, however, a form of vitamin B6 and the supplementation is expected to primarily increase the vitamin B6 pool in the body,” Prof. Thornalley says. “Some studies have found that diabetes is associated with a deficiency of vitamin B6 in the body. Pyridoxamine is expected to correct this, and the benefits accrued from pyridoxamine therapy may also be due to this.”
Work done by Prof. Jain and colleagues has shown that pyridoxamine also promotes activity of enzymes, known as sodium-potassium ATPase and calcium ATPase, which are needed for nerve cells to transmit impulses to one another. This effect of pyridoxamine helps explain why it could be particularly useful in diabetic neuropathy. By inhibiting oxygen free radical production, pyridoxamine prevents reduction of sodium-potassium ATPase activity caused by high blood sugar.8
“Activities of sodium-potassium ATPase and calcium ATPases are vital for the normal function of neurons,” Prof. Jain says. “The activity of these enzymes is low or diminished in diabetic patients. Supplementation with pyridoxamine prevents decrease in activity of these ATPases in cells.”
Prof. Voziyan also points out that “along with other forms of vitamin B6, pyridoxamine participates in many important natural metabolic reactions as an enzyme cofactor.”
To be biologically active, pyridoxamine is first converted by the body to pyridoxal 5-phosphate (PLP).11 Pyridoxine, which is the form of B6 primarily used in currently available supplements, is biochemically of no value to the human body until it is first converted to PLP.
Although the vitamin B6 activity of all three naturally occurring forms (pyridoxamine, pyridoxine, and pyridoxal) is comparable because the body contains enzymes that convert one form to another, the ability of pyridoxamine to inhibit glycation and AGE formation is superior to that of the other two forms (pyridoxine and pyridoxal).
“Regarding pyridoxamine and preventing secondary complications of diabetes, …the compound is able to scavenge the deleterious aldehydes which are thought to mediate these changes,” Dr. Hipkiss says.
Aldehydes are harmful chemicals, given off as byproducts of certain metabolic reactions in the body, which increase free radicals that wreak havoc in many tissues, culminating in disease and injury. Research by Prof. Voziyan and colleagues showed that pyridoxamine reacts rapidly with damaging aldehydes, thereby preventing chemical modification of tissue proteins and AGE/ALE formation.6
Even apart from its effect on AGE formation, pyridoxamine may hold promise in diabetes by reversing another of the most fundamental culprits underlying the disorder and its complications: beta-cell dysfunction.12 Beta cells are the specialized cells within the pancreas that secrete insulin, which is deficient in patients with diabetes.
In an experimental model of diabetes, hamsters treated with pyridoxamine for four weeks had fasting blood sugar and glucose tolerance test results similar to those of control animals without diabetes. Even more amazingly, insulin secretion improved and beta cells began to regenerate and grow in pyridoxamine-treated diabetic animals.12