Vanadium Supplementation in the Treatment of Type 2 Diabetes Mellitus
Vanadium Supplementation in the Treatment of Type 2 Diabetes Mellitus
By Dónal P. O’Mathúna, PhD
More than 10 million Americans have diabetes mellitus, and close to a million new cases are diagnosed each year.1 More than 90% of these cases are of Type 2 diabetes. Dietary changes are essential to control diabetic symptoms and to avoid the many secondary complications, such as atherosclerosis, cataracts, hypertension, and renal failure. As obesity and sedentary lifestyles proliferate and the population ages, some researchers are warning that diabetes has now reached epidemic proportions.1
Vanadium is an element named after Vanadis, the Scandinavian goddess of beauty, youth, and luster. Vanadium usually is not alleged to bring such blessings, but it has generated interest as a dietary supplement to prevent or treat Type 2 diabetes. Some athletes take vanadium as a performance-enhancing agent, though controlled research does not supported these claims.2 Vanadium is found in many foods, particularly in mushrooms, parsley, dill, and black pepper.3 Vanadium also occurs in many ores and crude petroleum from the Middle East and the Gulf of Mexico, from which it is extracted and purified.4 Animal research generated much enthusiasm about vanadium’s potential in treating diabetes mellitus, but the results from human studies have not been as encouraging.
Vanadium is one of several elements found in ultratrace amounts in humans. Although distributed throughout the body, adults on average have approximately 100 mcg.5 Vanadium exists predominantly in ionic form, with various charges ranging from -1 to +5. The most common form found to have biological activity is the +4 ion, also known as vanadium(IV), or vanadyl.6 The +5 form is called vanadate. Because of its ionic charge, vanadium always is found as an inorganic salt or complexed with organic ligands.7 Ongoing research is attempting to develop a ligand or chelated form that maximizes absorption, since most orally ingested vanadium is not absorbed.8
Debate continues as to whether vanadium is essential in humans. Several mammalian species appear to require it for optimal growth.5 To date, the biochemical role of vanadium has eluded researchers.
Numerous animal studies since the 1980s have demonstrated that vanadium reverses the symptoms of diabetes and insulin resistance in in vitro and animal models of Type 1 and Type 2 diabetes.9 Several secondary complications of diabetes also have been reversed in animal models.
Vanadium has been reported to mimic the many effects of insulin in several tissues in laboratory and animal models.10 Common measures of vanadium’s insulin-like actions are demonstrated reduction in serum glucose levels and increased lipogenesis.6
Mechanism of Action
Insulin interacts with cell receptors to activate several other enzymes through phosphorylation reactions. Vanadium’s insulin-like actions initially were believed to occur by preventing the inactivation of the enzymes that insulin activated.10 However, more recent studies have found conflicting results, and vanadium now is believed to work in part by stimulating an insulin-independent phosphorylating mechanism. However, this only partly explains vanadium’s mechanism of action, much of which remains to be determined.
Given the successes in animal trials, human trials of vanadium were begun in the mid-1990s. All published studies have been conducted with very few subjects.
The earliest study (published twice) gave 125 mg/d sodium metavanadate to 10 subjects, five with Type 1 diabetes and five with Type 2.11,12 After two weeks of supplementation, two of the five Type 1 diabetic patients showed improved glucose utilization, but the group as a whole showed no significant changes. Average daily insulin requirements decreased by 14% (P < 0.05). All Type 2 diabetic patients showed improved insulin sensitivity traced to increased peripheral glucose uptake (P = 0.05). No changes occurred in mean blood glucose levels or dose of oral hypoglycemic agents. Both groups had reduced serum cholesterol levels (P < 0.05).
The only other study of Type 1 diabetes gave five subjects 100 mg/d vanadyl sulfate for three weeks.13 No changes in insulin dose, weight, or appetite were reported, nor were there any changes in various measures of glucose and lipid metabolism.
In a single-blind study, six subjects with stable Type 2 diabetes received vanadyl sulfate (100 mg/d) for three weeks.14 They took a placebo for two weeks, vanadyl sulfate for three weeks, and then placebo for two weeks. Fasting plasma glucose levels were significantly lower after vanadium supplementation (210 mg/dL to 181 mg/dL; P < 0.05). HbA1c levels dropped from 9.7% to 8.8% (P < 0.002). The glucose and HbA1c levels remained lower during the second period taking placebo. No significant changes occurred in appetite, concomitant drug therapy, body weight, blood pressure, or serum lipids.
Another study compared the effect of vanadyl sulfate (100 mg/d) on six non-diabetic, obese subjects and seven Type 2 diabetic subjects.15 However, data from five of the diabetic patients were reported in the previous study, which had the same overall design.14 The non-diabetic patients had no change in plasma glucose, insulin, or HbA1c levels after vanadium supplementation.15 The diabetic patients had lower levels of plasma glucose (12.3 mmol.L to 10.6 mmol/L; P < 0.01) and HbA1c (9.4% to 8.8%; P < 0.01) following vanadium supplementation. Neither group reported changes in body weight, appetite, or liver and kidney function tests. A small but significant reduction in cholesterol occurred in the diabetic patients (5.25 mmol/L to 4.94 mmol/L; P < 0.05).
A single-blind study gave eight patients with Type 2 diabetes 100 mg/d vanadyl sulfate for four weeks.16 Following a 2-4 week break, six of the subjects received a placebo for four weeks, followed by the same meta-bolic tests. Over the course of vanadium supplementation, fasting plasma glucose decreased significantly (9.3 mmol/L to 7.4 mmol/L; P < 0.05) but was unchanged during placebo treatment. No significant differences in lipid levels or metabolism were detected.
Sixteen Type 2 diabetic patients were enrolled in a 12-week study.9 Following a one-week run-in, subjects took a placebo for three weeks, followed by vanadyl sulfate for six weeks, and then follow-up for two weeks. Three patients took 75 mg/d vanadyl sulfate, five took 150 mg/d, and eight took 300 mg/d. Mean HbA1c decreased significantly during the period subjects took 150 mg (7.8% to 6.8%; P < 0.05) and 300 mg vanadium (7.1% to 6.8%; P = 0.05). Only the 300 mg group showed significantly reduced fasting glucose (167.2 mg/dL to 144.1 mg/dL; P < 0.02) and cholesterol (5.28 mmol/L to 4.70 mmol/L; P < 0.05). However, high-density lipoprotein (HDL) decreased significantly (1.02 mmol/L to 0.83 mmol/L; P < 0.05), but triglycerides did not. Metabolic tests for insulin sensitivity showed no improvements for those taking 75 mg, while three of five taking 150 mg improved, and so did four of eight taking 300 mg. No group average was significantly changed. No significant changes in blood pressure were found.
The most recent study involved 11 Type 2 diabetic patients.17 Each participant was monitored for four weeks, and then was given gradually increasing doses of vanadium sulfate for two weeks, starting at 25 mg bid and ending at 50 mg tid, which was continued for four weeks. Plasma glucose levels dropped progressively during the six-week treatment period (194 mg/dL to 155 mg/dL; P < 0.01). HbA1c dropped significantly (8.1% to 7.6%; P < 0.01), as did fructosamine (348 micromol/L to 293 micromol/L; P < 0.01), total cholesterol (227 mg/dL to 205 mg/dL; P < 0.01), and low-density lipoprotein levels (141 mg/dL to 129 mg/dL; P < 0.05). There were no significant changes in HDL, triglyceride, fasting free fatty acid, or fasting insulin levels.
Metabolic tests were conducted on the 11 subjects and five healthy non-diabetic subjects. The latter released less glucose from the liver and had higher whole-body, insulin-mediated glucose uptake. After vanadium treatment, liver glycogen/glucose release dropped by 20% (P < 0.005) and glucose uptake increased by almost 20% (P < 0.03), although both values remained distant from those of the healthy controls.
Vanadium poisoning is of concern in factories that burn large quantities of vanadium-rich oil and natural gas.4 Toxicity is characterized by green discoloration of the tongue and upper respiratory tract irritation, sometimes leading to bronchitis. Symptoms usually resolve within a week. The Institute of Medicine tolerable upper level (UL) is 1.8 mg/d of elemental vanadium.18
Oral vanadium frequently leads to dose-dependent gastrointestinal disturbances, including diarrhea.8 One study found that those taking 75 mg/d had no side effects, most of those taking 150 mg/d had gastrointestinal problems, and all those taking 300 mg/d had gastrointestinal problems requiring Kaopectate® or Imodium®, although no one dropped out of the study.9 The newer organic vanadium ligands are tolerated better than inorganic vanadium salts.
Several other toxic effects have been reported in animals, including anorexia, kidney damage, delayed fetal development, and death.19 Vanadium compounds can stimulate mitogenesis and cell proliferation in vitro, which has raised concerns about carcinogenicity.7 These effects have not been found consistently.18
Long-term studies with humans have not been conducted, but a 12-week study found no changes in blood cell counts, blood viscosity, lipid levels, or biochemical indices of liver and kidney function in 31 athletes who received 40 mg/d vanadyl sulfate.20 The dose given to diabetic patients is much higher than this. Vanadium is known to accumulate in many tissues and to be a relatively non-specific enzyme inhibitor, which raises concerns about adverse effects that might occur after long-term administration.
No adverse drug interactions have been reported.
Most clinical trials have used vanadyl sulfate, available as 500 mcg capsules or 10 mg tablets. The usual dose is 50 mg tid taken with meals. About one-third of the dose of vanadyl sulfate corresponds to elemental vanadium. Doses of 150 mg/d far exceed the UL, a practice viewed as acceptable only in well-controlled clinical trials.18 Internet products commonly mix 500 mcg vanadium with several other ingredients. As noted above, numerous organic vanadium chelates are being investigated to develop a complex that allows higher dosing without adverse effects.
In contrast with the highly encouraging animal results, the insulin-mimicking effects of vanadium in humans have been much less dramatic. This may be related to the lower doses used so far with humans (about 1.5 mg/kg/d) compared to rodent studies (100 mg/kg/d).9 Human studies also have been of much shorter duration than animal studies. Concerns about vanadium toxicity have led researchers to approach human trials with much caution.
Vanadium treatment appears to have potential as an adjunct to conventional Type 2 diabetes therapy. However, no formulation currently is available that produces consistent results at well-tolerated doses. Concerns also have been expressed about its long-term safety, which has not been adequately investigated in humans.
Vanadium may become or lead to an alternative treatment for some Type 2 diabetic patients. At this point, however, much remains uncertain about the benefits and potential adverse effects of oral vanadium. Most significantly, long-term animal studies show that vanadium accumulates in many tissues and can lead to serious adverse effects.
Given the absence of long-term human studies and the frequent gastrointestinal problems with short-term studies, use of vanadium outside controlled clinical trials appears unwarranted. While researchers develop a safer, more effective formulation, diabetic patients should pursue appropriate dietary, weight management, and exercise guidelines, along with conventional medications when necessary.
Dr. O’Mathúna is Professor of Bioethics and Chemistry at Mount Carmel College of Nursing, Columbus, OH.
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