David S Klein, MD
Diabetes mellitus is a metabolic disorder characterized by elevation of fasting blood sugar (glucose). In adult onset diabetes (type II,) insulin levels are usually elevated. This occurs as a result of pathology of the insulin receptor, whereby the cellular need for insulin stimulation climbs, due to structural changes within the insulin receptor, itself. More on this, below.
While the cause of the elevated blood glucose may be associated with either too little or too much insulin, the complications of chronically high serum glucose are devastating to the individual. Complications of uncontrolled blood sugar include increased risk of heart disease, stroke, kidney disease, blindness, and loss of nerve function. Regulating blood sugar for diabetics is therefore crucial to both the immediate as well as long-term care of diabetic patients.
Type 1 Diabetes
Often called insulin-dependent diabetes mellitus (ID-DM), this form of diabetes is characterized by the destruction of the pancreatic beta cells that manufacture insulin. Typically this form diagnosed while the patient is a child or adolescent and requires insulin for the management of blood sugar. Many theories have attempted to account for the damage of these important insulin producing cells including autoimmune processes, chemical damages, viral infection, and genetic disposition.
Whatever the cause, the result is very low or no insulin; a protein that is the primary mediator of glucose transport into cells. This diminished insulin level leads to elevated levels of glucose in the blood, which then results in numerous complications. Of the more than 15 million Americans with diabetes, only about 10% are considered to have type 1 diabetes.
Type 2 Diabetes
Almost 90% of diabetics are considered to have non-insulin dependent diabetes mellitus (NIDDM) or type 2 diabetes. While also characterized by high blood glucose levels, type 2 diabetics often have high, rather than low, levels of serum insulin. Type 2 diabetics are typically insulin resistant, rather than insulin depleted.
A current report concludes that nearly one-fifth, or 47 million Americans are at an increased risk of type 2 diabetes, using the criteria of abdominal obesity, elevated triglycerides, low HDL cholesterol, high blood pressure and high normal blood sugar. Syndrome X and the subsequent diabetic condition that follows are preventable. Through an awareness of the various risk factors, proper diet and exercise; type 2 diabetes could be altered from a national epidemic to a manageable but minor disease.
History tells us, unfortunately, that the Western diet and lifestyle have a tenacious hold on the American culture and this trend toward obesity, insulin resistance and diabetes is unlikely to abate anytime soon.
Hyperglycemia (high blood glucose) causes complications in patients with diabetes, regardless of whether it is type 1 or 2. While some complications ca be of an acute nature (ketoacidosis due to low insulin or hypoglycemic shock due to insulin overdose), most complications are a result of years of unregulated and high serum glucose.
These complications include increased heart disease, retinopathy, nephropathy ending in renal failure, neuropathy, foot and leg ulcers, impotence, and the inhibition of many important metabolic enzymes. Most of these complications are due to hyperglycemic-induced increase reactive oxygen species (ROS) that cause glucose-induced activation of protein kinase c, increased formation of glucose-derived advanced glycation end products (AGEs) and increased glucose flux through the aldose reductase pathway. These vascular complications are cumulative, but preventable.
Maintaining proper blood glucose is vital to preventing these complications. Additionally, there are a number of natural ingredients that can prevent and even reverse the progress toward these devastating complications. Davis CM, Vincent JB: Chromium oligopeptide activates insulin receptor tyrosine kinase activity. Biochemistry. 1997 Apr 15;36(15):4382-5.
A possible new mechanism for the amplification of insulin receptor tyrosine kinase activity in response to insulin has been identified. The chromium-containing oligopeptide low molecular weight chromium-binding substance (LMWCr) does not effect the tyrosine protein kinase activity of rat adipocytic membrane fragments in the absence of insulin; however, insulin-stimulated kinase activity in the membrane fragments is increased up to 8-fold by the oligopeptide. Using isolated rat insulin receptor, LMWCr has been shown to bind to insulin-activated insulin receptor with a dissociation constant of circa 250 pM, resulting in the increase of its tyrosine protein kinase activity. The ability of LMWCr to stimulate insulin receptor tyrosine kinase activity is dependent on its chromium content. The results appear to explain the previously poorly understood relationship between chromium and adult-onset diabetes and cardiovascular disease.
Nutriceutical Treatment of Diabetes
Treatment of diabetes should begin long before blood sugar levels are found to be above a ‘critical level,’ generally considered to be around 100.
Diabetes begins as a cellular insensitivity to insulin. That is, it takes more and more insulin floating around in the blood to cause the cell to draw glucose (sugar) from the serum into the cell itself. As insulin levels increase, maintaining a ‘normal’ blood sugar, the other effects of insulin start to become problematic.
Most notably, increase in weight is observed because insulin stimulates the deposition of fat. This is one factor that explains why weight gain precedes the blood sugar elevation, in most patients. Simply, insulin levels climb, in an effort to maintain normal blood sugars, fat is deposited in the belly area, and weight climbs. Insulin levels also modulate inflammation, and pain problems tend to worsen, including arthritis and fibromyalgia.
Focus on the nutritional treatment and/or prevention of diabetes thereby centers around those nutrients that influence or modulate insulin, insulin receptors, and insulin metabolism. These include selected:
Essential Fatty acids& Oils
Mineral Metabolism: Vanadium – Insulin receptor activity
Mehdi MZ, Srivastava AK: Organo-vanadium compounds are potent activators of the protein kinase B signaling pathway and protein tyrosine phosphorylation: mechanism of insulinomimesis. Arch Biochem Biophys. 2005 Aug 15;440(2):158-64.
Organo-vanadium compounds (OVC) have been shown to be more effective than inorganic vanadium compounds in ameliorating glucose homeostasis and insulin resistance in rodent models of diabetes mellitus. However, the precise molecular mechanism of OVC efficiency remains poorly defined. Since inorganic vanadium compounds have been found to activate several key components of the insulin signaling cascade, such as protein kinase B (PKB), the objective of the present study was to investigate if stimulation of PKB and its downstream target glycogen synthase kinase-3 (GSK-3), are responsible for the more potent insulinomimetic effects of OVC. Among several vanadium compounds tested, vanadium (IV) oxo bis (acetylacetonate) and vanadium (IV) oxo bis(maltolato) markedly induced the phosphorylation of PKB as well as GSK-3beta compared to vanadyl sulfate (VS), an inorganic vanadium salts in Chinese hamster ovary cells overexpressing the insulin receptor (IR). Furthermore, the OVC were stronger inhibitors of protein tyrosine phosphatase (PTPase) activity than VS. The higher PTPase inhibitory potential of the OVC was associated with more robust tyrosine phosphorylation of several cellular proteins, including the IRbeta subunit and insulin receptor substrate-1 (IRS-1). In addition, greater IRS-1/p85alpha interaction was elicited by the OVC than by VS. These data indicate that the higher PTPase inhibitory potential of OVC translates into greater phosphorylation of PKB and GSK-3beta, which, in turn, may contribute to a more potent effect of OVC on glucose homeostasis.
NOTE: This is partial explains why the use of ‘organic trace minerals’ is so important to general health. The balance of vanadium and chromium is delicate, and it is dangerous to simply ‘throw’ supplements at a patient and expect anything but trouble.
Both vanadium and chromium are necessary for health, but too much is toxic. Chromium should be in the ‘polyniccotinate’ salt, not the piccolonate form, that is generally available.
Pain in the Diabetic Patient
Pain is the most common complaint that brings patients to seek medical care, and diabetes is a common medical condition in the general population. It follows, then, that many patients with diabetes will complain of pain. A diabetic with pain is a far cry from a patient with diabetic neuropathy. It is common to encounter patients who suffer from diabetes as well as any number of other medical conditions that present with pain, but it is most unfortunate to find that many of these patients are improperly diagnosed with diabetic neuropathy, when in fact they suffer from fibro-muscular pain, arthritic pain, or entrapment neuropathy.
Diabetic neuropathy does not imply nerve pathology coincidental to the presence of diabetes mellitus. Rather, diabetic neuropathy implies pathological changes of a characteristic nature that results from metabolic abnormalities. While this would appear to be a simplistic statement, the general approach to the complaint of pain in the diabetic population is probably the principal reason that diabetic neuropathy is often difficult to control. In the absence of an accurate diagnosis, successful treatment becomes unlikely.
The precise metabolic factor or factors that cause the neuropathic damage may not yet be precisely identified. It is known, however, that high blood glucose, longer duration of diabetes, insulin level, abnormal serum lipid levels, and co-morbid endocrinopathies are important to the development of diabetic neuropathy. Ischemia of the peripheral nerve due to damage to the vasovasorum is certainly a factor.
autoimmune factors that cause inflammation in nerves
mechanical injury to nerves, such as carpal tunnel syndrome
inherited traits that increase susceptibility to nerve disease
Diabetic neuropathy results in large part from damage to the microvasculature and nervous innervation of the peripheral nerves, themselves. That is, damage to the Nervi nervorum and vasonervorum. As these smaller nervous and vascular structures become damaged, and the peripheral nerve tissue becomes dysfunctional. The longer the nerve, the more susceptible to diabetic damage; the greater the degree of myelination, the greater the resistance to damage. The thin, unmyelinated portions of the peripheral nerves demonstrate dysfunction first, the thicker, myelinated portions demonstrate dysfunction last. The pathology is evident earliest in the autonomic nervous system, followed by the sensory portion of the peripheral nerve, and the motor component, last of all.
While diabetic neuropathy affects all nervous tissue, the peripheral nerves — those that are outside of the brain and spinal cord, such as nerves in the arms, legs, hands, and feet are first to become involved. Diabetic neuropathy is different from diabetic myopathy, in which the small muscles of the foot, as well as some other muscles, become weaker.
Typical complaints include numbness and tingling, beginning in the feet and hands. “Burning-numbness” is quite common. Symptoms are minimal, at first, and over the course of years, the severity can increase, insidiously. Nerve damage can take place over several years, and mild cases go unnoticed for a long time. Symptoms first involve the sensory and autonomic nervous system. Symptoms may include:
numbness, tingling, pain in the toes, feet, legs, hands, arms, and fingers
painless sores on the toes and soles
indigestion, nausea, ‘GERD’
diarrhea, constipation, bloating
dizziness or faintness due to changes in postural blood pressure
urinary hesitancy, difficulty voiding
erectile dysfunction, vaginal dryness, loss of libido, dysorgasmia
The diabetic neuropathy that involves the autonomic nervous system results in changes in digestion, bowel and bladder function, sexual response, and perspiration. Other, later complaints can include extreme sensitivity to touch, vertigo, tinnitus, and loss of balance. Blisters and sores appear on desensitized areas of the foot due to pressure and painless- injury that goes unnoticed.
Diagnosis The diagnosis of ‘diabetic neuropathy’ is not a diagnosis of exclusion. Established only after other treatable causes are ruled-out, diabetic neuropathy results in objective. Nerve Conduction Velocity Testing (NCV): NCV is an electro-diagnostic test that measures nerve function. Through analysis of wave form velocity, amplitude, and wave-form morphology, diabetic neuropathy is easily detected, in most clinical circumstances. The NCV measures both sensory and motor components of the peripheral nerves of the extremities, but the sensory component is clearly the most sensitive, and the damage manifests earliest in the Sural Nerve. Using surface electrodes, instead of needles, there is little risk of damage to the vulnerable tissues of the feet and hands.NCV should not be confused with Electro-myography (EMG), which is a needle study that looks for muscle pathology. Pathological changes in the muscle occur last, far after autonomic and sensory damage has occurred.
Somato-sensory Evoked Potentials (SSEP): SSEP is a technique that involves electrical stimulation of the peripheral nerves with observation of the physiological response to the spinal cord, cortex and back to the periphery. This is most useful in providing supplemental information to the NCV, in establishing differential diagnosis. It is often the first clinical test to demonstrate Multiple Sclerosis.
Impedence Cardiogram (ICG): The ICG is useful in the patient with known diabetic neuropathy. The cardiac output tracings that are available from the ICG demonstrate the presence and severity of autonomic nerve damage, as it influences cardiac performance. This non-invasive test is painless and provides information that is otherwise available only through cine-angiography.
Treatment Treatment of diabetic neuropathy is directed at the underlying pathology while simultaneously providing the patient with pain relief.
Oral and topical medications are used to decrease the automaticity of the peripheral nerve tissue. GABA agonists are quite effective, and when combinations of GABA(A)and GABA(B) agents are used, dose requirements are dramatically reduced.
Topical vasodilators provide rapid changes in blood flow, often within a minute or two of application. Topical nifedipine and clonidine work most consistently. Topical guanethidine is more difficult to make, and due to chemical instability, it has a short shelf life.
Tricyclic anti-depressants (TCA’s), such as amitryptaline and desipramine, are in common use, but they provide little, if any, meaningful benefit. It should be remembered that TCA’s are also anti-histaminic and anti-cholinergic; it is these properties that tend to exacerbate the symptoms of Alzheimer’s Disease.
Oral analgesics are useful to provide symptomatic relief. Personal preference tends to guide selection. The clinician must understand that all analgesics are different, and patient response may be unpredictable. Diabetics tend to suffer from gastro-intestinal dysfunction for the same reasons that they suffer from peripheral neuropathic symptoms. Differences in absorption result in sensitivity or resistance to therapeutic intervention. More importantly, these properties change over time.
The opiate analgesic with the most consistent gastro-intestinal absorption is methadone. Inexpensive and with a long duration of action, it is probably the most useful of all opiates in this population. The 24 hour elimination half-life determines the rate with which dosage changes are made, but the analgesic duration of action is only 6-8 hours. This dictates a q8H or q6H dosage regimen, not to be confused with the once-daily dose necessary to prevent opiate withdrawal. The longer the duration of action, the better the clinical effect.
NOTE: The diabetic patient has impaired GI mobility. Opiates can cause severe constipation. Consideration of prevention of constipation is essential to the safety and comfort of the patient with diabetic neuropathy.
Most other opiates will work well enough, but care must be exercised when using transdermal patches. The diabetic patient suffers from autonomic instability, and this results in unpredictable blood flow to the skin, changes in perspiration, and temperature regulation. The transdermal patch technology relies on consistencies in skin metabolism, and the diabetic patient cannot deliver this consistency in metabolism.
Tramadol (Ultram) can be used with caution. Difficulties arise with concomitant use of anti-epileptic medications, such as the GABA agents, discussed above. Meperidine is best avoided due to anti-cholinergic properties. Both of these agents can, on occasion, result in seizure.
Traditional medication intervention often overlooks the nutritional medications that are currently available.
Alpha Lipoic Acid (ALA) has been used in Europe for many years to treat diabetic neuropathy. Effective, when taken 300 to 1200 mg per day, in divided doses.
Omega-3 and Omega-9 Fatty acids are useful to treat both the neuropathy as well as the microvascular ischemia. Care must be taken to select a product that has been distilled, due to mercury problems with fish oils.
Chromium, Vanadium, Selenium and Zinc are useful in the long-term treatment of diabetic neuropathy. Chromium and Vanadium deficiencies result in insulin-resistance, and restoration of these micro-nutrients results in a drop in blood glucose. Eventually, insulin levels will stabilize, and these patients will start to lose weight.
B-Complex should be administered at levels that are much higher than the general population. This, too, is due to impaired gastro-intestinal absorption.
B-12 combined with Intrinsic Factor is useful in the treatment of many types of metabolic and traumatic neuropathies. Secretion of intrinsic factor decreases with age and many disease states, and sub-clinical B-12 deficiencies can predispose to diabetic neuropathy.
Folic acid 5 mg per day is helpful in diabetic neuropathy as well as in diabetic nephropathy. At this dosage, cholesterol and triglyceride levels will be lowered.
Hawthorne Extract is beneficial as a vasodilator.
Due to the nature of the nutraceutical industry, it should be understood that quality and purity of product are not something to be assumed. Fancy labels and names do not imply quality of product.
Many of the available products on the shelf are produced from non-assayed raw materials. By restricting recommended products to those produced by manufacturers that follow GMP manufacturing guidelines, the clinician will provide the patient with the most consistent results. High price does not guarantee quality, but quality is rarely delivered cheaply.