Chromium as an Essential Nutrient for Humans

Chromium is an essential nutrient required for sugar and fat metabolism. Normal dietary intake of Cr for humans is suboptimal. The estimated safe and adequate daily dietary intake for Cr is 50 to 200 microg. However, most diets contain less than 60% of the minimum suggested intake of 50 microg. Insufficient dietary intake of Cr leads to signs and symptoms that are similar to those observed for diabetes and cardiovascular diseases. Supplemental Cr given to people with impaired glucose tolerance or diabetes leads to improved blood glucose, insulin, and lipid variables. Chromium has also been shown to improve lean body mass in humans and swine. Response to Cr is dependent upon form and amount of supplemental Cr. Chromium is a nutrient; therefore, it will only be of benefit to those who are marginally or overtly Cr deficient. Trivalent Cr has a very large safety range and there have been no documented signs of Cr toxicity in any of the nutritional studies at levels up to 1 mg per day.


INTRODUCTION
for diabetes were unsuccessful, a new treatment was explored. The addition of Cr to her nutrient solutions The role of Cr in animals was reported almost four led to the reversal of diabetic symptoms. Blood glucose, decades ago (Mertz and Schwarz, 1959) and its essennerve conduction abnormalities, and problems associtiality in humans was documented in 1977 (Jeejeebhoy ated with protein utilization returned to normal within et al., 1977). The signs and symptoms of insufficient 3 weeks of the onset of Cr supplementation. Forty-five dietary Cr are listed in Table 1; all, except the last units of exogenous insulin administered to treat her four, are routinely observed in the general population.
diabetes was no longer required. This work has been Improvements in glucose and insulin variables followconfirmed in numerous laboratories (Freund et al., ing Cr supplementation are usually observed in the 1979;Brown et al., 1986;Anderson, 1989), and Cr is majority of the population. Anderson et al. (1983, now routinely added to TPN solutions. 1991a) have reported that the overwhelming majority of subjects with a 90-min blood glucose (following an oral glucose challenge of 1 g/kg body wt) greater than DIETARY CHROMIUM INTAKE 100 mg/dL improve following Cr supplementation. This is particularly important since the average person over Dietary Cr intake in the United States and most industrialized countries is suboptimal. The estimated 25 years has a 90-min glucose value greater than 100 mg/dL (Harris, 1990). safe and adequate daily dietary intake (ESADDI) for Cr is 50-200 mg. However, few diets contain even the The signs and symptoms listed in Table 1 are similar to those reported for non-insulin-dependent diabetes minimum ESADDI of 50 mg. The mean daily intake for men consuming normal diets is 33 { 3 mg and that for mellitus (NIDDM) and cardiovascular diseases. The connecting link among Cr, NIDDM, and cardiovascular women is 25 { 1 mg (Anderson and Kozlovsky, 1985).   (Hopkins et al., 1968;Gurson and Saner, Decreased lean body mass 1971), adults with varying degrees of impaired glucose Elevated percent body fat tolerance (Anderson et al., 1983(Anderson et al., , 1991a; Riales and Al-Increased ocular pressure Peripheral neuropathy brink, 1981), elderly subjects (Offenbacher and Pi-Sun- Encephalopathy yer, 1980;Potter et al., 1985;Urberg and Zemmel, 1987), Low respiratory quotient diabetics (Glinsmann and Mertz, 1966;Nath et al., 1979; Abnormal nitrogen metabolism Anderson et al., 1996a;Mossop, 1983), and hypoglycemics (Anderson et al., 1987;Clausen, 1988) is observed Note. Source: Adapted from Anderson (1994).
following Cr supplementation.
The relative improvements in blood glucose are proportional to the degree of glucose intolerance. Fasting Even well-balanced diets designed by nutritionists do blood glucose of subjects with 90-min glucose greater not provide 50 mg of Cr per day (Anderson et al., 1992). than fasting but not in the diabetic range decreased Chromium intake per 1000 kilocalories (kcal) usually from 90 { 3 to 84 { 2 mg/dL following 3 months of ranges from 5 to 24 mg with a mean Cr intake per daily supplementation with 200 mg of Cr as Cr chloride thousand kcal of 15 { 1.4 mg (Anderson et al., 1992). (Anderson et al., 1983). Fasting blood glucose of dia-Therefore, to meet the minimum estimated safe and betic subjects with higher fasting glucose decreased adequate intake for Cr would require in excess of 3000 from 254 to 119 mg/dL following supplementation with kcal. In one of our exercise studies, the well-balanced 600 mg of Cr per day as Cr chloride (Mossop, 1983). diets designed by nutritionists only contained 5 { 0.2 This not only illustrates the relative responses of mg of Cr per thousand kcal (Anderson et al., 1988). subjects with varying degrees of glucose intolerance Therefore, 10,000 kcal would need to be consumed to and/or diabetes, but also suggests that non-insulin-demeet the minimum ESADDI and 40,000 kcal to obtain pendent diabetic subjects require more Cr than subthe upper level of the suggested intake.
jects with marginally impaired blood glucose tolerance. It has been suggested that the ESADDI for Cr is Daily supplementation with 200 mg of Cr in the form too high since many diets do not provide the required of Cr chloride, Cr picolinate, Cr nicotinate, or Cr nicotiamounts of Cr. However, the ESADDI is not too high, nate-amino acid complex to diabetic subjects was not since people consuming these intakes of Cr respond to sufficient to elicit significant improvements in blood supplemental Cr. Chromium is a nutrient and not a glucose (Anderson et al., 1996b). In a follow-up study, therapeutic agent. Therefore, if subjects were consumsupplementation of 100 mg of Cr or 500 mg of Cr as Cr ing adequate amounts of dietary Cr, they would not picolinate twice daily to non-insulin-dependent diarespond to supplemental Cr. Glucose and insulin varibetic subjects resulted in improvements in the group ables of subjects with average glucose tolerance dereceiving 100 mg twice per day and larger consistent clined when they were maintained on diets containing improvements in the group receiving 500 mg of Cr two levels of dietary Cr found in the lowest quartile of nortimes per day (Anderson et al., 1996b). mal intake (Anderson et al., 1991a).
Not all studies have reported beneficial effects of sup-Foods high in Cr include high bran breakfast cereals, plemental Cr (see review: Anderson, 1989). The lack of broccoli, green beans, and some brands of beer and effects following Cr supplementation is likely due to wine (Anderson et al., 1992). Both the amount of dithe form and amount of supplemental Cr. In the past etary Cr and the selection of foods are important. Foods three decades there have been more than 36 studies high in simple sugars such as fructose (found in soft reporting beneficial effects of supplemental Cr, less drinks) and sucrose (table sugar) are not only low in than 10 that have reported no effects, and no controlled Cr but enhance Cr losses (Kozlovsky et al., 1986). This studies that have documented any negative effects of may partly explain the high incidence of marginal Cr supplemental Cr taken orally. deficiency since many diets are high in simple sugars.
Subjects with diabetes have altered Cr metabolism Chromium intakes below 50 mg appear to be adequate and require additional Cr due to impaired Cr utilization. if diets are high in fruits, vegetables, and grains and Diabetics absorb more Cr than nondiabetics but also low in simple sugars (Offenbacher and Pi-Sunyer, have higher urinary losses (Doisy et al., 1976;Anderson et al., 1996b). Diabetics appear to sense a need for addi-1980; Anderson et al., 1992).
tional Cr which is illustrated by the increased absorp-supplementation (600 mg/day as Cr chloride) of patients being treated for diabetes led to significant improve-tion but are unable to utilize the absorbed Cr which is reflected by the increased losses. While Cr concentra-ments in diabetic symptoms and also increases in HDLcholesterol (Mossop, 1983). tions in blood and urinary losses of diabetics are elevated, tissue levels of Cr in diabetic subjects are lower HDL-cholesterol of 40 patients with atherosclerotic disease increased from 36 to 44 mg/dL following supple-than those of controls. Diabetic mice also have inefficient utilization of Cr and do not respond to supplemental Cr mentation with 250 mg of Cr as Cr chloride for more than 3 months (Abraham et al., 1992). Triglycerides as Cr chloride but do respond to biologically active forms of Cr (Tuman et al., 1978). Biologically active forms of decreased from 186 to 148 mg/dL. HDL-cholesterol in 72 men taking b-blockers improved following 2 months Cr are defined as those that potentiate insulin action in an in vitro fat cell assay (Anderson et al., 1978). Exam-of Cr supplementation at 600 mg/day (Roeback et al., 1991). People who control their hypertension with b-ples of insulin-potentiating forms of Cr include Cr-nicotinic acid-glutathione (Anderson et al., 1978), Cr-nico-blockers still have increased risk of CVD due in part to the increase in triglycerides and decrease in HDL tinic acid-amino acid complexes, and Cr complexes isolated from natural products such as brewer's yeast associated with taking b-blockers (Lardinois and Neuman, 1988). Chromium counteracts these negative ef- (Mertz and Schwarz, 1959).
fects of b-blockers. Chromium may also help control hypertension. Chro-

CHROMIUM AND LIPID METABOLISM
mium prevents sugar-induced hypertension in spontaneously hypertensive rats (Preuss et al., 1995). Im-Several risk factors of cardiovascular disease, in addition to insulin (discussed above), are improved by provements in hypertension occur prior to improvements in glucose and insulin. Studies to elucidate the improved Cr nutrition. Total cholesterol, LDL-and HDL-cholesterol, total cholesterol/HDL ratio, and tri-role of Cr in hypertension in humans are in progress.
Improvements in total cholesterol, like those for glu-glycerides have all been shown to improve in humans as well as experimental animals following Cr supple-cose and insulin variables, are dependent upon the amount of supplemental Cr. Two hundred micrograms mentation. Chromium prevents and reverses aortic plaque accumulation in rabbits (Abraham et al., 1982, of supplemental Cr as Cr picolinate led to a decrease in total cholesterol with larger decreases when 1000 1991). Schroeder et al. (1970) reported that accident victims had higher aortic Cr concentrations than pamg was given per day (Anderson et al., 1996a). tients who died of cardiovascular diseases. Newman et al. (1978) reported that serum Cr correlated inversely

CHROMIUM AND STRESS
with coronary artery disease (CAD) with a less significant correlation with serum triglycerides. There was Chronic stresses may alter micronutrient requirements. If dietary intake is marginal, the effects of no correlation of CAD with serum cholesterol, weight, or blood pressure. Simonoff et al. (1984) expanded these stress could induce signs of deficiency. This is exemplified for the essential nutrient Cr. As discussed above, observations, stating that ''an upper limit for chromium may be established . . . beyond which CAD may be dietary Cr intake for humans is suboptimal. This is also true for farm animals. Chang and Mowat (1992) considered extremely unlikely, thus eliminating the need for a certain number of cineangiographic exami-demonstrated that average daily gain and feed efficiency increased more than 25% due to supplemental nations.'' Tissue and blood Cr levels reported in these early studies are higher than currently accepted val-Cr in steer calves following the stress of transit via shipping. Chromium was without effect in the non-ues, and these studies need to be repeated.
Chromium supplementation of elderly subjects stressed periods. Supplemental Cr also decreases serum cortisol and increases immunoglobulin M and total causes significant decreases in total cholesterol with larger decreases in subjects with the highest levels immunoglobulins. Humoral immune response of early lactating cows also improves due to supplemental Cr prior to supplementation (Doisy et al., 1976;Offenbacher and Pi-Sunyer, 1980). Cholesterol in one subject during times of stress (Burton et al., 1993). Supplemental Cr also counteracts the negative effects of the stress decreased from 339 to 280 mg/dL following 5 months of Cr supplementation at 200 mg/day as Cr chloride of growth hormone administration to pigs (Evock-Clover et al., 1993). plus 100 mg nicotinic acid/day (Urberg et al., 1988). Cholesterol of a second elderly patient decreased from Stresses that alter Cr metabolism in humans are glucose loading, high simple sugar diets, lactation, in-337 to 260 mg/dL following the same pattern of supplementation. Chromium supplementation (200 mg/day as fection, acute exercise, chronic exercise, and physical trauma (Anderson, 1994). Urinary losses can be used Cr chloride, 5 days/week for 12 weeks) of 12 men led to significant decreases in serum triglycerides and in-as a measure of the response to stress, since once Cr is mobilized in response to stress it is not reabsorbed creases in HDL-cholesterol compared to placebotreated subjects (Riales and Albrink, 1981). Chromium by the kidney but is lost in the urine (Doisy et al., 1976).  Borel et al. (1984) Note. Source: Anderson (1994).
The degree of stress as measured by the stress hor-symptoms of Cr deficiency that are similar to those for diabetes and/or cardiovascular diseases. Normal daily mone cortisol is correlated with urinary Cr losses (Anderson et al., 1991b). Mild stresses such as moderate stresses as well as those associated with aging increase Cr requirements. While signs and symptoms of Cr tox-acute exercise elicit increases in Cr losses that are much lower than the effects of severe trauma of sufficient mag-icity are usually limited to occupational exposure and involve a small portion of the population, the signs and nitude to elicit treatment in a shock trauma unit (Table  2). When urinary Cr losses are being used to monitor symptoms of Cr deficiency are widespread. Cr exposure, the dietary, physical, and environmental stresses of the subjects need to be monitored.

REFERENCES
Chronic stresses such as eating a high sugar diet may ultimately elicit negative effects on overall health. Not Abraham, A. S., et al. (1982). The action of chromium on serum lipids and on atherosclerosis in cholesterol-fed rabbits. Atherosclerosis only do high sugar diets increase Cr losses, but they are 42, 115-195. also usually low in dietary Cr. Therefore, sugar-induced Abraham, A. S., et al. (1991). Chromium and cholesterol-induced ath-Cr losses, coupled with low Cr intake, may lead to inerosclerosis in rabbits. Ann. Nutr. Metab. 35,[203][204][205][206][207] creased signs and symptoms of Cr deficiency. The in- Abraham, A. S., et al. (1992). The effects of chromium supplementacreases in the chronic diseases such as maturity onset or tion on serum glucose and lipids in patients with and without nontype II diabetes (NIDDM) and cardiovascular diseases insulin-dependent diabetes. Metabolism 41, 768-771. associated with aging may not be normal consequences Anderson, R. A. (1989). Essentiality of chromium in humans. Sci. of aging but rather consequences of suboptimal dietary Total Environ. 86, 75-81. patterns that are manifest with age. Anderson, R. A. (1994). Stress effects on chromium nutrition of humans and farm animals. In Biotechnology in the Feed Industry.

CHROMIUM TOXICITY
Press, Nottingham, England. Anderson, R. A., and Kozlovsky, A. S. (1985). Chromium intake, ab-The reference dose for trivalent Cr is 1000 mg/kg/day sorption and excretion of subjects consuming self-selected diets. and the upper limit of the ESADDI is only 3 mg/kg/day Am. J. Clin. Nutr. 41, 1177-1183. (Dourson, 1994. The reference dose is defined as ''an Anderson, R. A., et al. (1978). An improved assay for biologically estimate (with uncertainty spanning perhaps an order active chromium. J. Agric. Food Chem. 26, 1219-1221 of magnitude) of a daily exposure to the human popula- Anderson, R. A., et al. (1982). Effect of exercise (running) on serum glucose, insulin, glucagon and chromium excretion. Diabetes 32, tion, including sensitive subgroups, that is likely to be 212-216. without appreciable risk of deleterious effects over a Anderson, R. A., et al. (1983). Effects of chromium supplementation lifetime.'' Therefore, toxic effects of supplemental Cr on urinary Cr excretion of human subjects and correlation of Cr are highly unlikely. There have been no documented excretion with selected clinical parameters. J. Nutr. 113,[276][277][278][279][280][281] signs of Cr toxicity in any of the nutritional Cr supple- Anderson, R. A., et al. (1987). Effects of supplemental chromium on mentation studies conducted over the past three depatients with symptoms of reactive hypoglycemia. Metabolism 36, cades utilizing supplemental trivalent Cr at levels up 351-355. to 1 mg/day. Addition of Cr chloride or Cr picolinate to Anderson, R. A., et al. (1988). Exercise effects on chromium excretion the diet of rats at levels more than a thousand-fold of trained and untrained men consuming a constant diet. J. Appl. Physiol. 64,[249][250][251][252] comparable to intake for humans also did not elicit any Anderson, R. A., et al. (1991a). Supplemental-chromium effects on signs of toxicity of trivalent Cr (Anderson et al., 1997). glucose, insulin, glucagon and urinary chromium losses in subjects consuming controlled low-chromium diets. Am. J. Clin. Nutr. 54, SUMMARY 909-916. Anderson, R. A., et al. (1991b) mal. Suboptimal Cr intake is associated with signs and of people in your study population who might be taking patient receiving long-term total parenteral nutrition. Am. J. Clin. vitamin supplements plus added minerals, and did you Nutr. 30,[531][532][533][534][535][536][537][538] exclude those from your analysis? The third point is Kozlovsky, A. S., et al. (1986). Effects of diets high in simple sugars about diagnostic criteria. Did you have any preestabon urinary chromium losses. Metabolism 35, 515-518. lished diagnostic criteria to decide whether or not some Lardinois, C. K., and Neuman, S. L. (1988). Effects of antihypertenabnormality in spirometry, for example, is related to a sive agents on serum lipids and lipoproteins. Arch. Intern. Med. defect from chromium exposure? Thank you.

148, 1280-1288.
A: Let me start with the first point about whether Mertz, W., and Schwarz, K. (1959). Relationship of glucose tolerance factor to impaired glucose tolerance in rat diets. Am. J. Physiol. we gathered information on occupational questions. 614-618. First, of the people we screened from workplaces, we Mossop, R. T. (1983). Effects of chromium (III) on fasting glucose, had information on what they did at that workplace. cholesterol and cholesterol HDL levels in diabetics. Cent. Afr. J.

196,
There was one workplace, a leather-tanning operation, Med. 29,[80][81][82] which we did exclude. We included only those workers Nath, R., et al. (1979). Assessment of chromium metabolism in matuwho were not directly involved with that process. The rity onset and juvenile diabetes using chromium-51 and therapeutic response of chromium administration on plasma lipids, glucose second part of your question which was the. . . .