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Lois Schmidt Finney, RD, MPH, CDE, and J. Michael Gonzalez-Campoy, MD, PhD, FACP

In Brief

Chromium, an essential trace mineral, has been associated with diabetes mellitus. This paper reviews the relationship between chromium and diabetes and other diseases.

Chromium is an essential trace mineral. Trivalent chromium acts as a cofactor for insulin and is therefore an integral part of the cellular response to this hormone. Chromium deficiency has been associated with diabetes mellitus in laboratory animals, an observation that has fueled interest in the potential role of this element in human disease. This paper reviews what is known about chromium and its potential role in diabetes mellitus.

Background
When chromium and two molecules of nicotinic acid bond, a biologically active complex termed glucose tolerance factor (GTF) is formed. GTF also contains amino acids such as glutamic acid, glycine, and cysteine.¹ GTF, through mechanisms not yet defined, is capable of enhancing the biological efficacy of insulin. There is a 4-hour lag between administration of GTF and a measurable effect on insulin action.² This lag suggests that GTF administration leads to a complex series of events that ultimately potentiates insulin action.

Chromium is found in foods as both inorganic and organic salts. Brewer’s yeast contains a form of chromium with high bioavailability, chromium–dinicotinic acid–glutathione complex. The bioavailability of chromium in liver, American cheese, and wheat germ is also relatively high. Chromium is also available from a variety of sources including whole grains, potatoes and apples with skins, spinach, oysters, carrots, and chicken breast.³ Recent research has identified certain varieties of barley grown in Mesopotamia as rich sources of chromium.⁴ Yeast-free chromium picolinate supplements are available as 200 mg tablets at a cost of approximately $5/month.

Due to the technical limitations in measuring chromium status, it is difficult to quantify a chromium requirement. Therefore, there is no current Recommended Dietary Allowance for chromium.³ The Estimated Safe and Adequate daily dietary chromium intake for adults is between 50 and 200 痢/ day.³ This estimate may be elevated, since studies completed on an asymptomatic population in Bethesda, Md., showed a chromium intake of 33 痢/ day for adults consuming 2,300 calories/day. Similarly, the chromium intake was 25 痢/day for individuals on a 1,600-calorie intake.⁵ These caloric intakes correspond to the caloric intake for healthy men and women in the United States, respectively.

Only about 0.5% of dietary chromium is absorbed.³ Mean serum concentration of chromium is between 0.1 and 0.3 痢/liter in normal individuals, but the lower limit of detection by commercially available assays is 0.2 痢/liter.⁶ Animal studies document that chromium is widely distributed throughout the body. The majority of chromium localizes in the kidneys, spleen, and pancreas.⁷ Chromium concentrations decline with age in all tissues except the lungs. The lower tissue levels seen in healthy elderly populations has been theorized to indicate glucose intolerance in the elderly due to lowered levels of GTF.⁸ Chromium retention in rats is not affected by parenteral epinephrine, glucagon, cyclic adenosine monophosphate (cAMP), or prostaglandins, nor by oral glucose, sucrose, nicotinic acid, or glutathione.7 Urinary excretion, the major route of elimination of chromium in humans, is estimated at 1.8 痢/liter.⁹

Chromium Deficiency Studies
Three cases of severe human chromium deficiency, all of which involved patients who were on long-term total parenteral nutrition, have been documented in the literature.^10-11 Experimental chromium deficiency has been induced in several animal studies. Clinical evidence of decreased insulin action is common to all models of chromium deficiency. This decreased insulin sensitivity is manifested by elevated immunoreactive insulin levels, impaired glucose tolerance, and lipid abnormalities.¹ Additionally, a recent animal study demonstrated that chromium depletion in pregnant rats decreased insulin-like growth factor II concentrations in offspring, resulting in reduced tissue protein content.¹²

Chromium Supplementation Studies
At the American Diabetes Association’s 56th Annual Meeting and Scientific Sessions, Anderson and associates reported that dietary supplementation with both 200 痢/day and 1,000 痢/day of chromium picolinate led to improved glycemic control in a Chinese population with type II diabetes.¹³ After 4 months of treatment, the subjects receiving 1,000 痢/day of chromium picolinate had an average glycosylated hemoglobin A1c (HbA1c) of 6.6% compared to 8.5% for a placebo group. The group consuming 200 痢/day ended the study with an average HbA1c of 7.5%, also significantly lower than that seen in the control group. In addition, the group consuming the highest level of chromium had a significant drop in total cholesterol levels. Documentation of chromium intake at baseline was not noted, thus allowing the speculation that these individuals may have been significantly chromium-deficient at the start of the study. This report received attention in the national media but was quoted without the benefit of previously published information.

Improved glucose tolerance with chromium supplementation also has been reported in undernourished children, elderly subjects, a population of women with gestational diabetes, and individuals with type II diabetes.^1,8,814-16 Jovanovic-Peterson demonstrated an improvement in glucose tolerance and decreased insulinemia in 30 women with gestational diabetes on chromium supplementation (4 and 8 痢/kilogram body weight/day) compared to control subjects.¹⁴ Similarly, in an Israeli research study, chromium picolinate reduced the amount of diabetes medication required in 47% of the patients studied.¹⁵ The Israeli researchers showed that this significant reduction in diabetes medication occurred whether the subjects were being treated with metformin, a sulfonylurea, or insulin.

The beneficial effects of chromium supplementation in individuals with diabetes have not been confirmed in four double-blind crossover studies. In these studies, there was no improvement in glucose tolerance for individuals with diabetes when given chromium supplementation either as elemental chromium or brewer’s yeast.^6,17-19 Furthermore, it appears that most individuals with diabetes are not chromium deficient.1 Thus, although there is some reason for optimism, the role for chromium supplementation in the treatment of diabetes mellitus is not firmly supported.

Nonetheless, chromium supplementation may have other beneficial effects. Research by Lee and Reasner as part of a double-blind, placebo-controlled, crossover study showed that chromium picolinate supplementation significantly reduced triglyceride levels in a predominantly Hispanic population of patients with type II diabetes.⁶ This study found no differences in glycemic control between the control group and the group treated with 200 痢/day chromium. Levels of both high-density lipoprotein cholesterol and low-density lipoprotein cholesterol also remained unchanged between the two groups.

Although there is reason for optimism, the role for chromium supplementation in the treatment of diabetes is not firmly supported.

Another study of an elderly population both with and without diabetes also showed that chromium supplementation improved cholesterol and total lipid levels.¹⁶ However, as with the possible effects on glycemia, there are other studies showing no effect of chromium supplementation on lipid metabolism. In a study of 76 patients with established atherosclerotic disease, some of whom had type II diabetes, Abraham found no change in either blood glucose levels or serum cholesterol with chromium supplements.²⁰

Although no data is available from human studies, it is conceivable that chromium supplementation may lower blood pressure in patients with the insulin resistance syndrome. Chromium supplementation blunts the blood pressure elevation induced by sugar feeding in the spontaneously hypertensive rat model.²¹

One final potential benefit of chromium supplementation may be bone density preservation. In one study, chromium picolinate was shown to reduce urinary excretion of hydroxyproline and calcium in postmenopausal women, thus indicating a reduced rate of bone resorption with chromium.²² This observation has not yet been confirmed, and consequently, chromium supplementation is not recommended for the prevention or treatment of osteoporosis.²³

Chromium Toxicity
Dietary intakes of chromium up to 200 痢/day have been reported in several studies without adverse effects.³ Individuals employed in chromium-related industries (i.e., mining, electroplating, and tanning) are at risk of hexavalent chromium-induced toxicity. Toxic effects of hexavalent chromium may include hepatotoxicity;²⁴ mutagenesis²⁵ leading to fetotoxicity (postimplantation loss and decreased weight)²⁶ and carcinogenesis; impaired steroidogenesis²⁷ leading to impaired spermatogenesis ovarian dysfunction;²⁸ oxidation of hemoglobin;²⁹ and human lymphocyte apoptosis and decreased interleukin-6 levels.³⁰ However, humans cannot oxidize the nontoxic trivalent dietary chromium to its hexavalent form. Therefore, dietary chromium toxicity is virtually nonexistent.

Conclusion
Chromium, as an essential trace element, is required for effective insulin action. Available data in the literature do not show a consistent beneficial effect of chromium supplementation. Accordingly, the American Diabetes Association (ADA) does not recommend supplementation with chromium for individuals with diabetes until further testing is completed. This is especially important given the potential for unforeseen side effects that may develop from long-term dietary chromium supplementation.

The ADA position on chromium, as published in its position statement titled "Nutrition Recommendations and Principles for People with Diabetes Mellitus,"³¹ states: "The only known circumstance in which chromium replacement has any beneficial effect on glycemic control is for people who are chromium deficient as a result of long-term chromium-deficient parenteral nutrition. However, it appears that most people with diabetes are not chromium deficient and, therefore, chromium supplementation has no known benefit."

Nonetheless, given the low toxicity of trivalent chromium and the low cost of dietary chromium supplementation, further studies to assess the effects of dietary chromium supplementation on insulin sensitivity, bone mass, blood pressure, and lipid profiles in humans are needed.

¹Mooradian A, Failla M, Hoogwerf B, Maryniuk M, Wylie-Rosett J: Selected vitamins and minerals in diabetes. Diabetes Care 17:464-79, 1994.

²Tuman R, Doisy R: Metabolic effects of the glucose tolerance factor (GTF) in normal and genetically diabetic mice. Diabetes 26:820-26, 1977.

³Food and Nutrition Board: Recommended Dietary Allowances, 10th edition. Washington, D.C., National Academy of Sciences, 1989.

⁵Anderson R, Kozlovsky A: Chromium intake, absorption, and excretion of subjects consuming self-selected diets. Am J Clin Nutr 41:1177-83, 1985.

⁶Lee N, Reasner C: Beneficial effect of chromium supplementation on serum triglyceride levels in NIDDM. Diabetes Care 17:1449-52, 1994.

⁷Anderson R, Polansky M: Dietary and metabolite effects on trivalent chromium retention and distribution in rats. Biological Trace Element Research 50:97-108,1995.

⁸International Programme on Chemical Safety: Environmental Health Criteria 61. Geneva, World Health Organization, 1988.

⁹Gargas M, Norton R, Paustenbach D, Finley B: Urinary excretion of chromium by humans following injection of chromium picolinate. Implications for biomonitoring. Drug Metabolism & Disposition 22:522-29, 1994.

¹⁰Brown R, Forloines-Lynn S, Cross R, Heizer W: Chromium deficiency after long-term total parenteral nutrition. Dig Dis Sci 31:661-64, 1986.

¹¹Jeejeebhoy K, Chu R, Marliss E, Greenberg G, Bruce-Robertson A: Chromium deficiency, glucose intolerance, and neuropathy reversed by chromium supplementation in a patient receiving long-term total parenteral nutrition. Am J Clin Nutr 30:531-38, 1977.

¹²Spicer M, Stoecker B, Spicer L: The effect of chromium depletion and streptozotocin (STZ)-induced diabetes on maternal and fetal insulin and insulin-like growth factor-I (IGF-I) and IGF-II concentration and fetal growth of rats. Diabetes 45 (Suppl 2):335A, 1996.

¹³Anderson R, Cheng N, Bryden N, Polansky M, Cheng N, Chi J, Feng J: Beneficial effects of chromium for people with type II diabetes. Diabetes 45 (Suppl 2):124A, 1996.

¹⁴Jovanovic-Peterson L, Gutierrrez M, Peterson C: Chromium supplementation for gestational diabetic women (GDM) improves glucose tolerance and decreases hyperinsulinemia. Diabetes 45 (Suppl 2):337A, 1996.

¹⁵Ravina A, Slezak L: Chromium in the treatment of clinical diabetes. Harefuah 125:142-45, 1993.

¹⁶Offenbacher E, Pi-Sunyer X: Beneficial effect of chromium-rich yeast on glucose tolerance and blood lipids in elderly subjects. Diabetes 29:919-25, 1980.

¹⁷Sherman L, Glennon J, Brech W, Klomberg G, Gordon E: Failure of trivalent chromium to improve hyperglycemia in diabetes mellitus. Metabolism 17:439-42, 1968.

¹⁸Uusitupa M, Kuumpulainen J, Voutilainene E, Hersio K, Sarlund H, Pyorala K, Koivistoinen P, Lehto J: Effect of inorganic chromium supplementation on glucose tolerance, insulin response, and serum lipids in non-insulin dependent diabetics. Am J Clin Nutr 38:404-10, 1983.

¹⁹Rabinowitz M, Gonick H, Levin S, Davidson M: Effect of chromium and yeast supplements on carbohydrate and lipid metabolism in diabetic men. Diabetes Care 6:319-27, 1983.

²⁰Abraham A, Brooks B, Eylath U: The effects of chromium supplementation on serum glucose and lipids in patients with and without non-insulin-dependent diabetes. Metabolism 41:768-71, 1992.

²¹Preuss H, Gondal J, Bustos E, Bushehri N, Lieberman S, Bryden N, Polansky M, Anderson R: Effects of chromium and guar on sugar-induced hypertension in rats. Clinical Nephrol 44:170-77, 1995.

²²McCarty M: Anabolic effects of insulin on bone suggest a role for chromium picolinate in preservation of bone density. Medical Hypotheses 45:241-46, 1995.

²³Riggs B, Melton L, Eds.: Osteoporosis Etiology, Diagnosis, and Management, 2nd edition. Philadelphia, Pa., Lippincott-Raven, 1995.

²⁴Ueno S, Susa N, Furukawa Y, Sugiyama M: Formation of paramagnetic chromium in liver of mice treated with dichromate (VI). Toxicol & Applied Pharmacol 135:165-71, 1995.

²⁵da Cruz Fresco P, Shacker F, Kortenkamp A: The reductive conversion of chromium (VI) by ascorbate gives rise to apurinic/apyrimidinic sites in isolated DNA. Chem Res Toxicol 8:884-90, 1995.

²⁶Junaid M, Murthy R, Saxena D: Chromium fetotoxicity in mice during late pregnancy. Veterinary & Human Toxicol 37:320-23, 1995.

²⁷Chowdhury A: Spermatogenic and steriodogenic impairment after chromium treatment in rats. Indian J Experiment Biol 33:480-84, 1995.

²⁸Lu YY, Yang JL: Long-term exposure to chromium (VI) oxide leads to defects in sulfate transport system in Chinese hamster ovary cells. J Cell Biochem 57:655-65, 1995.

²⁹Alpoim MC, Geraldes CF, Oliveira CR, Lima MC: Molecular mechanisms of chromium toxicity: oxidation of hemoglobin. Biochem Soc Transact 23:241S, 1995.

³⁰Rajaram R, Nair BU, Ramasami T: Chromium (III) induced abnormalities in human lymphocyte cell proliferation: evidence for apoptosis. Biochem & Biophys Res Comm 210:434-40, 1995.

³¹American Diabetes Association: Position statement: Nutrition recommendations and principles for people with diabetes mellitus. Diabetes Care 19 (Suppl): S16-19, 1996.

Dr. Gonzales’ work is supported by a grant from the Endocrine Fellows Foundation (12-03-96) and by NIH grant IF32DK094490-01.

Lois Schmidt Finney, RD, MPH, CDE, is a trial coordinator for the Diabetes Prevention Trial at the University of Minnesota. J. Michael Gonzalez-Campoy, MD, PhD, FACP, is a fellow in the Division of Diabetes, Endocrinology, and Metabolism at the University of Minnesota in Minneapolis.