A number of studies have reported an association between diabetes mellitus (DM) and
alterations in the metabolism of several trace minerals. Impaired insulin release, insulin
resistance and glucose intolerance in experimental animals and humans with DM have been
linked to a compromised status of chromium, magnesium, selenium, vanadium and zinc. Some
of these minerals (e.g., zinc, chromium, magnesium) are excreted at higher than normal
rates in patients with DM, often leading to excessive urinary mineral wasting. The
characteristic polyuria of DM that results from the glucose-mediated hyperosmotic
glomerular filtrate may be largely responsible for enhanced urinary mineral loss. If such
losses were found to translate to lowered availability of a mineral required for optimal
insulin secretion and/or action, then it would be important to correct the altered mineral
status. Solving this problem could include increasing dietary intake of the mineral or
utilizing supplemental sources of the mineral.
The most difficult aspect of assessing the influence of a particular mineral in DM involves the compartmentalization of many of these minerals. For most, more than 99% of the mineral is in a non-blood compartment not routinely measured by laboratories. Thus, typically in general medical practice, accurate mineral status is unknown.
A large body of experimental evidence in animals and humans supports a significant role for minerals in DM,1,2 but controversy remains regarding supplemental minerals as adjuncts in the therapy of patients with DM.3 Although the use of supplemental minerals to correct mineral deficiencies is widely accepted, supplementation in nondeficient DM patients is less accepted. The risk-to-benefit ratio for a particular mineral needs to be carefully assessed by the healthcare provider. However, because the risk associated with these minerals appears extremely low when used appropriately, healthcare providers may consider trials with their DM patients. Along with clinical observations, carefully designed, controlled double-blind trials are needed to determine the efficacy and safety of such approaches.
Chromium was initially suspected to be an essential dietary mineral in the late 1950s after studies in patients receiving total parenteral nutrition (TPN) demonstrated a severe deficiency of chromium, resulting in impaired glucose tolerance and subsequent hyperglycemia and glycosuria. Other signs of chromium deficiency include hyperinsulinemia (common in type 2 DM), decreased insulin receptor number, decreased insulin binding, and DM-associated neuropathies and vascular pathologies.1
Because data are lacking to establish a recommended dietary allowance (RDA) for chromium, an estimated safe and adequate daily dietary intake (ESADDI) value has been established by the Food and Nutrition Board.4 The ESADDI for chromium, 50–200 mcg per day for adults, is believed by nutritionists to be a value that would provide adequate and safe chromium intake. On the other hand, toxicologists have been interested in determining an absolute upper safe value for oral intakes of trace minerals. The oral reference dose (RfD) for chromium has been established at 70,000 mcg/day for adults. Philosophical differences exist between the development of RDAs/ESADDIs and RfDs in that the former are conservative and address the needs of the healthy population, while the latter are meant to protect from toxicity population groups at highest risk, including infants and pregnant women.
Values of daily chromium intake from subjects with self-selected diets have been estimated at 33 ± 3 mcg for men and 25 ± 1 mcg for women,5 well below the established ESADDI. Some nutritionists and other healthcare providers have suggested the need for dietary supplementation because even well-balanced diets fall extremely short of providing the minimum ESADDI for chromium. In order to meet the ESADDI for chromium via the diet, some investigators have suggested that diets containing between 10,000 and 40,000 kilocalories per day would be required.6 Although the relative lack of chromium may have minor, if any, consequences in nondiabetic patients with normal glucose homeostasis reserves, patients with DM are more likely to be adversely affected.
Chromium is generally found in minute amounts in foods. Canned foods, due to leaching from the can, and homogenization in a food processor equipped with a stainless steel blade can impart significant amounts of chromium to food. Brown sugar, many spices, coffee, tea, as well as some beers and wines generally have significant chromium contents, but the only food-like product that appears to contain consistently high levels of chromium is brewer’s yeast. However, there is no reliable information available on the differences between various sources of brewer’s yeast and chromium content for consumers to make informed decisions.
Only 1%–2% of the chromium delivered by the diet is absorbed in the small intestine. Like many other trace minerals, chromium interacts with various dietary components which enhance or retard its absorption. Chelation with dietary amino acids, especially L-histidine; or complexation with oxalate, abundant in many dietary vegetables and grains, or with nicotinic acid or ascorbic acid, can significantly augment the intestinal absorption of this mineral.7,8 However, chromium complexed with dietary phylate, or if given with pharmacological doses of zinc or iron in multivitamin preparations, decreases chromium absorption.9 Once absorbed in the intestine chromium is bound by transferrin and albumin for transport through the circulation and storage throughout the body. Excretion of chromium is largely via the kidneys. Since chromium is not actively reabsorbed in the renal tubules, the amount excreted is proportional to the amount filtered at the glomerulus. Even though diabetic patients have increased renal excretion of chromium, an observed compensatory increase in intestinal chromium absorption may help to offset the renal chromium loss.
A major challenge to understanding chromium’s role in DM is a lack of standard techniques to assess chromium status. Blood, urinary and hair chromium values do not provide accurate information on chromium stores in the body. Despite this limitation, supplemental chromium has been shown effective in many studies of patients with DM. However, most of these studies fail to document the chromium status of subjects prior to the therapeutic intervention.
Physiological actions: Insulin’s ability to regulate glucose levels and lipid metabolism depends on its binding to specific receptors found in many peripheral tissues, e.g., adipocytes, muscle, liver. In addition to increasing the number of insulin receptors present in a target tissue, chromium also has been demonstrated to increase the binding of insulin to its receptors.10 The latter action may involve chromium’s ability to regulate key reactions involving phosphorylation/dephosphorylation, which turn on and off insulin action. Insulin activates its receptor by binding to the extracellular alpha subunit. This leads to phosphorylation of the membrane-bound beta subunit. Chromium, via the enzyme insulin receptor tyrosine kinase, catalyses the phosphorylation in the presence of insulin. Additionally, chromium inhibits tyrosine phosphatase, which is responsible for terminating the insulin receptor response. Thus, by both increasing activation and inhibiting termination of insulin receptor-mediated responses, chromium can significantly influence glucose utilization by peripheral tissues.
Chromium’s action on insulin receptors may be mediated via a chromium complex, termed the “glucose tolerance factor.” While the exact identity of this factor has not been elucidated, chromium may be an essential component, in addition to some amino acids and vitamins. Most believe that insulin can function in the absence of chromium; however, its activity appears greatly enhanced in the presence of this mineral.
In addition to many in vitro and in vivo studies demonstrating chromium’s ability to improve glucose tolerance in experimental animals, most studies of patients with DM have regularly demonstrated beneficial effects of chromium supplementation on glucose tolerance, especially in patients with more pronounced intolerance.11 Most of the positive studies with chromium have been in patients with type 2 DM who have used at least 400 mcg of chromium, both in the picolinate and chloride forms. In one study by Mossop,12 fasting glucose levels were decreased from 14.4 mmol/L to 6.6 mmol/L following 16–32 weeks of chromium chloride (600 mcg/day) supplementation. Similar beneficial results have been demonstrated with lower doses (200–300 mcg/day) of the picolinate form,13,14 and even greater responses with higher doses.15 Anderson et al.,15 studying type 2 DM subjects (180 men and women), utilized three groups (placebo, 200 mcg/day, and 1,000 mcg/day chromium). Glycosylated hemoglobin (HbA1c) levels were significantly decreased after four months of treatment (8.5% ± 0.2%, 7.5% ± 0.2% and 6.6% ± 0.1%, respectively, for the three groups). Reductions in HbA1c levels are significant because they represent long-term glucose control, which is closely correlated to the prevention of complications of diabetes, such as neuropathy and vascular disease. Fasting blood glucose and total cholesterol were also decreased in the chromium-treated groups. While the highest dose of chromium used was well beyond the ESADDI value, no adverse effects were reported.
Ravina et al.,16 recently demonstrated the effectiveness of 600 mcg chromium (as picolinate) to reverse the glucose intolerance associated with glucocorticoid administration. While steroid-induced DM led to an increase in blood glucose to 250 mg/dL and an increase in renal chromium loss, supplementation with chromium decreased blood glucose to 150 mg/dL and significantly improved glucose tolerance. Although this study size was small, the findings are consistent with a beneficial effect of chromium on glucose tolerance when chromium status is compromised. A study in women with gestational DM demonstrated the ability of chromium (4 and 8 mcg/kg) to significantly improve glucose tolerance, HbA1c levels, and insulin sensitivity.17 Double-blind, follow-up studies are needed to confirm and extend these observations.
Portuguese medicinal plants used specifically for DM had a chromium content approximately 3X that found in other plants from the same area that were not used for DM.18 Whether the amount of chromium present in these preparations accounts for the anecdotally reported benefits in DM is unknown.
Numerous case reports and small, limited studies on the effectiveness of chromium as an adjunct in the treatment of patients with DM have appeared in the literature. Many have documented the ability of this mineral to lower fasting glucose, serum lipids and HbA1c levels, while some also demonstrate increases in HDL cholesterol. Clearly more large, well-controlled, double-blind studies are needed to fully characterize the effectiveness of chromium in DM. Attention should be paid to the starting chromium status of the subjects. Healthcare providers should be aware of the potential utility of this mineral, and its use should be accompanied by close monitoring for any adverse effects.
Adverse effects: No credible data to date have documented adverse effects associated with the oral intake of trivalent chromium in experimental animals or humans.19,20 Trivalent chromium administered long-term to animals at doses on a per kg basis several thousand times the upper limit of the ESADDI for humans failed to produce any discernible toxicity. However, a recent study presented at the Annual Meeting of the American Chemical Society in 1999 reported that chromium picolinate could enter cells in culture and induce DNA strand breakage. Critics of the study argue that the concentrations of chromium were excessive and the relevance of cells in tissue culture to the human organism is questionable, especially in light of the long history of the reported safe use of trivalent chromium in humans.
Available products: Many OTC multivitamin/mineral supplements are available for patients wishing to enhance their chromium status. Their chromium content typically ranges from 6–200 mcg, although some have higher amounts (400 mcg). Although the picolinate form often is utilized, the chloride and polynicotinate forms are also an option; all are bioavailable. Some multicomponent preparations contain large amounts of zinc or iron, which decrease the absorption of chromium. Due to chromium’s role in glucose homeostasis, one vitamin/mineral preparation specifically designed for patients with diabetes contains chromium.
Since many of these preparations are sold as dietary supplements, they are regulated by the provisions of the Dietary Supplements Health and Education Act of 1994. Concerns regarding the content uniformity, bioavailability, stability, dissolution characteristics and manufacturing controls of many dietary supplements have been voiced. However, to date no published studies question or confirm the various quality assurance issues related to chromium-containing products. Patients and healthcare providers should realize that the manufacturing standards and regulations associated with chromium, and some other minerals discussed below, are very different from those associated with a prescription or OTC drug.
Magnesium is an important intracellular cation that is distributed into three major compartments: mineral phase of bones (65%), intracellular space (34%), and extracellular fluid (1%).21 About one-third of the circulating magnesium is bound to plasma proteins, with the remaining two-thirds free and presumably biologically available. Because such a small percentage of the total body magnesium is present in the compartment typically sampled (the plasma), the diagnosis of magnesium deficiency can be difficult. Severe deficiency may cause muscle weakness, tremor, irritability, lethargy, agitation, hallucinations, anorexia, paresthesia and tetany. Patients with normal plasma magnesium levels may actually be hypomagnesemic.22 While deficiency of this mineral was considered rare, more recent findings have suggested that as many as 25% of patients with DM may have suboptimal magnesium status.23 The most accurate technique for measuring magnesium status involves biopsy of a tissue (e.g., muscle), but this technique is not routinely performed.
About one-third of an orally administered load of magnesium is absorbed in the intestines; excretion is primarily via the kidneys, but also via the feces. Hormones that help regulate magnesium levels include calcitonin, parathyroid hormone and insulin. Insulin administration, or insulin released in response to an oral glucose load, has been shown to enhance the uptake of magnesium into cells via an ATPase pump. Magnesium, as an integral part of the activated MgATP complex regulating protein kinases, is directly involved in the control of glucose metabolism, peptide hormone receptor signal transduction, ion channel translocation, stimulus-secretion coupling and stimulus contraction-coupling. Decrements in the enzymatic activities of several metabolic pathways are seen in DM as a result of relative magnesium deficiency.24
Induction of a hypomagnesemic state in rats is known to significantly decrease sensitivity to insulin via an alteration at the insulin receptor-associated tyrosine kinase. Supplementation with magnesium has been shown to delay the development of type 2 DM in experimental animal models. Early studies demonstrated an inverse relationship between plasma magnesium levels and fasting blood glucose levels in insulin-treated patients with diabetes.25 A recent human, placebo-controlled study by deValk et al.,26 reported on the effects of supplemental magnesium (15 mmol/day for 3 months) in 50 patients with type 2 DM who required insulin. While plasma magnesium and urinary magnesium excretion increased with magnesium therapy, other parameters measured (HbA1c, blood glucose, lipids) failed to change.
However, there was a slight reduction in diastolic blood pressure in those patients experiencing increases in plasma magnesium. Although a reduced release of insulin has been reported in individuals with compromised magnesium status, most of the focus on magnesium supplementation in DM now involves interest in preventing long-term complications. Magnesium deficiency has been associated with hypertension, dyslipidemia and retinopathy,27 all common to DM.
Monitoring magnesium status is important in DM. Hypomagnesemia can be treated with a number of interventions. Diet alone is not a practical approach because many of the foods high in magnesium (e.g., peanuts, soy beans, cashews, chocolate, and dried fruits) are not recommended for patients with diabetes due to their high caloric and/or lipid contents. Oral magnesium products should be taken with meals to minimize the likelihood of diarrhea. The salts of magnesium available for oral use include the oxide, gluconate, carbonate, chloride, and amino acid chelates. A number of antacids and laxatives also contain magnesium. Patients should be made aware of potential drug interactions (e.g., tetracycline and sodium polystyrene sulfonate use). Overall, magnesium supplementation appears very safe.
There has been much excitement about the antioxidant properties of selenium and its potential health benefits. Selenium is found in varying concentrations in the soil, where it is incorporated into plants. The selenium in plants is then consumed by humans and animals and this mineral enters the human food chain. When an identical diet (breakfast, lunch and dinner totaling approximately 2,500 calories) is constructed and analyzed from various regions in the U.S., an approximate threefold difference in selenium content is found (85–240 mcg).28 In China that difference can be as much as 300-fold (13–3,950 mcg) depending upon which geographic areas are utilized to harvest the meal constituents. A syndrome known as Keshan disease, occurring in Keshan, China, probably as a result of selenium deficiency, affects children in their first decade of life and is characterized by cardiomegaly, pulmonary edema and premature mortality. Selenium, which acts with vitamin E via the enzyme glutathione peroxidase to prevent the accumulation of free radicals, has been shown effective in preventing this disease.
to increase the number of insulin receptors in target tissue as well as increase the
binding of insulin to its receptors; shown to improve glucose tolerance.
Magnesium—Interest in Mg supplementation is in the hopes of preventing long-term complications of diabetes.
Selenium—Its ability to control free radical production may help to prevent glucose intolerance and the complications of DM.
Vanadium—In vitro studies showed an ability to mimic the actions of insulin; animal and human studies showed improved sensitivity to insulin.
Zinc—Patients with diabetes are more likely to have suboptimal status of this essential cofactor for metalloenzymes that regulate the metabolism of carbohydrates, lipids, and proteins.