Alterations of antioxidant trace elements (Zn, Se, Cu) and related metallo-enzymes in plasma and tissues following burn injury in rats.

To improve the nutritional support for burn patients, we evaluated the alterations of selenium, zinc and copper (Se, Zn and Cu) and their possible contributions to an unbalanced antioxidant response to burn injury. These trace elements and the related antioxidant enzymes, glutathione peroxidase (GPx) and superoxide dismutase (SOD), were studied both in plasma (or serum) and tissues of 20% total body surface area (TBSA) burned rats for 10 days. While plasma Se and serum Zn levels significantly decreased 6 h after burn injury, serum Cu levels increased after 1 day and remained elevated the following 9 days. Selenium levels increased in kidney but decreased progressively in liver. The hepatic Zn and Cu concentrations followed a biphasic increase following burn injury. During the first day, GPx activity decreased in plasma and remained unchanged in the organs, except for a moderate diminution in the liver. Liver Cu/Zn SOD activity increased from 6 h to 4 days. In summary, following burn injury, copper and zinc were redistributed to the liver and selenium to the kidney with non-detectable changes in the muscle and brain. Changes in antioxidant enzyme activities following burn injury were significant mainly in the plasma. Early combined antioxidant supplementation to maintain and restore antioxidant status in burn patients requires further study.

EDTA chelation effects on urinary losses of cadmium, calcium, chromium, cobalt, copper, lead, magnesium, and zinc.

The efficacy of a chelating agent in binding a given metal in a biological system depends on the binding constants of the chelator for the particular metals in the system, the concentration of the metals, and the presence and concentrations of other ligands competing for the metals in question. In this study, we make a comparison of the in vitro binding constants for the chelator, ethylenediaminetetraacetic acid, with the quantitative urinary excretion of the metals measured before and after EDTA infusion in 16 patients. There were significant increases in lead, zinc, cadmium, and calcium, and these increases roughly corresponded to the expected relative increases predicted by the EDTA-metal-binding constants as measured in vitro. There were no significant increases in urinary cobalt, chromium, or copper as a result of EDTA infusion. The actual increase in cobalt could be entirely attributed to the cobalt content of the cyanocobalamin that was added to the infusion. Although copper did increase in the post-EDTA specimens, the increase was not statistically significant. In the case of magnesium, there was a net retention of approximately 85% following chelation. These data demonstrate that EDTA chelation therapy results in significantly increased urinary losses of lead, zinc, cadmium, and calcium following EDTA chelation therapy. There were no significant changes in cobalt, chromium, or copper and a retention of magnesium. These effects are likely to have significant effects on nutrient concentrations and interactions and partially explain the clinical improvements seen in patients undergoing EDTA chelation therapy.

EDTA chelation therapy does not selectively increase chromium losses.

Chelation therapy and supplemental Cr have both been shown to lead to improved blood glucose, lipids, and insulin activity. Chelation therapy leads to the removal of toxic as well as essential metals. To determine if chelation therapy leads to increased urinary Cr losses and altered Cr homeostasis, 2 groups of subjects (1 group that had undergone only 1 or no chelation therapy and 1 group in which all subjects had undergone at least 19 chelation sessions) were evaluated for differences in possible Cr homeostasis based on urinary Cr losses. There were no significant differences in urinary Cr losses between the two groups of subjects and there were no significant increases in urinary Cr losses resulting from chelation therapy. Increases in urinary Cr losses were strongly influenced by supplementation but not chelation therapy.

Reversal of corticosteroid-induced diabetes mellitus with supplemental chromium.

AIMS: To determine if the stress of corticosteroid treatment increases chromium (Cr) losses and if corticosteroid-induced diabetes (steroid diabetes) can be reversed by supplemental chromium. METHODS: The effects of corticosteroid treatment on chromium losses of 13 patients 2 days prior to steroid administration and the first 3 days following treatment were determined. Since steroid-induced diabetes was associated with increased chromium losses and insufficient dietary chromium is associated with glucose intolerance and diabetes, we treated three patients with steroid-induced diabetes with 600 microg per day of chromium as chromium picolinate. RESULTS: Urinary chromium losses following corticosteroid treatment increased from 155+/-28 ng/d before corticosteroid treatment to 244+/-33 ng/d in the first 3 days following treatment. Chromium supplementation of patients with steroid-induced diabetes resulted in decreases in fasting blood glucose values from greater than 13.9 mmol/l (250 mg/dl) to less than 8.3 mmol/l (150 mg/dl). Hypoglycaemic drugs were also reduced 50% in all patients when given supplemental chromium. CONCLUSIONS: These data demonstrate that corticosteroid treatment increases chromium losses and that steroid-induced diabetes can be reversed by chromium supplementation. Follow-up, double-blind studies are needed to confirm these observations.

Elevated intakes of supplemental chromium improve glucose and insulin variables in individuals with type 2 diabetes.

Chromium is an essential nutrient involved in normal carbohydrate and lipid metabolism. The chromium requirement is postulated to increase with increased glucose intolerance and diabetes. The objective of this study was to test the hypothesis that the elevated intake of supplemental chromium is involved in the control of type 2 diabetes. Individuals being treated for type 2 diabetes (180 men and women) were divided randomly into three groups and supplemented with: 1) placebo, 2) 1.92 micromol (100 microg) Cr as chromium picolinate two times per day, or 3) 9.6 micromol (500 microg) Cr two times per day. Subjects continued to take their normal medications and were instructed not to change their normal eating and living habits. HbA1c values improved significantly after 2 months in the group receiving 19.2 pmol (1,000 microg) Cr per day and was lower in both chromium groups after 4 months (placebo, 8.5 +/- 0.2%; 3.85 micromol Cr, 7.5 +/- 0.2%; 19.2 micromol Cr, 6.6 +/- 0.1%). Fasting glucose was lower in the 19.2-micromol group after 2 and 4 months (4-month values: placebo, 8.8 +/- 0.3 mmol/l; 19.2 micromol Cr, 7.1 +/- 0.2 mmol/l). Two-hour glucose values were also significantly lower for the subjects consuming 19.2 micromol supplemental Cr after both 2 and 4 months (4-month values: placebo, 12.3 +/- 0.4 mmo/l; 19.2 micromol Cr, 10.5 +/- 0.2 mmol/l). Fasting and 2-h insulin values decreased significantly in both groups receiving supplemental chromium after 2 and 4 months. Plasma total cholesterol also decreased after 4 months in the subjects receiving 19.2 micromol/day Cr. These data demonstrate that supplemental chromium had significant beneficial effects on HbA1c, glucose, insulin, and cholesterol variables in subjects with type 2 diabetes. The beneficial effects of chromium in individuals with diabetes were observed at levels higher than the upper limit of the Estimated Safe and Adequate Daily Dietary Intake.

Lack of toxicity of chromium chloride and chromium picolinate in rats.

OBJECTIVE: To evaluate the safety of chromium (Cr) as a nutrient supplement. Several recent studies have reported beneficial effects of supplemental Cr at levels higher than the upper limit of the suggested intake for Cr. Trivalent Cr is considered relatively nontoxic but some recent unconfirmed studies have questioned its toxicity. We evaluated the toxicity of Cr chloride and a more bioavailable form of trivalent Cr, Cr tripicolinate. METHODS: Harlan Sprague Dawley rats (4 weeks of age) were fed a stock diet to which was added 0, 5, 25, 50 or 100 mg of Cr per kg of diet as chloride or picolinate. Fasting blood samples were taken at 11 and 17 weeks and animals sacrificed at 24 weeks of age. Lack of toxicity was demonstrated by blood and histological measurements. Chromium incorporation into tissues was determined by graphite furnace atomic absorption. RESULTS: There were no statistically significant differences in body weight, organ weights or blood variables among all the groups tested at 11, 17 and 24 weeks. Blood variables measured were glucose, cholesterol, triglycerides, blood urea nitrogen, lactic acid dehydrogenase, transaminases, total protein and creatinine. Histological evaluation of the liver and kidney of control and animals fed 100 mg/kg Cr as Cr chloride or picolinate also did not show any detectable differences. Liver and kidney Cr concentrations increased linearly for both the Cr chloride and picolinate fed animals. CONCLUSIONS: These data demonstrate a lack of toxicity of trivalent Cr, at levels that are on a per kg basis, several thousand times the upper limit of the estimated safe and adequate daily dietary intake for humans. Animals consuming the picolinate supplemented diets had several-fold higher Cr concentrations in both the liver and kidney than those fed Cr chloride.

Beneficial effects of chromium on glucose and lipid variables in control and somatotropin-treated pigs are associated with increased tissue chromium and altered tissue copper, iron, and zinc.

Chromium (Cr) and somatotropin have been shown to increase lean body mass in pigs but by independent mechanisms. Somatotropin and Cr also affect blood glucose, lipids, and tissue trace metal concentrations. Twenty-four castrated male pigs were divided into four groups: 1) control basal diet; 2) basal diet + 300 micrograms of Cr/kg of diet as Cr picolinate; 3) basal diet + pituitary porcine somatotropin (ppST; 100 micrograms/kg live weight injected daily); and 4) basal diet + Cr + ppST. Pigs were fed the diets from 30 to 60 kg body weight and then killed. Supplemental Cr led to increased total Cr in kidney (1.1 vs 2.3 micrograms) and liver (5.9 vs 8.8 micrograms) but not in the heart independent of ppST treatment. Chromium concentrations in longissimus muscle were less than 1.5 ng/g in all samples, and any increases due to supplemental Cr were not detected. Somatotropin treatment led to decreased hepatic Cr, Cu, Fe, and Zn concentrations and increased total renal Cu, Fe, and Zn. These data demonstrate that supplemental Cr causes increased tissue Cr in the liver and kidney but not in the heart or muscle in control and somatotropin treated pigs. Somatotropin treatment caused decreased kidney and liver Cr concentrations that were offset by increased tissue weights. Somatotropin effects on tissue Cr, Cu, Zn, and Fe were variable and difficult to evaluate due in part to growth hormone-induced changes in organ weights.

Effects of chromium and guar on sugar-induced hypertension in rats.

Ingestion of sugars (sucrose, fructose, glucose) by various rat strains is associated with perturbations in the glucose/insulin system and higher systolic blood pressure (SBP). The association suggests causality, because alterations in insulin metabolism have been found in essential hypertension and many experimental forms of hypertension. To test the hypothesis that sugar-induced SBP elevation is secondary to perturbed insulin metabolism, we examined in 2 experiments effects of chromium and guar, substances known to affect insulin metabolism, on SBP of Spontaneously Hypertensive Rats (SHR). In both studies, sucrose compared to starch ingestion caused significant elevation of SBP; but addition of 2 chromium nicotinate complexes and guar prevented development of sugar-induced SBP elevations. The basal, genetic hypertension of the SHR was not affected by either nutrient. An additional finding in the first study was that sugar-consuming SHR supplemented with chromium had greater BW and increased organ weight (kidney, spleen, and liver) than nonsupplemented SHR. Accordingly, we have shown that two different mechanisms known to ameliorate insulin perturbations, use of chromium and guar, prevent sugar-induced SBP elevations. Since essential hypertension may be due to insulin perturbations and high dose chromium supplementation seems nontoxic, this may prove to be a useful means to lower blood pressure (BP) in some essential hypertensives, as well as diabetic hypertensives. Soluble fiber in the form of guar is also quite effective in favorably influencing sugar-induced SBP elevations.

Supplemental-chromium effects on glucose, insulin, glucagon, and urinary chromium losses in subjects consuming controlled low-chromium diets.

The effects of low-chromium diets containing chromium in the lowest quartile of normal intake on glucose tolerance and related variables in 11 females and 6 male subjects were evaluated. Subjects with glucose concentration greater than 5.56 mmol/L but less than 11.1 mmol/L 90 min after an oral-glucose challenge were designated as the hyperglycemic group and the remainder, the control group. Glucose tolerance and circulating insulin and glucagon of the hyperglycemic group all improved during chromium supplementation (200 micrograms/d) whereas those of the control group were unchanged. Glucose and insulin concentrations 60 min after the oral-glucose challenge and the sum of the 0-90 min and 0-240 min glucose values were all significantly lower after chromium supplementation in the hyperglycemic group. These data demonstrate that consumption of diets in the lowest 25% of normal chromium intake lead to detrimental effects on glucose tolerance, insulin, and glucagon in subjects with mildly impaired glucose tolerance.

Exercise training and dietary chromium effects on glycogen, glycogen synthase, phosphorylase and total protein in rats.

The effects of exercise training and dietary chromium intake on rat liver and muscle glycogen metabolism, tissue and body weight and feed consumption were examined. After 16 wk of training, liver, gastrocnemius and biceps femoris glycogen concentrations were higher in the trained compared to sedentary groups, independent of dietary chromium. There was a chromium x training interaction on glycogen synthase activities in the liver and gastrocnemius muscle. Liver glycogen phosphorylase activities (expressed per g liver) were lower in the chromium-supplemented rats as compared to the non-supplemented rats after 5 wk of dietary treatment, but were similar after 8 wk and higher after 18 wk. Gastrocnemius phosphorylase activity (expressed per mg protein) was lower in the trained rats as compared to the sedentary rats after 16 wk, independent of dietary chromium. Biceps femoris phosphorylase activities were not altered due to training or dietary chromium. Total protein concentration increased in the liver but decreased in the gastrocnemius due to dietary chromium. In summary, liver glycogen synthase and phosphorylase activities were dependent upon dietary chromium. Dietary chromium altered gastrocnemius synthase, but not phosphorylase activities. Changes in enzyme activities may be related to the chromium-dependent effects on liver protein and the chromium and training-dependent effects on gastrocnemius total protein.

Effects of supplemental chromium on patients with symptoms of reactive hypoglycemia.

To determine if chromium (Cr) is involved in hypoglycemia, eight female patients with symptoms of hypoglycemia were supplemented with 200 micrograms of Cr as chromic chloride for three months in a double-blind crossover experimental design study. Chromium supplementation alleviated the hypoglycemic symptoms and significantly raised the minimum serum glucose values observed two to four hours following a glucose load. Insulin binding to red blood cells and insulin receptor number also improved significantly during Cr supplementation. These data suggest that impaired Cr nutrition and/or metabolism may be a factor in the etiology of hypoglycemia.

Serum chromium of human subjects: effects of chromium supplementation and glucose.

Seventy-six adult subjects, 48 males and 28 females, were given placebo or 200 micrograms Cr in the form of chromic chloride in a double-blind crossover study, with 3-month experimental periods, to determine basal serum Cr levels and the effects of Cr supplementation on serum Cr and related variables. Basal serum Cr determined by graphite furnace atomic absorption for all subjects was 0.13 +/- 0.02 ng/ml (mean +/- SEM), and increased significantly to 0.38 +/- 0.02 ng/ml following 3 months of Cr supplementation. There were no significant differences in the serum Cr values for males and females. Serum Cr 90 min following a glucose load (1 g per kg body wt) was not significantly different from fasting during either the placebo or Cr supplementation periods. These data demonstrate that serum Cr increased significantly following Cr supplementation and is a reflection of Cr intake, but serum Cr concentration, even that following a glucose load, does not appear to be a meaningful indicator of Cr status.

Chromium supplementation of human subjects: effects on glucose, insulin, and lipid variables.

Seventy-six normal, free-living subjects were given supplements of 200 micrograms chromium (Cr) in the form of chromic chloride or a placebo in a double-blind crossover study with 3-month experimental periods. Twenty of the 76 subjects had serum glucose concentrations greater than or equal to 100 mg/dL 90 minutes after a glucose challenge (1 g glucose per kilogram of body weight). Chromium supplementation significantly decreased (P less than 0.05) the 90-minute glucose concentration of these subjects from 135 +/- 9 to 116 +/- 11 mg/dL; fasting glucose concentrations also decreased significantly. The 90-minute serum glucose levels of the 35 subjects with glucose concentrations less than the fasting serum glucose level were increased significantly by Cr supplementation, from 71 +/- 1 to 81 +/- 4 mg/dL. Fasting and 90-minute serum glucose concentrations of the remaining subjects who displayed 90-minute glucose concentrations greater than fasting levels but less than 100 mg/dL were not affected by Cr supplementation. In this study, immunoreactive serum insulin concentration, body weight, lipids, and other selected clinical variables did not change significantly during Cr supplementation. These data demonstrate that Cr supplementation decreases the serum glucose levels of subjects with 90-minute glucose concentrations greater than or equal to 100 mg/dL following a glucose challenge, increases serum glucose levels of subjects with 90-minute glucose concentrations less than fasting levels, and has no effect on the serum glucose levels of subjects with 90-minute glucose values similar to but greater than fasting levels.

Effects of chromium supplementation on urinary Cr excretion of human subjects and correlation of Cr excretion with selected clinical parameters.

Daily urinary chromium (Cr) excretion of 15 healthy free-living female subjects was 0.20 +/- 0.03 microgram (mean +/- SEM) and nearly identical for 27 male subjects, 0.17 +/- 0.02 microgram. Minimum Cr absorption calculated from urinary Cr excretion was about 0.4 percent. Increasing intake fivefold by Cr supplementation led to a nearly fivefold increase in Cr excretion suggesting that the extent of absorption of supplemental inorganic chromium was similar to that from normal dietary sources. Correlations between 24-hour Cr excretion and urine volume, age, total creatinine and body weight were not found. Urinary Cr concentration of samples obtained following a morning void correlated with creatinine and Cr concentration following a glucose challenge but not with serum glucose, insulin, lipid parameters, age or body weight. Similar results were obtained for urine samples obtained from subjects during Cr supplementation. These results suggest that urinary Cr excretion does not appear to be a meaningful indicator of Cr status but is a meaningful indicator of Cr intake and that the absorption of supplemental inorganic Cr was similar to that of Cr from normal dietary sources.

Urinary chromium excretion of human subjects: effects of chromium supplementation and glucose loading.

The utilization of inorganic chromium by free-living human subjects was studied in 76 volunteers (male, 48; female, 28) who were supplemented with 200 micrograms of inorganic chromium as chromic chloride or a placebo tablet for 3 months in a double-blind, cross-over experiment. For all subjects, initial mean +/- SEM urinary chromium (Cr) level was 0.20 +/- 0.01 (range, 0.05 to 0.58) ng/ml and did not differ by sex. Initial chromium/creatinine ratio (Cr/Ct) was 0.15 +/- 0.01 (range 0.03 to 0.36) ng Cr/mg creatinine for females and was significantly lower, 0.10 +/- 0.01 (range 0.03 to 0.36) for males. Mean urinary Cr level increased to 1.0 +/- 0.12 after 2 and to 1.13 +/- 0.08 ng/ml after 3 months' supplementation. The Cr/Ct ratio increased to 0.69 +/- 0.10 for females and to 0.50 +/- 0.04 for males after 2 months' supplementation; values were similar after 3 months. An increase in urinary Cr excretion in response to a glucose load was demonstrated for nonsupplemented normal free-living subjects but not for subjects supplemented daily with trivalent chromium. Urinary Cr excretion after a glucose challenge was not predictable and did not depend on Cr status.