Background

Diabetes is common, affecting 16 million people or 6.9% of the US adult population; 800,000 new cases are diagnosed each year. The Diabetes Control and Complications Trial (DCCT), for type 1 diabetes, and the United Kingdom Prospective Diabetes Study (UKDPS), for type 2 diabetes, established the importance of intensive diabetes control in dramatically reducing the devastating complications that result from poorly controlled diabetes. Both the DCCT and the UKPDS demonstrated the efficacy of intensive glucose control in reducing the risk for the microvascular complications of diabetes, such as retinopathy, neuropathy, and nephropathy. In addition, results from the UKPDS suggested that strokes may be reduced in patients with type 2 diabetes through a combined regimen of intensive blood pressure and glycemic control.

Unfortunately, the advances of these studies have not been successfully incorporated into general health care practice. Prevention and treatment of long-term micro- and macrovascular complications remain critical problems in the management of type 1 and type 2 diabetes mellitus. In the United States, diabetes is the leading cause of new blindness in working-age adults, of new cases of end-stage renal disease and of non-traumatic lower leg amputations. In addition, cardiovascular complications are now the leading cause of diabetes-related morbidity and mortality, particularly among women and the elderly. In adult patients with diabetes, the risk of cardiovascular disease (CVD) is three-to-five fold greater than in the general population. Diabetes is the seventh leading cause of death in the United States and costs the American economy approximately $98 billion annually.

Type 2 diabetes is treated with diet, exercise and medication. However, for many patients, achievement of tight glucose control is difficult with current regimens. Given the enormous public health cost of diabetes, the prospect of being able to use a relatively low-cost dietary supplement, such as chromium, as an adjuvant therapy to help in achieving euglycemia merits further study. Despite the large gaps in our knowledge regarding chromium, the US public uses chromium supplements for the treatment of diabetes and its complications. This widespread use warrants extensive testing of its efficacy and monitoring of its safety for long-term use.

Chromium

Chromium remains the only essential transition metal whose mechanism of action is not known. Chromium is thought to play a role in normal carbohydrate metabolism by potentiating the action of insulin. Chromium may increase insulin binding to cells and insulin receptor number, as well as activate insulin receptor kinase, leading to increased insulin sensitivity.

Chromium exists in several valence states, the most prevalent oxidation states being hexavalent chromium (which is associated with industrial exposure and toxicity) and trivalent chromium (which is stable and the biologically active form). Chromium supplements are available as trivalent chromium in the chloride or picolinate salt form. Trivalent chromium also occurs in organic complexes with nicotinic acid. For purposes of this document, chromium will refer to trivalent chromium unless otherwise noted.

The concentration of chromium in foods varies widely; there is also considerable variation between batches or lots of the same foods. Therefore, chromium intakes cannot be accurately predicted from dietary information. Survey data exist for a small number of isolated groups; however, no comprehensive studies exist determining intakes of individual subgroups. No national survey data are available. Estimates of chromium intake from diet in the United States are roughly 25 ug for women and 33 ug for men, which are thought to be reflective of an adequate intake for the population.

The frequency of actual chromium deficiency in the general population is unknown; however, an intake level of 5 ug /1,000 kcal has been shown to deplete subjects in well-controlled studies. Clinically, chromium deficiency has been well characterized in three patients who did not receive chromium in total parenteral nutrition solutions. Reliable measures for assessing chromium status in humans are limited. Chromium is present in biological tissues and fluids at extremely low levels, so many of the problems associated with finding a measure of status have been analytical in nature. Only three analytical techniques have the required sensitivity to make these measurements; however, neutron activation analysis and mass spectrometry are not widely available, and graphite furnace atomic absorption spectrometry is the one most susceptible to interference from the sample matrix. Collecting samples without contaminating them and generating sufficiently low analytical and reagent blanks is extremely difficult. Therefore, plasma chromium is unlikely to be a viable clinical indicator because it is easily contaminated. Additional investigation of urinary chromium in response to very low levels of intake is needed.

A putative chromium deficiency, as induced by feeding a chromium-deficient diet, has been reported in mammals and centers on disturbances involving insulin insensitivity. The signs and symptoms of chromium deficiency in mammals include impaired glucose tolerance, elevated circulating insulin concentration, glycosuria, fasting hyperglycemia, impaired growth, hypoglycemia, elevated circulating cholesterol and triglyceride concentrations, neuropathy, decreased insulin binding, decreased insulin receptor number and impaired humoral immune response.

Chromium Supplementation in Diabetes

Several studies have suggested that chromium supplementation might be beneficial in individuals with glucose intolerance, type 2 diabetes, gestational diabetes or steroid-induced diabetes, as evidenced by decreased blood glucose values or decreased insulin requirements. However, randomized trials of chromium supplementation in diabetes have not been definitive. Many studies have not been blinded, have used inappropriate glucose metabolism assessment parameters, or have included heterogeneous and not well- characterized patient populations. In addition, studies are difficult to compare because they have used different doses (ranging from 200 ug to 1000 ug) and formulations of chromium (such as chromium rich yeast, chromium chloride, chromium picolinate and chromium nicotinate), and have been short in duration. More rigorous, blinded and well-controlled studies are needed to fully assess the efficacy and mechanism of action of chromium supplementation as an adjuvant therapy for type 2 diabetes and impaired glucose tolerance.

Trivalent chromium, the form found in foods and dietary supplements, is believed to be safe. The Environmental Protection Agency established a reference dose (an estimate of daily exposure that is likely to be without appreciable risk of deleterious effect over a lifetime) for chromium that is 350 times the estimated safe and adequate daily dietary intake. Because of the widespread use of supplementation, more research is needed to assess the safety of high-dose chromium.

Most reports of adverse events to the Food and Drug Administration involved chromium taken in conjunction with various herbal preparations or other pharmacological agents, which may have been responsible for the adverse events. In a recent review of 19 randomized controlled trials in which individuals received between 175 and 1,000 ug /day chromium for duration of between 6 and 64 weeks, there was no evidence of any toxic effects. However, there are data to suggest that individuals with preexisting renal and liver disease may be particularly susceptible to adverse effects from excess chromium intake. There have been only a few confirmed case reports of toxicity attributed to chromium chloride and picolinate, including induced rhabdomyolysis and acute renal failure due to interstitial nephritis.

In vivo genotoxicity assays for chromium and most studies of genotoxicity in cellular systems have been negative. Chromium picolinate is extremely stable, but concern has been expressed that reduction of chromium picolinate within cells could lead to the generation of hydroxyl radicals and potential DNA lipid damage. In fact, a few studies suggest that chromium picolinate and tri-picolinate may cause DNA damage. Therefore, there is a need to consider the genotoxicities of a variety of chromium complexes particularly when high doses are administered.

There are no human studies that report reproductive toxicity or fetotoxic effects with chromium supplementation, but animal studies suggest reduced fertility in male mice, a reduction in the number of implantation sites and the number of viable fetuses, and delayed sexual maturity.

In November 1999, the Office of Dietary Supplements (ODS) sponsored a workshop on Chromium and Diabetes (http://ods.od.nih.gov/news/conferences/chromium_diabetes.html), to review studies of chromium supplementation in diabetes and identify priority research areas. Workshop members reached consensus that small-scale, focused clinical studies might be warranted in certain population groups. In addition, in a recent report, the Institute of Medicine (IOM) of the National Academy of Sciences also recommended the need for research related to chromium and diabetes. Research initiatives should be directed at investigating the possible relationships between chromium status and insulin resistance, impaired glucose tolerance, and type 2 diabetes; monitoring any adverse effects of self-supplementation; and design of controlled studies to assess potential beneficial, as well as, adverse effects of high-dose chromium supplementation (IOM, 2001).

As a follow-up to the workshop and prior to initiating clinical studies, the ODS sponsored a systematic review and meta-analysis of published clinical trial reports evaluating the role of chromium in individuals with glucose intolerance or type 2 diabetes. The report concluded “there was strong evidence that chromium has no effect on glucose control in healthy subjects.” However, the data for patients with diabetes were found to be equivocal and pointed to the need for small, focused, clinical trials in glucose-intolerant and diabetic subjects. These studies would further explore the efficacy of chromium as an adjunct treatment in type 2 diabetes and impaired glucose tolerance and determine the effective dose and formulation of chromium supplementation. In addition, they would provide additional information on the long-term safety of chromium supplementation.