Key words: chromium, diabetes, glucose tolerance, trace elements, insulin In addition, diabetes and the neuropathy of a women with gestational diabetes. …
Review Article
Chromium, Glucose Intolerance and Diabetes
Richard A Anderson, PhD, FACN Nutrient Requirements and Functions Laboratory, Beltsville Human Nutrition Research Center, US Department of Agriculture, ARS, Beltsville, Maryland Key words: chromium, diabetes, glucose tolerance, trace elements, insulin
Within the last 5 years chromium Cr has been shown to play a role in glucose intolerance, Type 2 diabetes mellitus Type 2 DM, and gestational diabetes In addition, diabetes and the neuropathy of a patient on home parenteral nutrition were alleviated when supplemental Cr was added to total parenteral nutrition TPN solutions In a study conducted in China that has been supported by studies in the United States, supplemental Cr as Cr picolinate improved the blood glucose, insulin, cholesterol, and hemoglobin A1C in people with Type 2 DM in a dose dependent manner Follow-up studies of 1 year have confirmed these studies The requirement for Cr is related to the degree of glucose intolerance: 200 g/day of supplemental Cr is adequate to improve glucose variables of those who are mildly glucose intolerant However, people with more overt impairments in glucose tolerance and diabetes
usually require more than 200 g/day Daily intake of 8 g of Cr per kg body weight was also more effective than 4 g/kg in women with gestational diabetes The mechanism of action of Cr involves increased insulin binding, increased insulin receptor number, and increased insulin receptor phosphorylation In summary, supplemental Cr has been shown to have beneficial effects without any documented side effects on people with varying degrees of glucose intolerance ranging from mild glucose intolerance to overt Type 2 DM
Key teaching points:
Chromium Chromium Chromium Chromium alleviates glucose intolerance alleviates Type 2 DM and gestational diabetes increases insulin receptor phosphorylation is a safe nutrient supplement
INTRODUCTION
Chromium Cr is an essential element required for normal carbohydrate and lipid metabolism [1 4] Signs of Cr deficiency have been documented on numerous occasions, including elevated blood glucose, insulin, cholesterol and triglycerides, and decreased high density lipoproteins HDL in humans consuming normal diets Table 1 More severe signs of Cr deficiency including nerve and brain disorders that are reversed by supplemental Cr have been reported for
patients on total parenteral nutrition TPN [57] Chromium is now routinely added to TPN solutions [8] While there are numerous, well controlled studies reporting
the beneficial effects of improved Cr nutrition, there are also a few well controlled studies reporting no or minimal beneficial effects of Cr Table 1 This review will attempt to evaluate the Cr nutrition studies involving humans and try to clarify the field of Cr nutrition
CHROMIUM ESSENTIALITY IN HUMANS
The essentiality of Cr in human nutrition was documented in 1977 [5] when a female patient on total parenteral nutrition TPN developed severe diabetic-like symptoms that were refractory to insulin Before Cr supplementation, the patient was
Presented in part as the American College of Nutritions ACN Award Lecture, Albuquerque, NM, October, 1998, and at the International Symposium on the Health Effects of Dietary Chromium, Tufts University School of Medicine, United States Department of Agriculture, and Chromium Information Bureau, Inc, Dedham, MA, May, 1998 Address reprint requests to: Richard A Anderson, PhD, FACN, USDA, ARS, BHNRC, NRFL, Bldg 307, Rm 224, BARC-East, Beltsville, MD 20705-2350
Journal of the American
College of Nutrition, Vol 17, No 6, 548 555 1998 Published by the American College of Nutrition 548
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Table 1 Chromium Supplementation Studies of Subjects Without Diabetes
Authors Glinsmann Mertz, 1966 [33] Hopkins et al, 1968 [58] Levine et al, 1968 [59] Carter et al, 1968 [60] Gurson Saner, 1971 [61] Offenbacher Pi-Sunyer, 1980 [62] Riales Albrink, 1981 [63] Anderson et al, 1983 [23] Subjects 10 adults 12 malnourished children 10 elderly 9 children w/kwashiorkor 15 malnourished children 8 elderly 14 men 76 adults Form g/day CrCl3 1501000 CrCl3 250 CrCl3 150 CrCl3 250 CrCl3 50 Yeast Cr 11 CrCl3 200 5 days/ wk CrCl3 200 Duration week 3 011 1216 014043 16 8 12 12 Significant Cr effects No effects Improved glucose tolerance Improved glucose tolerance No effects, elevated basal Cr intake Improved glucose tolerance Improved glucose tolerance; decreased cholesterol Increased HDL cholesterol Decrease 90-minute glucose in subjects w/90-minute glucose 556 mmol/L; increased 90minute glucose in subjects w/90minute glucose fasting No effects: subjects were nutritionoriented consumed intakes at or above RDA for 8 indicator nutrients Increased
-cell sensitivity using euglycemic clamp Decreased plasma glucose of 80 subjects w/12 minute glucose 556 mmol/L not on medication No effects in women on medication Increased HDL decreased total cholesterol:HDL ratio in 21 women not on medication No effects in women on medication Decreased fasting glucose; improved glucose tolerance Decreased total cholesterol Decreased total LDL-cholesterol Decreased total cholesterol, LDL apoprotein B; increased apoprotein A-1 Decreased total cholesterol total cholesterol:HDL ratio Improved glucose tolerance decreased circulating insulin in 9 subjects w/90-minute glucose 556 mmol/L Increased HDL cholesterol No effects Increased HDL cholesterol; decreased triglycerides Decreased insulin in subjects w/ initial fasting insulin 35 pmol/L w/o diabetes No effects
Offenbacher et al, 1985 [22]
8 elderly
CrCl3 200
10
Potter et al, 1985 [49] Martinez et al, 1985 [64]
5 elderly 85 elderly women
CrCl3 200 CrCl3 200
5 10
Bourn et al, 1986 [65]
47 women
CrCl3 200
10
Urber Zemmel, 1987 [66] Urberg et al, 1988 [67] Wang et al, 1989 [68] Press et al, 1990 [69]
16 elderly 2 men 10 adults 28 adults
CrCl3 200 100 mg niacin CrCl3 200 100 mg niacin
CrCl3 50 Cr picolinate 200
4 52 12 6
Lefavi et al, 1993 [70] Anderson et al, 1991 [26]
34 men 17 adults
Cr nicotinate 200 and 800 CrCl3 200
8 5
Roeback et al, 1991 [71] Uusitupa et al, 1992 [40] Abraham et al, 1992 [27]
Wilson Gondy, 1995 [72]
63 adults on betablockers 26 elderly 51 adults w/atherosclerotic disease 26 adults
Biologically active Cr 600 Yeast Cr 160 CrCl3 250
8 24 2864
Cr picolinate 220
14
Thomas Gropper, 1996 [73]
14 adults
Cr nicotinate 200
14
losing weight, accompanied by glucose intolerance and neuropathy, even when she received 50 units of exogenous insulin per day When 200 g of Cr as Cr chloride was added to her TPN solutions for 3 weeks, her diabetic-like symptoms were
alleviated and exogenous insulin was no longer required This work has been confirmed several times and documented in the scientific literature on two occasions [6,7] In one of our studies involving Cr supplementation of
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trauma patients on TPN [9], one patient had abnormally high blood glucose although the patient was receiving more than 12 g of Cr daily When an additional 12 g of
Cr as Cr chloride was added daily to the TPN solutions, the blood glucose dropped from approximately 25 mmol/L to 83 mmol/L Subsequent elimination of the additional Cr from the TPN solutions led to a return of the elevated glucose levels, but these levels were reversed when the additional 12 g daily of Cr was added back [10] Beneficial effects of Cr are not limited to patients on TPN Children, the elderly, people with Type 1 and 2 diabetes mellitus DM, as well as those with low blood sugar, have all been shown to display positive effects in response to supplemental Cr Table 1 In addition to humans, beneficial effects of supplemental Cr have been observed in rats, mice, squirrel monkeys, guinea pigs, rabbits, fish, pigs, cattle, and horses [2 4] source of nutrients for children from 4 to 6 months of age Based on the present ESADDI of 10 g to 40 g for children, children would need to consume more than 556 liters of breast milk daily to obtain the minimum suggested daily intake of 10 g [17] Although breast milk is likely to have a higher Cr bioavailability than other sources, this has not been documented The normal dietary Cr intake for adults is also below the minimum ESADDI of 50 g
Anderson and Kozlovsky [19] measured the daily Cr intake of 22 female and 10 male subjects for 7 consecutive days Not a single subject had a mean daily Cr intake of 50 g or more Mean SEM daily intake was 25 1 g for the women and 33 3 g for the men Similar or slightly higher values have been reported in other countries [20] The Cr content of 22 daily diets designed by nutritionists to be well balanced ranged from 84 g to 237 g per 418 MJ 1000 kcal with a mean SEM Cr concentration of 134 1 g per 418 MJ [21] Mean Cr intake for freely chosen diets was 15 1 g per 418 MJ, which is nearly identical to the value observed previously [19] Assuming a mean Cr concentration of 15 g per 418 MJ, more than 12 MJ would have to be consumed to obtain the minimum ESADDI and more than 50 MJ 12,000 kcal for the upper limit of 200 g of the ESADDI Since it is difficult to obtain the minimum suggested Cr intake of 50 g, does this mean that the ESADDI is too high? On the contrary There is no evidence that the ESADDI for adults is too high, and numerous studies have documented that normal dietary Cr intake is suboptimal Table 1 Over the past three decades there have been more than 23 published Cr
supplementation studies involving subjects who do not have clinical diabetes Table 1 All but five of these reported at least one significant positive effect of supplemental Cr The most readily observed benefit reported in the majority of the studies was improved blood sugar and/or insulin Table 1 Not only is the amount of Cr consumed daily important, but specific foods may negatively affect Cr status as well For example, foods high in simple sugars are not only usually low in Cr but enhance Cr losses Chromium intakes of 30 g to 40 g per day would likely be adequate if well balanced diets low in simple sugars and high in fresh fruits and vegetables were consumed This inference would be similar to the well balanced diets in the study by Offenbacher et al [22], in which subjects consuming diets containing 37 g/day of Cr and adequate in eight other indicator nutrients did not respond to supplemental Cr
SUGGESTED AND/OR ESTIMATED SAFE AND ADEQUATE DAILY DIETARY INTAKES FOR CHROMIUM
In 1979, an American Medical Association Panel [11] recommended the daily administration of 10 to 15 g of Cr for adult TPN patients and 014 g/kg to 020 g/kg for pediatric patients Fleming et al [12]
recommended 10 g to 20 g daily for adults, and Green et al [13] proposed 02 g/kg/day for infants and children However, the Cr content of adult TPN solutions may not be adequate for severely stressed patients For example, neurological symptoms of a patient on TPN, who was also receiving metronidazole returned to normal within 3 weeks after further addition of Cr 250 g/day for 2 weeks to the TPN fluids [14] By contrast, TPN solutions may be too high for infants and children [15], leading to negative effects that include reduced growth [16] The basal Cr content of TPN solutions varies widely and should be monitored [8] The estimated safe and adequate daily dietary intake ESADDI for Cr is shown in Table 2 [1] Similar values were proposed in 1980 The ESADDI for infants of 10 g to 40 g is based upon breast milk Cr concentrations obtained before 1980 that were often 10-fold higher than presently accepted values [17] Recent values for breast milk Cr are in the region of 018 g/L [17 and cited references] The American Academy of Pediatrics [18] recommends that breast milk be the sole Table 2 Suggested and/or Estimated Safe and Adequate Daily Dietary Intakes for Chromium
Age group Children 7
years to adult Ages 4 to 6 years Children 1 to 3 years Infants 05 months to 1 year Infants aged 6 months Recommended Cr dose 50200 30120 2080 2060 1040 g g g g g
CHROMIUM SUPPLEMENTATION IN PEOPLE WITH GLUCOSE INTOLERANCE AND DIABETES
The response to Cr is related to the degree of glucose intolerance We [23] conducted a study involving Cr supplementation of normal free-living subjects free of diabetes Subjects with 90-minute glucose greater than 556 mmol/L oral
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glucose challenge of 1 g/kg body wt responded to supplemental Cr with a decrease in 90-minute blood glucose Blood glucose of subjects with good glucose tolerance defined as 90-minute glucose less than 556 mmol/L but greater than fasting was unchanged by supplemental Cr These subjects had good glucose tolerance and showed no signs of Cr deficiency; therefore they did not respond to additional Cr The blood glucose of subjects who tended to have low blood sugar 90minute glucose less than fasting increased after Cr supplementation A follow-up study confirmed that subjects with low blood sugar respond to supplemental Cr [24] In the follow-up study, a decrease in the
area of the glucose tolerance curve below fasting increased blood glucose in response to a glucose challenge was associated with increased insulin binding, increased insulin receptor number, and alleviation of hypoglycemic symptoms, including blurred vision, sweating, trembling, sleepiness, etc This work has been confirmed [25] The mechanism whereby supplemental Cr leads to a decrease in blood glucose of subjects with elevated blood glucose and an increase in people with hypoglycemia is that Cr functions by regulating or potentiating insulin action Improved insulin efficiency in people with elevated blood glucose leads to a more efficient removal of glucose from the blood In people with hypoglycemia, supplemental Cr also leads to a normalization of insulin function that leads to increased insulin efficiency and a return to normal concentrations more quickly in response to a glucose challenge [24] Further documentation that the Cr requirement is related to the degree of glucose intolerance was reported by Anderson et al [26] in a study in which subjects consumed low Cr diets Consumption of diets comprised of normal foods containing less than 20 g of Cr daily resulted in no
significant changes in the glucose and insulin variables of subjects with good glucose tolerance as defined above, but consumption of these same diets by people with 90-minute glucose values greater than 556 mmol/L resulted in increased blood glucose and insulin levels that were reversed by supplemental Cr 200 g/d as Cr chloride on blood lipids in 3 months or less The variable response to Cr in blood lipids is likely similar to responses in blood glucose and will be discussed later see the section on Why Arent All the Studies Positive?
CHROMIUM AND DIABETES
In Table 3, it is clear that 200 g of Cr as Cr chloride is not sufficient to elicit a positive response in those with Type 2 DM The studies of Sherman et al [28] and Rabinowitz et al [29] with 150 g of Cr as CrCl3 showed no effects of supplemental Cr The positive effect of 200 g as CrCl3 in the study of Uusitupa et al [30] on 60-minute insulin is questionable; moreover, the remaining variables measured were not altered by supplemental Cr The studies that report positive effects of supplemental Cr on people with diabetes usually involve 400 g or more of Cr Mossop [31] reported a decrease in fasting glucose from 144 mmol/L to 66
mmol/L following 16 to 32 weeks of daily supplementation with 600 g of Cr as Cr chloride Nath et al [32] reported positive effects with 500 g/day, and Glinsmann and Mertz [33] used up to 1000 g/day of Cr as Cr chloride Abraham et al [27] reported positive effects on blood lipids with 250 g/day, but it took 28 to 64 weeks for effects to be significant The reasons for the slow response may be due to the form and amount of Cr Other forms of Cr, especially Cr picolinate, are more effective than Cr chloride in human and animal studies [34] Two hundred micrograms of Cr daily as Cr picolinate leads to improved glucose and lipid variables in people with Type 2 DM [35,36] with a better response at 1000 g/day [37] Women with gestational diabetes also respond better to 8 g per kg body weight of Cr as Cr picolinate than to 4 g/kg [38]
WHY ARENT ALL THE STUDIES POSITIVE?
If Cr has an effect on those with impaired glucose tolerance and Type 2 DM, why arent all the studies involving these subjects positive? There are a number of reasons First of all, human studies include subjects of diverse genetic and nutritional backgrounds living in environments of varying degrees of stress, all of which may
affect Cr metabolism [39] Varying results of supplemental Cr may also be due to the diet, selection of subjects, the duration of the study, and the amount and type of supplemental Cr In Table 3 it is obvious that studies involving subjects with diabetes receiving 200 g/day of supplemental Cr as Cr chloride did not report beneficial Cr effects [28 30], whereas similar studies employing 400 g or more of Cr as Cr chloride reported positive effects of supplemental Cr [3133] Essentially all the studies employing the more bioavailable Cr picolinate have reported positive effects Table 3, with greater effects reported at 1000 g/day than at 200 /day [37] In addition, response to Cr is related to the degree of glucose
CHROMIUM AND BLOOD LIPIDS
In addition to improvements in blood glucose and insulin due to supplemental Cr, there have been at least 8 studies involving Cr supplementation of subjects without diabetes whose blood lipids improved following Cr supplementation Such improvements are usually greatest in subjects with the highest blood lipids, but significant changes may take several months to appear [3] In the study of Abraham et al [27], with 250 g Cr as Cr chloride, increased HDL
cholesterol and decreased triglycerides did not appear until 6 to 16 months Although we have not observed significant effects of 200 g/day of Cr as CrCl3 on blood lipids in our studies, Cr supplementation periods only lasted 3 months or less Even so, several studies Table 1 have reported beneficial effects of Cr
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Table 3 Chromium Supplementation Studies of Subjects With Type 2 Diabetes Mellitus
Authors Glinsmann Mertz, 1966 [33] Sherman, 1968 [28] Nath et al, 1979 [32] Offenbacher Pi-Sunyer, 1980 [62] Subjects 6 adults 7 men 12 adults 8 adults Form g/days CrCl3 1801000 CrCl3 150 Reduced Cr 500 Yeast 109 Duration weeks Up to 20 16 8 8 Significant Cr effects Improved glucose tolerance No effects Decreased glucose, insulin cholesterol Improved glucose tolerance; decreased circulating insulin No effects Improved fasting glucose Decreased 60-minute insulin Decreased fasting glucose; increased insulin sensitivity Decreased blood glucose, hemoglobin A1c, cholesterol LDL cholesterol Increased HDL cholesterol involved subjects w w/o diabetes on betablockers Increased HDL cholesterol;
decreased triglycerides Decreased triglycerides Decreased glucose; decreased insulin, sulfonyl urea or metformin requirements Improved blood glucose
Rabinowitz et al, 1983 [29] Mossop, 1983 [31] Uusitupa et al, 1983 [30] Elias et al, 1984 [74] Evans, 1989 [35]
43 men 26 adults 10 adults 6 adults 11 adults
CrCl3 150 CrCl3 600 CrCl3 200 Yeast Cr 21 Cr picolinate 200
16 1632 6 2 6
Roeback et al, 1991 [71]
63 adults
Biologically active Cr 600
8
Abraham et al, 1992 [27]
Lea Reasner, 1994 [75] Ravina et al, 1995 [36]
25 diabetics w/ atherosclerotic disease 28 adults 114 Type 2; 48 Type 1 8 women w/gestational diabetes 5 adults 185 adults
CrCl3 250
2864
Cr picolinate 200 Cr picolinate 200
8 14
Jovanovic-Peterson et al, 1995 [38]
Cr picolinate 2,4, or 8 g/kg bwt Cr nicotinate 200 Cr picolinate 200 or 1000
–
Thomas Gropper, 1996 [73] Anderson et al, 1997 [37]
8 16
No effects Increased glucose tolerance; decreased circulating insulin, fasting glucose, cholesterol, hemoglobin A1c
intolerance Subjects with good glucose tolerance who do not need additional Cr do not respond to supplemental Cr [2,3] Subjects consuming adequate Cr and well balanced diets also do not
respond to additional Cr [22] This correlation is consistent with the study of Uusitupa et al [40] in which subjects with glucose intolerance that did not improve when subjects were put on a good diet also did not improve when they were given supplemental Cr Chromium is a nutrient and not a drug, and it will therefore benefit only those who are deficient or marginally deficient in Cr In addition, glucose intolerance and Type 2 DM are due to a number of causes, only one of which is Cr deficiency
CHROMIUM: MODE OF ACTION
A proposed mode of action of Cr in the regulation of insulin is shown in Fig 1 Chromium increases insulin binding to cells due to increased insulin receptor numbers [24] The insulin
receptor is present in essentially all cells, but its concentration varies from approximately 40 receptors per cell for erythrocytes to more than 200,000 receptors for adipocytes and hepatocytes [41] The insulin receptor is composed of two extracellular alpha subunits with a molecular weight of 135,000 that contain the insulin binding site, and two transmembrane betasubunits with a molecular weight of 95,000 [42] Wortmanin is an antifungal agent that inhibits phosphotidylinositol 3
-kinase, which in turn also inhibits many effects of insulin stimulation in insulin-dependent cells [43,44] Wortmanin also inhibits Cr potentiation of insulin activity [45, unpublished observations] This suggests that Cr, like insulin, affects protein phosphorylation-dephosphorylation reactions Once insulin binds to the alpha subunit of the insulin receptor, a specific phosphorylation of the beta subunit occurs through a cascade of intermolecular phosphorylation reactions [41,42,46] The enzyme partly responsible for the phosphorylation, which leads to increased insulin sensitivity, is insulin
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reference dose to the RDA is 350 for Cr, compared to less than 2 for zinc, roughly 2 for manganese, and 5 to 7 for selenium [50] We [51] demonstrated a lack of toxicity of Cr chloride and Cr picolinate in rats at levels several thousand times the upper limit of the ESADDI for humans based on body weight There was no evidence of toxicity, nor have there been any documented toxic effects in any of the human studies involving supplemental Cr
SUMMARY
Fig 1 Mode of action of Cr in potentiation of insulin Cr increases insulin binding
to cells by increasing insulin receptor number Cr also increases insulin sensitivity by increasing insulin receptor phosphorylation Cr potentiation of insulin is inhibited by wortmanin, which inhibits the enzyme, PI 3-kinase phosphotidylinositol 3 -kinase
receptor tyrosine kinase, which is activated by Cr [47] A low molecular weight Cr binding compound does not affect the protein kinase activity of rat adipocytes in the absence of insulin but stimulates kinase activity 8-fold in the presence of insulin Removal of Cr from the low molecular weight Cr binding compound results in the loss of kinase potentiating activity [47] Chromium also inhibits phosphotyrosine phosphatase PTP-1, a rat homolog of a tyrosine phosphatase PTP-1B that inactivates the insulin receptor [45, unpublished observation] The specific inhibition of insulin receptor phosphotyrosine phosphatase activity needs to be studied more closely since a low molecular weight Cr binding substance has also been shown to activate a membrane phosphotyrosine phosphatase [48] The activation by Cr of insulin receptor kinase activity and the inhibition of insulin receptor tyrosine phosphatase would lead to increased phosphorylation
of the insulin receptor, which is associated with increased insulin sensitivity [41,42,46] Increased glucose utilization and beta-cell sensitivity have also been demonstrated using the hyperglycemic clamp technique [49]
The response to Cr supplementation for glucose, insulin, lipids, and related variables is related to the amount and form of supplemental Cr, the degree of glucose intolerance, and the duration of the study Subjects with glucose intolerance but not diabetes usually respond to 200 g of Cr daily as Cr chloride or other more bioavailable forms of Cr People with good glucose tolerance 90 minute glucose less than 556 mmol/L but greater than fasting following an oral glucose challenge do not respond to supplemental Cr regardless of form Patients with Type 2 DM require more than 200 g daily of supplemental Cr Diabetics usually have a higher requirement for Cr and have impaired mechanisms to convert Cr to a usable form [52,53] Response time to Cr varies from less than 10 days to sometimes more than 3 months Response to Cr is also related to stress, and beneficial effects are greater under physical or dietary stresses [39,54 56] Also, response to supplemental Cr is related
not only to dietary Cr intake but also to the types of diets consumed, since some dietary components such as simple sugars increase Cr losses [57] Glucose intolerance and diabetes are also due to a number of causes unrelated to dietary Cr intake
REFERENCES
1 National Research Council: Recommended Dietary Allowance, 10 ed Washington, DC: National Academy Press, 1989 2 Anderson RA: Recent advances in the clinical and biochemical effects of chromium deficiency In Prasad AS ed: Essential and Toxic Trace Elements in Human Health and Disease New York: Wiley Liss, pp 221234, 1993 3 Anderson RA: Chromium, glucose tolerance, diabetes and lipid metabolism J Adv Med 8:3749, 1995 4 Mertz W: Chromium in human nutrition: a review J Nutr 123: 626633, 1993 5 Jeejeebhoy KN, Chu RC, Marliss EB, Greenberg GR, BruceRobertson A: Chromium deficiency, glucose intolerance, and neuropathy reversed by chromium supplementation in a patient receiving long-term total parenteral nutrition Am J Clin Nutr 30:531 538, 1977 6 Freund H, Atamian S, Fischer JE: Chromium deficiency during total parenteral nutrition JAMA 241:496498, 1979 7 Brown RO, Forloines-Lynn S, Cross RE, Heizer WD: Chromium
SAFETY OF
SUPPLEMENTAL CHROMIUM
Trivalent Cr, the form of Cr found in foods and nutrient supplements, is considered one of the least toxic nutrients The reference dose established by the US Environmental Protection Agency for Cr is 350 times the upper limit of the ESADDI of 200 g/day The reference dose is defined as an estimate with uncertainty spanning perhaps an order of magnitude of a daily exposure to the human population, including sensitive subgroups, that is likely to be without an appreciable risk of deleterious effects over a lifetime [50] This conservative estimate of safe intake has a much larger safety factor for trivalent Cr than for almost any other nutrient The ratio of the
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deficiency after long-term total parenteral nutrition Dig Dis Sci 31:661664, 1986 Anderson RA: Chromium and parenteral nutrition Nutrition 11: 8386, 1995 Borel JS, Majerus TC, Polansky MM, Moser PB, Anderson RA: Chromium intake and urinary chromium excretion of trauma patients Biol Trace Elem Res 6:317326, 1984 Anderson RA: Essentiality of chromium in humans Sci Total Environ 86:7581, 1989 American Medical
Association Department of Foods and Nutrition: Guidelines for essential trace element preparations for parenteral use A statement by an expert panel JAMA 241:20512054, 1979 Fleming CR: Trace element metabolism in adult patients requiring total parenteral nutrition Am J Clin Nutr 49:573579, 1989 Green HL, Hambidge KM, Schankler R: Guidelines for the use of vitamins, trace elements, calcium, magnesium and phosphorus in infants and children receiving total parenteral nutrition: report of the subcommittee on pediatric parenteral nutrient requirements from the committee on clinical practice issues of the American Society for Clinical Nutrition Am J Clin Nutr 48:1324, 1988 Verhage AH, Cheong WK, Jeejeebhoy KN: Neurologic symptoms due to possible chromium deficiency in long-term parenteral nutrition that closely mimic metronidazole-induced syndrome JPEN 20:123127, 1996 Bougle D, Bureau F, Deschrevel G, Hecquard C, Neuville D, Drosdowsky M, Duhamel JF: Chromium and parenteral nutrition in children J Pediat Gastr Nutr 17:7274, 1993 Moukarzel AA, Song MK, Buckman AL, Vargas J, Gass W, McDirmid S, Reyen L, Ament M: Excessive chromium intake in children receiving total parenteral nutrition
Lancet 339:385388, 1992 Anderson RA, Bryden NA, Patterson KY, Veillon C, Andon M, Moser-Veillon P: Breast milk chromium and its association with chromium intake, chromium excretion, and serum chromium Am J Clin Nutr 57:519523, 1993 American Academy of Pediatrics: Commentary on breast feeding and infant formulas including proposed standards for formulas Pediatrics 57:278285, 1976 Anderson RA, Kozlovsky AS: Chromium intake, absorption and excretion of subjects consuming self-selected diets Am J Clin Nutr 41:11771183, 1985 Cauwenbergh RV, Hendrix P, Robberecht H, Deelstra HA: Daily dietary chromium intake in Belgium, using duplicate portion sampling Z Lebenson Unters Forsch 203:203206, 1996 Anderson RA, Bryden NA, Polansky MM: Dietary chromium intake - freely chosen diets, institutional diets and individual foods Biol Trace Elem Res 32:117121, 1992 Offenbacher KG, Rinko CJ, Pi-Sunyer X: The effects of inorganic chromium and brewers yeast on glucose tolerance, plasma lipids and plasma chromium in elderly subjects Am J Clin Nutr 42:454 461, 1985 Anderson RA, Polansky MM, Bryden NA, Roginski EE, Mertz W, Glinsmann W: Chromium supplementation of human subjects: effects on glucose, insulin
and lipid parameters Metabolism 32: 894899, 1983 Anderson RA, Polansky MM, Bryden NA, Bhathena SJ, Canary J: Effects of supplemental chromium on patients with symptoms of reactive hypoglycemia Metabolism 36:351355, 1987 25 Clausen J: Chromium induced clinical improvement in symptomatic hypoglycemia Biol Trace Elem Res 17:229236, 1988 26 Anderson RA, Polansky MM, Bryden NA, Canary J: Supplemental-chromium effects on glucose, insulin, glucagon, and urinary chromium losses in subjects consuming controlled low-chromium diets Am J Clin Nutr 54:909916, 1991 27 Abraham AS, Brooks BA, Eylath U: The effects of chromium supplementation on serum glucose and lipids in patients with and without non-insulin-dependent diabetes Metabolism 41:768771, 1992 28 Sherman L, Glennon JA, Brech WJ, Klomberg GH, Gordon ES: Failure of trivalent chromium to improve hyperglycemia in diabetes mellitus Metabolism 17:439442, 1968 29 Rabinowitz MB, Gonick HC, Levine SR, Davidson MB: Clinical trial of chromium and yeast supplements on carbohydrate and lipid metabolism in diabetic men Biol Trace Elem Res 5:449466, 1983 30 Uusitupa MIJ, Kumpulainen JT, Voutilainen E, Hersio K, Sarlund H, Pyorala KP, Koivistoinen P,
Lehto JT: Effect of inorganic chromium supplementation on glucose tolerance, insulin response and serum lipids in noninsulin-dependent diabetics Am J Clin Nutr 38:404410, 1983 31 Mossop RT: Effects of chromium III on fasting glucose, cholesterol and cholesterol HDL levels in diabetics Cent Afr J Med 29:8082, 1983 32 Nath R, Minocha J, Lyall V, Sunder S, Kumar V, Kapoor S, Dhar KL: Assessment of chromium metabolism in maturity onset and juvenile diabetes using chromium-51 and therapeutic response of chromium administration on plasma lipids, glucose tolerance and insulin levels In Shapcott D, Hubert J eds: Chromium in Nutrition and Metabolism Amsterdam: Elsevier/North Holland, pp 213222, 1979 33 Glinsmann W, Mertz W: Effect of trivalent chromium on glucose tolerance Metabolism 15:510520, 1966 34 Anderson RA, Bryden NA, Polansky MM, Gautschi K: Dietary chromium effects on tissue chromium concentrations and chromium absorption in rats J Trace Elem Exper Med 9:1125, 1996 35 Evans GW: The effect of chromium picolinate on insulin controlled parameters in humans Int J Biosoc Med Res 11:163180, 1989 36 Ravina A, Slezak L, Rubal A, Mirsky N: Clinical use of the trace element chromium III in
the treatment of diabetes mellitus J Trace Elem Exper Med 8:183190, 1995 37 Anderson RA, Cheng N, Bryden NA, Polansky MM, Chi J, Feng J: Beneficial effects of chromium for people with diabetes Diabetes 46:17861791, 1997 38 Jovanovic-Peterson L, Gutierry M, Peterson CM: Chromium supplementation for gestational diabetic women GDM improves glucose tolerance and decreases hyperinsulinemia Diabetes 43:337a, 1996 39 Anderson RA: Stress effects on chromium nutrition of humans and farm animals In Anonymous ed: Proc Alltechs Tenth Symposium Biotechnology in the Feed Industry Nottingham, England: Univ Press, pp 267274, 1994 40 Uusitupa MIJ, Mykkanen L, Siitonen O, Laakso M, Sarlund H, Kolehmainen P, Rasanen T, Kumpulainen J, Pyorala K: Chromium supplementation in impaired glucose tolerance of elderly: effects on blood glucose, plasma insulin, C-peptide and lipid levels Br J Nutr 68:209216, 1992 41 Saad MJA: Molecular mechanisms of insulin resistance Brazilian J Med Biol Res 27:941957, 1994
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42 Kahn CR: Current concepts of the molecular mechanism of insulin action Ann
Rev Med 36:429451, 1985 43 Okaka T, Sakuma L, Fukui Y, Hageki O, Ui M: Blockage of chemotactic peptide-induced stimulation of neutrophils by wortmanin as a result of selective inhibition of phosphatidylinositol kinase J Biol Chem 269:35633567, 1994 44 Kanai F, Ito K, Todaka M, Hayashi O, Kamohara S, Ishii K, Okada T, Kakakie O, Ui M, Ebina Y: Insulin-stimulated glut 4 translocation is relevant to the phosphorylation of IRS 1 and the activity of PI3-kinase Biochem Biophys Res Comm 195:762768, 1993 45 Imparl-Radosevich J, Deas S, Polansky MM, Baedke DA, Ingrebritsen TS, Anderson RA, Graves DJ: Regulation of phosphotyrosine tyrosine phosphatase PTP-1 and insulin receptor kinase by fractions from cinnamon: implications for cinnamon regulation of insulin signalling Hormone Research in press 46 Roth RA, Lui F, Chin JE: Biochemical mechanisms of insulin resistance Hormone Res 41suppl2:5155, 1994 47 Davis CM, Vincent JB: Chromium oligopeptide activates insulin receptor kinase activity Biochemistry 36:43824385, 1997 48 Davis CM, Sumall KH, Vincent JB: A biologically active form of chromium may activate a membrane phosphotyrosine phosphatase PTP Biochemistry 35:1296312969, 1996 49 Potter JF,
Levin P, Anderson RA, Freiberg JM, Andres R, Elahi D: Glucose metabolism in glucose-intolerant older people during chromium supplementation Metabolism 34:199204, 1985 50 Mertz W, Abernathy CO, Olin SS: Risk Assessment of Essential Elements, Washington, DC: ILSI Press, pp xix-xxxviii, 1994 51 Anderson RA, Bryden NA, Polansky MM: Lack of toxicity of chromium chloride and picolinate J Am Coll Nutr 16:273279, 1997 52 Doisy RJ, Streeten DHP, Freiberg JM, Schneider AJ: Chromium metabolism in man and biochemical effects In Prasad AS, Oberleas D eds: Trace Elements in Human Health and Disease, Vol II Essential and Toxic Elements, New York: Academic Press, pp 79104, 1996 53 Tuman RW, Bilbo JT, Doisy RJ: Comparison and effects of natural and synthetic glucose tolerance factor in normal and genetically diabetic mice Diabetes 27:4956, 1978 54 Striffler JS, Law JS, Polansky MM, Bhathena SJ, Anderson RA: Chromium improves insulin response to glucose in rats Metabolism 44:13141420, 1995 55 Yang WZ, Mowat DN, Subiyatno A, Liptrap RM: Effects of chromium supplements on early lactation performance in Holstein cows Can J Anim Sci 76:221230, 1996 56 Kegley EB, Spears JW, Brown TT Jr: Immune response
and disease resistance of calves fed chromium nicotinic acid complex or chromium chloride J Dairy Sci 79:12781283, 1996 57 Kozlovsky AS, Moser PB, Reiser S, Anderson RA: Effects of diets high in simple sugars on urinary chromium losses Metabolism 35:515518, 1986 58 Hopkins LL Jr, Ransome-Kuti O, Majaj AS: Improvement of impaired carbohydrate metabolism by chromium III in malnourished infants Am J Clin Nutr 21:203211, 1968 59 Levine RA, Streeten DHP, Doisy RJ: Effects of oral chromium supplementation on the glucose tolerance of elderly subjects Metabolism 17:114125, 1968 60 Carter JP, Kattab A, Abd-El-hadi K, Davies JT, Gholmy AK, Patwardhan VN: Chromium III in hypoglycemia and impaired glucose utilization in kwashiorkor Am J Clin Nutr 21:195202, 1968 61 Gurson CT, Saner G: Effect of chromium on glucose utilization in marasmic protein-calorie malnutrition Am J Clin Nutr 24:1313 1319, 1971 62 Offenbacher KG, Pi-Sunyer X: Beneficial effect of chromium-rich yeast on glucose tolerance and blood lipids in elderly subjects Diabetes 29:919925, 1980 63 Riales R, Albrink MJ: Effect of chromium chloride supplementation on glucose tolerance and serum lipids including high density lipoprotein
of adult men Am J Clin Nutr 34:26702678, 1981 64 Martinez OB, MacDonald AC, Gibson RS, Bourn O: Dietary chromium and effect of chromium supplementation on glucose tolerance of elderly Canadian women Nutr Res 5:609620, 1985 65 Bourn DM, Gibson RS, Martinez OB, MacDonald AC: The effect of chromium supplementation on serum lipids in a selected sample of Canadian postmenopausal women Biol Trace Elem Res 9:197 205, 1986 66 Urberg M, Zemmel MB: Evidence for synergism between chromium and nicotinic acid in the control of glucose tolerance in elderly humans Metabolism 36:896899, 1987 67 Urberg M, Benyi J, John R: Hypocholesterolemic effects of nicotinic acid and chromium supplementation J Fam Pract 27:603 606, 1988 68 Wang MM, Fox EA, Stoecker BJ, Menendez CE, Chan SB: Serum cholesterol of adults supplemented with brewers yeast or chromium chloride Nutr Res 9:989998, 1989 69 Press RI, Geller J, Evans GW: The effect of chromium picolinate on cholesterol and apolipoprotein fractions in human subjects West J Med 152:4145, 1990 70 Lefavi RG, Wilson GD, Keith RE, Anderson RA, Blessing DL, Hames CG, McMillan JL: Lipid lowering effect of dietary chromium III-nicotinic acid complex in male
athletes Nutr Res 13:239249, 1993 71 Roeback JR Jr, Mae K, Chambless LE, Fletcher RH: Effects of chromium supplementation on serum high-density lipoprotein cholesterol levels in men taking beta-blockers Ann Intern Med 115: 917924, 1991 72 Wilson BE, Gondy A: Effect of chromium supplementation on fasting insulin levels and lipid parameters in healthy, non-obese young subjects Diabetes Res Clin Prac 28:179184, 1995 73 Thomas VLK, Gropper SS: Effect of chromium nicotinic acid supplementation on selected cardiovascular disease risk factors Biol Trace Elem Res 55:297305, 1997 74 Elias AN, Grossman MK, Valenta LJ: Use of the artificial beta cell ABC in the assessment of peripheral insulin sensitivity; effect of chromium supplementation in diabetic patients Gen Pharmacol 15:535539, 1984 75 Lee NA, Reasner CA: Beneficial effect of chromium supplementation on serum triglyceride levels in NIDDM Diabetes Care 17:14491452, 1994
Received July 1998; revision accepted August 1998
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