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High postprandial blood glucose levels are associated with increased mortality, cardiovascular events and development of diabetes in the general population. Interventions targeting postprandial glucose have been shown to prevent both cardiovascular events and diabetes. This study evaluates the efficacy and safety of a novel nutritional supplement targeting postprandial glucose excursions in non-diabetic adults. Sixty overweight healthy male and female participants were recruited at two centers and randomized in a double-blind, placebo-controlled, crossover design. The supplement, a water-based drink containing 2.6g of amino acids (L-Leucine, L-Threonine, L-Lysine Monohydrochloride, L-Isoleucine, L-Valine) and 250 mcg of chromium picolinate, was consumed with a standardized carbohydrate-rich meal. The primary endpoint was the incremental area under the curve (iAUC) for venous blood glucose from 0 to 120 minutes. Secondary endpoints included glucose iAUC 0-180 minutes and the maximum glucose concentration (Cmax), for both venous and capillary blood glucose. In the intention-to-treat-analysis (n = 60) the supplement resulted in a decreased venous blood glucose iAUC0-120min compared to placebo, mean (SE) of 68.7 (6.6) versus 52.2 (6.8) respectively, a difference of -16.5 mmol/L•min (95% CI -3.1 to -30.0, p = 0.017). The Cmax for venous blood glucose for the supplement and placebo were 6.45 (0.12) versus 6.10 (<0.12), respectively, a difference of -0.35 mmol/L (95% CI -0.17 to -0.53, p<0.001). In the per protocol-analysis (n = 48), the supplement resulted in a decreased Cmax compared to placebo from 6.42 (0.14) to 6.12 (0.14), a difference of -0.29 mmol/L (95% CI -0.12 to -0.47, p = 0.002). No significant differences in capillary blood glucose were found, as measured by regular bed-side glucometers. The nutritional supplement drink containing amino acids and chromium improves the postprandial glucose homeostasis in overweight adults without diabetes. Future studies should clarify, whether regular consumption of the supplement improves markers of disease or could play a role in a diet aiming at preventing the development of diabetes., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: EÖ, IB and RÖ are inventors of a patent family describing the supplement studied. EÖ and IB jointly own the right to the patent and Aventure AB/Double Good AB (RÖ) owns a license to use the patent. EÖ is an employee of Good Idea, Inc since August 2017. starScience GmbH (AS, PMH) have received funding for other studies by Aventure AB/Double Good AB. PH holds shares of Double Good AB. KA and LHL are employees of Aventure AB, the parent company of Double Good AB and Good Idea, Inc. The commercial affiliations of the authors do not alter our adherence to PLOS ONE policies on sharing data and materials.

Purpose of Review: Chromium(III) has been proposed to have a nutritional or pharmacological role in changing body composition and improving symptoms of insulin resistance, type 2 diabetes, and related conditions although the mode of action of Cr(III) at a molecular level has failed to be elucidated. This review details the current status of studies into Cr(III) supplementation., Recent Findings: Clinical trials, meta-analyses and systematic reviews have failed to demonstrate clinically significant effects from Cr(III) supplementation on body composition or symptoms of insulin resistance and related conditions in humans and farm animals. Although new Cr(III) supplements continue to appear in the scientific literature, studies have failed to elucidate the mechanism of chromium action at a molecular level. Conflicting results on a role of transferrin in Cr(III) transport and detoxification have appeared., Summary: Cr(III) supplementation cannot currently be recommended in humans or farm animals. Further studies are required to probe the mechanism of Cr(III) action in increasing insulin sensitivity and glucose uptake in rodent models of insulin resistance and diabetes, with particular attention being turned to a potential role of transferrin in Cr(III) transport and detoxification.

An 11-week feeding trial was carried out to investigate the effects of supplemented chromium picolinate (Cr-Pic) on the growth, whole-body composition, and relative mRNA expression related to lipogenesis and glucose metabolism in juvenile blunt snout bream. Seven isonitrogenous and isoenergetic diets with graded Cr supplementation levels were fed to triplicate groups. The final weight (FW), feed conversion ratio (FCR), and specific growth rate (SGR) were improved with increasing dietary Cr supplementation levels up to 0.4 mg/kg, and thereafter showed relatively constant. However, 12.0 mg/kg dietary Cr supplementation decreased growth and feed utilization. Based on SGR and FCR, the optimal dietary Cr supplementation level for the juvenile was estimated to be 0.28 mg/kg. Significantly higher plasma insulin levels were found in juvenile fed diets with 0.4 and 0.8 mg/kg Cr supplementation compared to those fed diet sans supplemented Cr. Plasma glucose levels decreased with increasing dietary Cr supplementation, and the lowest value was remarked in the group added 3.2 mg/kg of Cr. Adding 0.4-0.8 mg/kg Cr enhanced insulin receptor substrate 1 (IRS-1), phosphoinositide-3-kinase (PI3K), and pyruvate kinase (PK) and inhibited expression of phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase), and glycogen synthase (GS) mRNA levels. High dietary Cr (12.0 mg/kg) supplementation resulted in high G6Pase and PEPCK expression. The highest content of whole-body lipid was remarked in fish fed with 0.4 mg/kg dietary Cr, which related to the enhanced gene expression related to lipogenesis; thereafter, mRNA levels showed a diminishing trend. These findings indicate that optimum dietary Cr-Pic supplementation has a positive effect on growth and blood glucose homeostasis by modifying the mRNA levels related to glucose metabolism and lipogenesis in juvenile blunt snout bream.

Objectives: Early hyperglycemia is prevalent in preterm infants receiving parenteral nutrition (PN) therapy. Chromium improves glucose tolerance by potentiating the action of insulin. Therefore, we hypothesized that supplementing PN with chromium would improve glucose tolerance and PN calorie delivery in infants during the first week of life., Methods: We collected data on neonates receiving PN initiated at birth with chromium (0.2 mcg/kg/d) started either on days 5-7 (group A) vs day 1 (group B) on PN and compared glucose tolerance and PN calorie administration over the first week of life., Results: For similar mean serum glucose concentrations between group A (n = 348) and B (n = 358) (107 ± 48 vs 111 ± 52 mg/dL, P = .3), infants in group B tolerated higher glucose infusion rates and received more PN calories during the first week of life: 8.4 ± 2 vs 8 ± 2 mg/kg/min (P < .001) and 74.8 ± 23 vs 71.5 ± 12 kcal/kg/d (P = .017), respectively. The difference in calories delivered was more pronounced among very low birth weight (VLBW) infants compared with infants >1500 g: 76.5 ± 14 vs 72.4 ± 11 kcal/kg/d (P = .009) and 73.8 ± 27 vs 70.3 ± 12 kcal/kg/d (P = .079), respectively., Conclusions: PN chromium supplementation resulted in better glucose tolerance and calorie delivery during the first week of life, especially in VLBW infants. This supports chromium's essential role in enhancing glucose tolerance during PN therapy in VLBW infants at risk for early hyperglycemia., (© 2017 American Society for Parenteral and Enteral Nutrition.)

Objective: To evaluate the effect of chromium supplementation on the glucose homeostasis and anthropometry of type 2 diabetic patients., Material and Methods: Fifty-six individuals with type 2 Diabetes were randomized on a double blind clinical trial into three groups: placebo (NC0), 50μg (NC50) and 200μg (NC200) of chromium nicotinate. Glucose homeostasis, anthropometry and physical activity intensity were evaluated at the beginning, at day 45 and at day 90. Energy intake was evaluated at the beginning, between the beginning and 45 days, and between days 45 and 90 of the study., Results: There were no differences within or between groups for HOMA-IR, waist circumference, body fat percentage, lean body mass percentage and total energy intake during the trial. There was an increase of the HOMA-β in group NC0 (p=0.0349) and a decrease of 1.08kg in group NC50 (p=0.0048) at 90 days. The relation between body mass index, body fat percentage and insulin sensitivity did not change in the placebo and supplemented groups (p>0.05). In the effect of the intervention, for each 1cm increase in waist circumference there was an increase of 1.90±0.63 in HOMA-IR (p=0.0087) and 16.31±5.27% in HOMA-β (p=0.0073) in group NC200. No difference was seen in the intensity of physical activity within the groups and in the comparison between the supplemented groups (NC50 and NC200) and placebo (NC0) at 90 days. There was an increase in energy expenditure in physical activity at 90days (p=0.0371) of intervention in the group subjects NC50. As for total energy intake, there were no differences within or between the groups during the study., Conclusion: 50μg and 200μg supplementation with chromium nicotinate for 90days did not promote improvements in glucose homeostasis and anthropometry in individuals with type 2 diabetes mellitus., (Copyright © 2016 Elsevier GmbH. All rights reserved.)

Our previous study showed that chromium malate improved the regulation of blood glucose in mice with alloxan-induced diabetes. The present study was designed to evaluate the effect of chromium malate on glycometabolism, glycometabolism-related enzymes and lipid metabolism in type 2 diabetic rats. Our results showed that fasting blood glucose, serum insulin level, insulin resistance index and C-peptide level in the high dose group had a significant downward trend when compared with the model group, chromium picolinate group and chromium trichloride group. The hepatic glycogen, glucose-6-phosphate dehydrogenase, glucokinase, Glut4, phosphor-AMPKβ1 and Akt levels in the high dose group were significantly higher than those of the model, chromium picolinate and chromium trichloride groups. Chromium malate in a high dose group can significantly increase high density lipoprotein cholesterol level while decreasing the total cholesterol, low density lipoprotein cholesterol and triglyceride levels when compared with chromium picolinate and chromium trichloride. The serum chromium content in chromium malate and chromium picolinate group is significantly higher than that of the chromium trichloride group. The results indicated that the curative effects of chromium malate on glycometabolism, glycometabolism-related enzymes and lipid metabolism changes are better than those of chromium picolinate and chromium trichloride. Chromium malate contributes to glucose uptake and transport in order to improved glycometabolism and glycometabolism-related enzymes.

This study was designed to investigate the effects of chromium methionine (Cr-Met) on glucose metabolism, blood metabolites, meat lipid peroxidation, and tissue chromium (Cr) in Mahabadi goat kids. Thirty-two male kids (16.5 ± 2.8 kg BW, 4-5 months of age) were fed for 90 days in a completely randomized design with four treatments. Treatments were supplemented with 0 (control), 0.5, 1, and 1.5 mg Cr as Cr-Met/animal/daily. Blood samples were collected via heparin tubes from the jugular vein on 0, 21, 42, 63, and 90 days of experiment. On day 70, an intravenous glucose tolerance test (IVGTT) was conducted. At the end of the feeding trial, the kids were slaughtered, and the liver, kidney, and longissimus dorsi (LD) muscle samples were collected. Plasma glucose, insulin, and triglyceride concentrations were decreased by Cr supplementation (P < 0.05). LD muscle malondialdehyde (MDA) decreased, and plasma and tissue Cr contents increased with increasing supplemental Cr levels (P < 0.05). Plasma glucose concentrations at 30 and 60 min after glucose infusion were lower in the kids fed 1.5 mg Cr diet than the kids fed control diet (P < 0.05). The IVGTT indicated that the kids supplemented with 1.5 mg Cr had higher glucose clearance rate (K) and lower glucose half-life (T½; P < 0.05). Glucose area under the response curve (AUC) from 0 to 180 min after glucose infusion was decreased linearly (P < 0.01) by supplemental Cr. The results suggested that supplemental Cr may improve glucose utilization and lipid oxidation of meat in fattening kid.

Trivalent chromium (Cr(3+)) is a mineral nutrient reported to have beneficial effects in glycemic and cardiovascular health. In vitro and in vivo studies suggest that Cr(3+) supplementation reduces the atherogenic potential and lowers the risk of vascular inflammation in diabetes. However, effects of Cr(3+) in vascular cells under conditions of hyperglycemia, characteristic of diabetes, remain unknown. In the present study we show that a therapeutically relevant concentration of Cr(3+) (100 nM) significantly downregulates a potent proatherogenic matricellular protein, thrombospondin-1 (TSP-1), in human aortic smooth muscle cells (HASMC) stimulated with high glucose in vitro. Promoter-reporter assays reveal that this downregulation of TSP-1 expression by Cr(3+) occurs at the level of transcription. The inhibitory effects of Cr(3+) on TSP-1 were accompanied by significant reductions in O-glycosylation of cytoplasmic and nuclear proteins. Using Western blotting and immunofluorescence studies, we demonstrate that reduced protein O-glycosylation by Cr(3+) is mediated via inhibition of glutamine: fructose 6-phosphate amidotransferase, a rate-limiting enzyme of the hexosamine pathway, and O-linked N-acetylglucosamine (O-GlcNAc) transferase, a distal enzyme in the pathway that controls intracellular protein O-glycosylation. Additionally, we found that Cr(3+) attenuates reactive oxygen species formation in glucose-stimulated HASMC, suggesting an antioxidant effect. Finally, we report an antiproliferative effect of Cr(3+) that is specific for high glucose and conditions triggering elevated protein O-glycosylation. Taken together, these findings provide the first cellular evidence for a novel role of Cr(3+) to modulate aberrant vascular smooth muscle cell function associated with hyperglycemia-induced vascular complications., (Copyright © 2015 the American Physiological Society.)

Conditions in which glucose metabolism is impaired due to insulin resistance are associated with memory impairment. It was hypothesized that supplemental chromium (Cr) may alleviate insulin resistance in type 2 diabetes and consequently improve memory acquisition, depending upon its source and level. In a complete randomized design experiment, male Wistar rats (n=60; weighing 200-220 g) were fed either normal (8%, normal diet (ND)) or high-fat (40%, high-fat diet (HFD)) diet and supplemented with Cr as either chromium-glycinate (CrGly) or chromium-acetate (CrAc) at doses of 0, 40, or 80 μg/kg body weight (BW) via drinking water from 8 to 20 weeks of age. Feeding HFD induced type 2 diabetes, as reflected by greater glucose/insulin ratio (2.98 vs. 2.74) comparing to feeding ND. Moreover, HFD rats had greater BW (314 vs. 279 g) and less serum (53 vs. 68 μg/L) and brain (14 vs. 24 ng/g) Cr concentrations than ND rats. High-fat diet caused a 32% reduction in expressions of glucose transporters 1 and 3 (GLUTs) in brain tissue and a 27% reduction in mean percentage time spent in the target quadrant and a 38% increase in spatial memory acquisition phase (SMAP) compared with ND. Compared with supplemental Cr as CrAc, CrGly was more effective to ameliorate response variables (i.e., restoration of tissue Cr concentration, enhancement of cerebral GLUTs expressions, and reduction of the glucose/insulin ratio and SMAP) in a dose-response manner, especially in rats fed HFD. Supplemental Cr as CrGly may have therapeutic potential to enhance insulin action and alleviate memory acquisition in a dose-dependent manner, through restoring tissue Cr reserve and enhancing cerebral GLUTs expressions.

Modern data concerning biologic characteristics of chromium (Cr3+) its placement in nature, accessibility and metabolic action of its different forms in humans and animals is presented in this survey. Essentiality of chromium for humans is emphasized, data about consumption norms of this microelement and its use for curing different diseases especially diabetes mellitus and atherosclerosis of vessels are presented. The biochemical mechanisms of Cr3+ effect on the metabolism in the human and animal organism are analyzed. It is shown that the organism reacts to chrome additions by the change of some metabolism links. Chrome influences positively growth and development of foetus, stimulates metabolism of glucose and insulin in the humans and animals. However, at the set chromium requirements it is necessary to take into account its low availability in food, high release of Cr3+ from the organism under the influence of stress factors, considerable decline of its level with age, and also in the period of pregnancy and lactation. Therefore experimental researches of introduction of Cr3+ additions to the diet of people and forage of animals taking into account their body mass, age and clinical state, can explain the biochemical mechanisms of biological action of this microelement.

Chromium picolinate (CrPic) has been discovered as a supplemental or alternative medication for type 2 diabetes, but its mechanism of action is not well understood. The purpose of this study was to explore the possible anti-diabetic mechanisms of CrPic in insulin-resistant 3T3-L1 adipocytes; the insulin resistance was induced by treatment with high glucose and insulin for 24 h. The effects of CrPic on glucose metabolism and the glucose uptake-inducing activity of CrPic were investigated. Meanwhile, the effects of CrPic on glucose transporter 4 (GLUT4) translocation were visualized by immonofluorescence microscopy. In addition, its effects on insulin signaling pathways and mitogen-activated protein kinase (MAPK) signaling cascades were assessed by immunoblotting analysis and real-time PCR. The results showed that CrPic induced glucose metabolism and uptake, as well as GLUT4 translocation to plasma membrane (PM) in both control and insulin-resistant 3T3-L1 adipocytes without any changes in insulin receptor beta (IR-beta), protein kinase B (AKt), c-Cbl, extracellular signal-regulated kinase (ERK), c-Jun phosphorylation and c-Cbl-associated protein (CAP) mRNA levels. Interestingly, CrPic was able to increase the basal and insulin-stimulated levels of p38 MAPK activation in the control and insulin-resistant cells. Pretreatment with the specific p38 MAPK inhibitor SB203580 partially inhibited the CrPic-induced glucose transport, but CrPic-activated translocation of GLUT4 was not inhibited by SB203580. This study provides an experimental evidence of the effects of CrPic on glucose uptake through the activation of p38 MAPK and it is independent of the effect on GLUT4 translocation. The findings also suggest exciting new insights into the role of p38 MAPK in glucose uptake and GLUT4 translocation.

Elevated blood levels of the proinflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), and MCP-1 (monocyte chemoattractant protein-1) increase insulin resistance and the risk of cardiovascular disease (CVD). There is no previous study that has examined the effect of ketosis and trivalent chromium on IL-6, IL-8, or MCP-1 secretion in any cell type or in human or animal model. The authors examined the hypothesis that ketosis increases and trivalent chromium decreases the levels of cytokines and oxidative stress in diabetes using a U937 monocyte cell culture model. Cells were cultured with control, high glucose (HG), and acetoacetate (AA) in the absence or presence (0.5-10 microM) of CrCl(3), chromium picolinate (Cr-P), or chromium niacinate (Cr-N) at 37 degrees C for 24 h. The data show a significant stimulation of IL-6, IL-8, and MCP-1 secretion and an increase in oxidative stress in cells treated with HG or AA. The effect of HG on cytokine secretion was reduced by Cr-N, and to a lesser extent by CrCl(3) and Cr-P. The effect of HG on oxidative stress was reduced by Cr-N and CrCl 3, but not by Cr-P. Similarly, Cr-N decreased the cytokine secretion in HG + AA-treated cells. Cr-N significantly decreased standard oxidant (H(2)O(2)) induced cytokine secretion, which suggests that reduction of cytokine secretion by Cr-N is in part mediated by its antioxidative effect. In a cell culture model, Cr-N appears to be the most effective form of chromium in inhibiting oxidative stress and proinflammatory cytokine secretion by monocytes. This study suggests that chromium niacinate supplementation may be useful in reducing vascular inflammation and the risk of CVD in diabetes.

Insulin activates signaling pathways in target tissues through the insulin receptor and Tyr phosphorylation of intracellular proteins. Vanadate mimics insulin and enhances its actions through inhibition of protein Tyr phosphatases. Chromium is a micronutrient that enhances insulin action to normalize blood glucose, but the mechanism is not understood. Here we show that either vanadate or chromium stimulates Tyr phosphorylation of insulin receptor in mouse 3T3-L1 adipocytes compared to insulin alone, but a combination of vanadate and chromium is not additive. Phosphorylation of MAPK or 4E-BP1 as markers for insulin signaling is stimulated by vanadate plus insulin, and chromium does not enhance the effects. Vanadate robustly activates glucose uptake by 3T3-L1 adipocytes even without added insulin and increases insulin-stimulated glucose uptake. Chromium pretreatment of adipocytes slightly enhances glucose uptake in response to insulin, but significantly increases glucose uptake above that induced by insulin plus vanadate. These data show that chromium enhances glucose uptake even when Tyr phosphorylation levels are elevated by vanadate plus insulin, suggesting separate mechanisms of action for vanadate and chromium.

In experiment 1, 21 male Holstein calves (43.9 kg) were fed only milk replacer at 1.4% of their body weight as dry matter for 6 wk. Dietary treatments included a commercial milk replacer (22% protein, 15% fat) containing (dry basis) either 6.4% Ca propionate or 6.4% dextrose (control) and either 0 or 0.5 mg/kg of supplemental Cr as Cr propionate. Neither Cr nor Ca propionate affected body weight gain; however, Ca propionate tended to increase the growth of the entire foregut measured after slaughter at 6 wk of age. A Minimal Model glucose tolerance test indicated that insulin sensitivity was not affected by treatment. However, calves fed Cr had higher glucose disappearance indexes than controls when propionate was not fed (0.013 vs. 0.019 units) but similar clearance when propionate was included (0.018 vs. 0.018 units, Cr x P interaction). The area under the glucose response curves after propionate-loading tests was much greater for calves fed the Cr versus control replacer when propionate was not present; however, when propionate was included, the response was less dramatic. In experiment 2, 25 Holstein calves were used to study performance and metabolic responses when milk replacer, and then postweaning starter, were supplemented with 0.5 mg/kg of Cr as Cr propionate. The metabolic responses of these calves were not affected by treatment. Overall, combined data suggested that supplemental Cr may improve glucose effectiveness; however, these responses seemed to be attenuated by supplemental propionate.

The dose-dependent effects of chromium chloride (CrCl3) and chromium picolinate (CrPic) were evaluated for their glucose uptake, superoxide anion (O2-) production, activity of glucose-6-phosphate dehydrogenase, and phagocytosis of incubated pulmonary alveolar macrophages in medium containing no or 5 x 10(-8)M insulin. Glucose uptake was found to increase in cells treated with 20 microg/L CrCl3. Incubation with 20 microg/L of CrPic enhanced glucose uptake and O2- production in an insulin-dependent manner. However, the inclusion of CrPic to 100 microg/L in the medium absent of insulin also increased O2- production. The activity of glucose-6-phosphate dehydrogenase was not affected by either the addition of Cr or insulin. The phagocytosis of Escherichia coli by macrophages was enhanced significantly (p < 0.05) in medium containing 10-100 microg/L CrCl3 or 20-100 microg/L CrPic in the presence of insulin. These results suggest that the addition of 10-20 microg/L CrCl3 enhances directly the cellular activity of macrophages, whereas the effect of CrPic requires the cooperative action of insulin in enhancing their glucose uptake and phagocytosis.

Thoroughbred and Quarter Horse yearlings (n = 24; 335+/-7 d of age) were used in a 112-d feeding trial to determine whether chromium (Cr) supplementation would alter growth, development, and energy metabolism of growing horses on high-concentrate diets. The horses were assigned at random within breed and gender subgroups to one of four treatment groups: A) basal concentrate; B) basal plus 175 microg of Cr/kg concentrate; C) basal plus 350 microg of Cr/kg concentrate; and D) basal plus 700 microg of Cr/kg concentrate. Chromium was provided via Cr tripicolinate (Prince Agri Products, Quincy, IL). The horses were weighed, measured for withers and hip height, heart girth, and body length and underwent ultrasound evaluation for croup fat thickness. The concentrate was fed for ad libitum consumption for two, 1.5-hr feeding periods daily. Coastal bermudagrass (Cynodon dactylon) hay was group-fed (six animals/group) at 1% of BW daily. Feed intake was 60% concentrate and 40% hay, resulting in a supplemental Cr intake of 0, 105, 210, and 420 microg/kg diet for groups A, B, C, and D, respectively. Colts consumed more concentrate and total feed than did fillies (P < .05), but no dietary effect on feed intake was detected. Colts weighed more than fillies at the completion of the experiment (P = .0754), but no dietary effects on weight, body measurements, or croup fat were detected. An i.v. glucose tolerance test (.2 g of glucose/kg BW) and an i.v. insulin sensitivity test (.1 IU of insulin/kg BW) were conducted on each animal during the third 28-d period of the experiment. Plasma glucose peaked immediately following injection and decreased more rapidly in animals consuming the high-Cr diet than in those consuming the control diet (P < .01). Mean glucose fractional turnover rate values increased (P = .0369) and mean half-life of glucose decreased (P = .0634) in response to the high Cr supplementation. Plasma glucose depletions in animals fed the other two diets were between and not different from (P > .10) the depletions in control animals or in those fed high-Cr diets. No difference in insulin sensitivity was detected (P > .10). Results indicate that Cr tripicolinate supplementation of yearling horses increases the rate at which glucose is metabolized and may lower the plasma glucose concentration. No effect of Cr supplementation on development of the animals was detected.

The effects of chromium (Cr) supplementation on insulin secretion and glucose clearance (KG) during intravenous glucose tolerance tests (IVGTTS) were assessed in rats with impaired glucose tolerance due to dietary Cr deficiency. Male Wistar rats were maintained after weaning on a basal low-Cr diet containing 55% sucrose, 15% lard, 25% casein. American Institute of Nutrition (AIN)-recommended levels of vitamins, no added Cr, and an altered mineral content as required to produce Cr deficiency and impaired glucose tolerance. The Cr-supplemented group ([+Cr] n = 6) were provided with 5 ppm Cr as CrCl3 in the drinking water, and the Cr-deficient group ([-Cr]n = 5) received purified drinking water. At 12 weeks on the diet, both groups of rats were hyperinsulinemic (+Cr, 103 +/- 13; -Cr, 59 +/- 12 microU/mL) and normoglycemic (+Cr, 127 +/- 7; -Cr, 130 +/- 4 mg/dL), indicating insulin resistance. After 24 weeks, insulin levels were normal (+Cr, 19 +/- 5; -Cr, 21 +/- 3 microU/mL) and all rats remained normoglycemic (+Cr, 124 +/- 8; -Cr, 131 +/- 6 mg/dL). KG values during IVGTTS were lower in -Cr rats (KG = 3.58%/min) than in +Cr rats (KG = 5.29%/min), correlating with significantly greater 40-minute glucose areas in the -Cr group (P < .01). Comparisons of 40-minute insulin areas indicated marked insulin hyperresponsiveness in the -Cr group, with insulin-secretory responses increased nearly twofold in -Cr animals (P < .05). Chromium deficiency also led to significant decreases in cyclic adenosine monophosphate (cAMP)-dependent phosphodiesterase (PDE) activity in spleen and testis (P < .01). In these studies, Cr deficiency was characterized by both beta-cell hypersecretion of insulin and tissue insulin resistance that were associated with decreased tissue levels of cAMP PDE activity.

One hundred twenty-five Angus crossbred steers (215 +/- 2 kg initial BW) were blocked by weight and assigned to pens. Pens were randomly assigned to treatment (six pens/treatment). Treatments consisted of 1) control (no supplemental Cr), 2) CrCl3, 3) high-Cr yeast, or 4) Cr nicotinic acid complex. Chromium was added to provide .4 mg of supplemental Cr/kg of DM. Steers were fed diets containing 90% corn silage (DM basis) and 10% soybean meal-mineral-vitamin supplement. Steers were allowed to consume the diets on an ad libitum basis during the 56-d study. Performance was not affected by treatment. On d 52, steers supplemented with high-Cr yeast had a greater response to an intradermal injection of phytohemagglutin (PHA) for 8 h after injection than control steers (P < .10) or those supplemented with CrCl3 (P < .05) or Cr nicotinic acid (P < .05). Peripheral lymphocytes from steers supplemented with Cr nicotinic acid had a greater (P < .05) blastogenic response to 12.5 micrograms PHA/mL than lymphocytes from steers supplemented with CrCl3. After an i.v. infusion of glucose (.25 g of glucose/kg BW), plasma glucose tended (P < .11) to decrease at a faster rate from 15 to 45 min after infusion in steers fed Cr nicotinic acid. Steers supplemented with Cr nicotinic acid had greater (P < .05) serum insulin 15 and 30 min after infusion than those supplemented with CrCl3 and high-Cr yeast. Controls had lower serum insulin than those supplemented with Cr nicotinic acid 30 min after infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Twenty-four Suffolk lambs (average BW 38 +/- 2.7 kg; 16 ewes and 8 wethers) were fed either a corn-cottonseed hull-based control diet (CON) or CON plus 250 ppb of Cr as chromium tripicolinate (CrPic). Lambs were penned in groups of three and ADG and DMI were measured through d 85 of the experiment. Jugular blood samples were obtained during wk 2, 7, and 11. An i.v. glucose tolerance test (IVGTT; 500 mg of glucose/kg BW) and an i.v. insulin challenge test (IVICT; .1 IU of ovine insulin/kg BW) were performed during wk 2 and 10 of the trial. This was followed by a N balance trial during wk 3 and 11. Wethers were slaughtered at the end of the experiment and carcass characteristics determined. No differences (P > .10) were observed between dietary treatments in DMI, ADG, or N balance; however, the CrPic-fed wethers had 18% less fat over the 10th rib (P = .082) and a lower yield grade (P = .014). Plasma NEFA was lower throughout the trial (P < .03) and cholesterol was 17% lower during wk 2 (P < .02) in lambs fed CrPic. There were no differences due to diet (P > .10) in plasma concentrations of urea N, glucose, albumin, total protein, insulin, glucagon, triiodothyronine, or thyroxine. Glucose clearance rate and half-life during the IVGTT and IVICT did not differ (P > .10) between CON and CrPic groups; however, during the IVGTT on wk 2, plasma insulin was elevated (P < .05) and glucose reduced (P = .067) in the lambs fed CrPic. Supplemental CrPic seems to influence metabolic measurements that may affect performance of growing lambs.

Two experiments were conducted to evaluate the effect of Cr as Cr tripicolinate (CrPic) on growth, glucose tolerance, insulin sensitivity, plasma metabolites, and growth hormone (GH) in pigs. Pigs were fed a control diet or a diet supplemented with 200 micrograms of Cr/kg of diet as CrPic. Thirty (15 per diet, initial BW was 21.3 kg) and 24 (12 per diet, initial BW was 24.9 kg) crossbred barrows were used in Exp. 1 and 2, respectively. The diets were formulated to provide 120% of the lysine requirement for 20- to 50-kg pigs. A glucose tolerance test (IVGTT; 500 mg of glucose/kg BW) and an insulin challenge test (IVICT; .1 IU of porcine insulin/kg BW) were conducted. In addition, during Exp. 1, a GH-releasing hormone (GHRH) challenge was conducted. All data were pooled across experiments, except where noted. Average daily gain, ADFI, gain/feed, and fasting (15 to 18 h) plasma glucose and total protein concentrations were not affected (P > .10) by dietary treatment. Fasting plasma cholesterol (P < .05) was increased and NEFA (Exp. 2 only, P < .02), urea N (P < .07), and insulin (P < .10) concentrations were decreased in pigs fed CrPic. During the IVGTT and IVICT, glucose disappearance rate (k, percentage/minute) was increased (P < .04) and glucose half-life (t1/2, minutes) was decreased (P < .04) in pigs fed CrPic; however, insulin kinetics were not altered (P > .10). During the GHRH challenge, pigs fed CrPic had decreased (P < .09) area under the response curve for GH.(ABSTRACT TRUNCATED AT 250 WORDS)

Holstein calves, 10 steers (98 +/- 16 kg; Exp. 1) and 14 heifers (122 +/- 7 kg; Exp. 2), were fed either corn-cottonseed hull basal diets (CON; 15.1 and 13.2% CP, respectively) or CON plus 370 micrograms/kg of Cr as Cr-tripicolinate (CrP). After either 58 (Exp. 1) or 56 (Exp. 2) days of ADG and DMI measurement, calves were individually fed 1.4% of their BW every 12 h through the end of each experiment. Nitrogen balance, i.v. glucose tolerance tests (IVGTT), i.v. insulin challenge tests (IVICT), baseline growth hormone (GH) measurements, and GH-releasing hormone challenges were then performed on calves in split groups on d 70 through 87 in Exp. 1. In Exp. 2, all challenges began on d 78 and N balance was not determined. Inclusion of CrP did not affect (P > .10) ADG, DMI, or ADG/DMI of pooled data from Exp. 1 and 2 or N balance criteria in Exp. 1. Plasma glucose, insulin, and NEFA concentrations were not affected (P > .10) by CrP. Total plasma cholesterol was lower (P < .05) for CrP- than for CON-fed calves at wk 4 in Exp. 1 and wk 6 in Exp. 2. During IVGTT, calves fed CrP vs CON had higher (P < .05) clearance rates for glucose in Exp. 1 (2.68 vs 1.88%/min) and in Exp. 2 (2.64 vs 2.08%/min). During IVICT, calves fed CrP vs CON had higher clearance rates for glucose in Exp. 1 (2.98 vs 2.34%/min; P = .12) and in Exp. 2 (2.89 vs 2.00%/min; P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Brewers yeast contains factors that increase and decrease glucose tolerance. Hop components (lupulones) that adhere to yeast during the brewing process elicit a variety of biological effects including the induction of hepatic cytochrome P4503A. Colupulone was tested for its effects on glucose tolerance and cytochrome P450. Serum glucose levels 30 min after the injection of glucose were lowered by colupulone in nondiabetic Swiss-Webster mice, elevated in diabetic C57B1/KSJ-db/db mice, and unaffected in nondiabetic C57B1/KSJ+m/+m mice. Colupulone lowered hemoglobin glycation slightly in +m/+m mice but not in db/db mice. The cytochrome P450 system was highly induced by colupulone in both db/db and +m/+m mice. Chromium, which acts in concert with the factor in yeast that enhances glucose tolerance, had little or no effect on the plasma glucose level or the cytochrome P450 system in either +m/+m or db/db mice.

The present study was conducted to assess the effect of chromium (Cr) administration on glucose tolerance in insulin-dependent diabetes that accompanies hypertension. Four rat groups were used: stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar Kyoto rats (WKY) with and without streptozotocin (SZ, 40 mg/kg)-induced diabetes. Each group of rats was subdivided to the Cr-dose group and the control group. The Cr-dose group, which was intraperitoneally administered Cr solution (20 micrograms trivalent chromium/kg body weight/d for 4 weeks), and the control group (saline) were studied for plasma glucose and plasma insulin during intraperitoneal glucose tolerance test (IPGTT) and insulin action by isolated adipocytes. For diabetic SHRSP showing the highest plasma glucose and lowest plasma insulin among the four groups, Cr administration led to the greatest reduction in plasma glucose without a significant effect on plasma insulin during IPGTT. For each diabetic WKY and normal SHRSP and WKY, those given Cr showed lower levels of plasma glucose with lower levels of plasma insulin than the controls. For diabetic SHRSP, glucose uptake by isolated adipocytes in the Cr-dose group was higher than that in the control group. This effect of Cr administration involved enhancement of insulin responsiveness and sensitivity, attributed to enhanced affinity of the insulin receptor. A similar tendency was observed for diabetic WKY. However, for normal SHRSP and WKY, the increase in glucose uptake due to Cr administration coincided only with enhanced insulin responsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)

Low-molecular-weight, cationic samples, that were previously reported to contain a glucose tolerance factor, were obtained by partial purification from yeast extract. These samples increased the rate of glucose transport in isolated cardiomyocytes 2.0- to 2.5-fold. A further purification by gel filtration led to the separation of two active components that were identified as (i) L-alanine and (ii) an elevated osmolarity. Moreover, the effect of partially purified fractions (before gel filtration) (i) was decreased upon alanine depletion with alanine dehydrogenase and (ii) was mimicked by the additive action of alanine and of a hyperosmolar medium. These findings indicate that the effect of this partially purified material is not accounted for by a putative glucose tolerance factor. Interestingly, alanine elicited its effect at concentrations that correspond to physiological plasma values, which suggests that this amino acid might be involved in the regulation of glucose transport in cardiomyocytes. Furthermore, the effect of alanine was prevented by DL-cycloserine (1 mM) or aminooxyacetate (1 mM), but not by cycloheximide (35 microM), indicating that (a) transamination reaction(s), but not protein synthesis, is required.

The nature of the dietary component responsible for adipocytes having the ability to respond to Glucose Tolerance Factor (GTF) was investigated. Rats were raised on either a control diet or one of three diets differing only in the protein source (torula yeast, brewer's yeast, or casein). Only in adipocytes from rats fed the torula yeast diet did a GTF fraction prepared from brewer's yeast potentiate the action of suboptimal concentrations of insulin in the incorporation of label from D-[1-14C]-glucose and D-[U-14C]-glucose into CO2 and fatty acids. It was concluded that this potentiation was not the result of a deficiency of GTF activity in torula yeast, because a GTF fraction prepared from torula yeast had similar insulin potentiating activity. Differences in response among diets were not owing to differences in levels of amino acids or owing to concentrations of 22 (Al, As, B, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mo, Na, Ni, P, Pb S, Se, Si, Sn, Sr, Zn) of the 23 trace elements investigated. The level of Mn was low in all diets, but particularly low in the torula yeast diet. Mn deficiencies have previously been implicated in perturbations of glucose metabolism, so that it is possible that this deficiency may be responsible for the effects attributed to the torula yeast diet.

The prolonged effects of glucose and insulin on cultured human microvascular endothelial cells from omental tissue (HOMEC) were observed to identify the contribution of sustained hyperglycemia and/or hyperinsulinemia to the pathogenesis of diabetic microangiopathy. When the cells were cultured for 10 days in Medium 199 with 100 or 500 mg/dl glucose, the number of cells was reduced to 78% in the culture of 500 mg/dl glucose as opposed to that of 100 mg/dl glucose. The difference in the number of cells between these two groups became obvious between the 5th and the 7th culture days. The replacement of D-glucose with L-glucose did not show any reduction in the number of cells, indicating the impertinence of high osmolarity, induced by high glucose (305 mOsm/kg) to the number of cells. This reduction resulted from the cellular damage during the culture period rather than the retardation of growth, according to the experiments of [3H]thymidine uptake and the 51Cr release assay. Since the uptake of glucose, measured as the uptake of 3-O-methyl-alpha-D-glucose, was higher and the Na+/K+ pump activity decreased in high glucose condition, it is suggested that the excessive intracellular accumulation of glucose caused the damage of cells through the disturbance of ion exchange. Insulin augmented the reduction in the number of cells induced by high glucose when supplemented together for 10 days at concentrations of 10(-6)-10(-12)M. The uptake of glucose increased further to 154% by the addition of insulin to high glucose as compared to that of high glucose alone, however, the decreased Na+/K+ pump activity by high glucose was restored to the control level by insulin. The aggravating effect of insulin to the cellular damage induced by high glucose seems to be mediation via the mechanism other than the decreased Na+/K+ pump activity. In conclusion, HOMEC were gradually damaged by high glucose and by insulin, and hyperglycemia and hyperinsulinemia would be of pathogenetic importance for diabetic microangiopathy.

Impaired glucose tolerance results from Cr restriction in animals, and Cr supplementation improves glucose tolerance in diabetic animals. These effects are presumably due to the role of Cr in glucose tolerance factor (GTF), a complex of Cr and nicotinic acid believed to facilitate insulin binding. Humans, however, do not uniformly respond to Cr supplementation. The present study was designed to evaluate the possibility that the failure results from inadequate levels of dietary nicotinic acid to serve as substrate for GTF synthesis. Sixteen healthy elderly volunteers were divided into three groups and given either 200 micrograms Cr, 100 mg nicotinic acid, or 200 micrograms Cr + 100 mg nicotinic acid daily for 28 days and evaluated on days 0 and 28. Fasting glucose and glucose tolerance were unaffected by either chromium or nicotinic acid alone. In contrast, the combined chromium-nicotinic acid supplement caused a 15% decrease in a glucose area integrated total (p less than .025) and a 7% decrease in fasting glucose. None of the treatments exerted any effect on fasting or one-hour insulin levels. Thus, these data suggest that the inability to respond to chromium supplementation may result from suboptimal levels of dietary nicotinic acid.

A series of experiments were conducted with turkey poults to ascertain the effects of supplemental chromium or excess of nicotinic acid on growth and carbohydrate metabolism. A 23% protein starter diet was selected to emphasize the effect of chromium under basal, starvation for 48 hr, and refeeding periods. Thirty percent protein diets were also used to determine if the effects were compounded by protein levels. Supplemental chromium (20 ppm) significantly increased (P less than .05) weight at 3 weeks of age of poults consuming 23% protein diets, while an additional 250 ppm of nicotinic acid had little effect on poult weight at 3 weeks (P greater than .05). Supplemental chromium did not increase (P greater than .05) feed consumption of poults consuming both 23 and 30% protein diets. Supplemental chromium increased liver glycogen at 3 weeks of age and following refeeding after the 48 hr fast (P less than .05). Blood glucose was significantly affected by starvation-refeeding (P less than .05) but was not affected by either chromium or nicotinic acid. Supplemental chromium increased (P less than .01) active glycogen synthetase, while nicotinic acid increased (P less than .01) active phosphorylase at both protein levels. Synthetase was not decreased by starvation but was increased (P less than .01) by refeeding regardless of protein level fed. Phosphorylase was not affected by a starvation-refeeding regimen. Chromium supplementation increased in the vitro incorporation of (14C) glucose into glycogen during basal, starvation and refeeding periods (P less than .01), again, regardless of protein level.

The effect of chromium on glucose removal rate (GRR) was investigated in the first 48 hr of life in 22 full-term newborns. Intravenous glucose tolerance test was performed in all babies in the first 24 hr. GRR was found 1.22 +/- 0.17% min. Sixteen of 22 babies received orally 250 micrograms CrCl3 6 H2O and the other six served as controls (no chromium). Intravenous glucose tolerance test was repeated on the 2nd day in all subjects. In the chromium administered group GRR increased from 1.34 +/- 0.19 to 2.58 +/- 0.45% min (P less than 0.01). In the controls, GRR on 2 consecutive days were found 0.90 +/- 0.36 and 2.04 +/- 0.32% min, respectively (P less than 0.05). The ratio of the difference between two GRR values to initial GRR showed no significant difference between the chromium-administered group and the controls. Chromium did not cause a significant change in plasma insulin. The low GRR observed in the newborn irrespective of administered chromium may be taken as evidence that similar to the relative delay in insulin release, the active role of chromium in plasma as glucose tolerance factor may also be inadequate in the early newborn period.

A placebo-controlled double-blind cross-over study was carried out to assess the effect of chromium supplementation (200 micrograms trivalent chromium daily for 6 wk) on glucose tolerance, insulin response, long-term diabetic control, and serum lipids in 10 noninsulin-dependent diabetics aged 37 to 68 yr. After chromium supplementation 24-h urinary chromium excretion showed a 9-fold increase indicating a positive chromium balance in the subjects. There was no significant difference between chromium supplementation and placebo periods in glucose tolerance and in fasting or 2-h postglucose serum insulin levels but the 1-h postglucose serum insulin level was slightly lower on chromium supplementation than on the placebo (55 +/- 9.0 versus 64 +/- 11; p less than 0.01, paired t test). Serum total cholesterol and triglycerides and their high-density, low-density, and very low-density lipoprotein subfractions showed no change after chromium supplementation as compared to the placebo period.

The effects of feeding three levels of dietary chromium (Cr) to non-pregnant guinea pigs, guinea pigs during pregnancy and lactation and F-1 offspring guinea pigs on weight gain, glucose tolerance, glucose peak time value and serum cholesterol concentration has been investigated. Dietary levels of Cr were: Basal Diet (B) = 0.125 ppm; B supplemented with 0.5 ppm Cr (S1 Diet) and B supplemented with 50 ppm Cr (S2 Diet). All groups had similar weight gain patterns and daily feed intake levels. Parent generation guinea pigs fed the B diet consumed less than 10 mug Cr/kg body weight/day while F-U guinea pigs consumed more than this amount. Mortality rates during pregnancy were greater in guinea pigs fed the B diet than in the Cr supplemented groups suggesting a possible protective effect by Dr. Glucose tolerance, glucose peak time values and serum cholesterol appeared to be more affected by pregnancy and generation of guinea pigs than by the level of dietary Cr. Results suggest that species differences may exist between Cr requirements of guinea pigs and rodents for avoiding glucose tolerance.

The effects of 20 ppm chromium (CrCl3.6H2O) and/or 20 ppm vanadium (NaVO3.nH2O) on growth, glucose metabolism, and lipid synthesis in chicks were studied in a 2 X 2 factorial experiment. Chicks were fed experimental diets from day-old to 3 weeks of age. At 3 weeks, four chicks per treatment were injected intraperitoneally (i.p.) with 250 mu Ci 3H2O and 4 mu Ci [U-14C]glucose. Chicks were bled by cardiac puncture and killed 30 min postinjection. Dietary vanadium reduced body and liver weights and liver cholesterol while serum cholesterol was increased. Chromium had no effect on these parameters and there was no significant interaction of chromium with vanadium. Chromium and vanadium each increased 14C incorporation into liver fatty acids over that of controls. However, the combination of chromium and vanadium was without effect so that the interaction was significant. Incorporation of 3H from H2O into liver fatty acids paralleled that of 14C from glucose for all treatments. In vitro studies on the uptake and oxidation of glucose by liver slices from chicks fed the basal diet were conducted. Chromium increased the rate of glucose utilization 16% over control and vanadium increased the rate by 33%. The combination of chromium and vanadium was no different from vanadium alone. A chromium vanadium antagonism was observed in some metabolic processes but not on body or organ weight.

The acute metabolic effects of glucose tolerance factor (GTF), the biologically active form of trivalent chromium, were studied in normal and genetically diabetic (db/db) mice. A single intraperitoneal injection of GTF significantly reduced the nonfasting plasma glucose level in normal mice by 38 per cent, and in diabetic mice by 14 to 29 per cent. Time course studies in normal and diabetic mice showed a maximal lowering of plasma glucose at four hours after GTF treatment. Furthermore, a single injection of GTF significantly lowered the elevated plasma triglyceride and cholesterol levels by 47 and 35 per cent, respectively, four hours after injection. Genetically diabetic mice are refractory to insulin, and treatment with exogenous insulin produced a smaller decrement in plasma glucose (11-18 per cent). The combination treatment of diabetic mice with GTF and exogenous insulin was significantly more effective in reducing plasma glucose (39-51 per cent) and triglycerides (76 per cent) than either treatment alone. These findings are consistent with the suggestion that GTF and insulin act synergistically.

Glucose tolerance factor partially purified from yeast extract powder stimulated [U-14C]-D-glucose uptake to a level 5.6 times greater than the basal level in the absence of insulin in isolated adipocytes prepared from rats fed with normal laboratory chow. The factor also stimulated 3-O-methylglucose transport 2.2-fold from the basal level in the absence of insulin, but not in the presence of 8 nM insulin. Kinetic analysis revealed that glucose tolerance factor increased 3-O-methylglucose transport by decreasing the Ks value for 3-O-methylglucose with little change in the Vmax.

The incorporation of trivalent chromium into S. carlsbergensis as function of time, the effects of chromium and glucose concentrations in the medium on the uptake of 51Cr by the yeast cells, and the effect of chromium on growth of the yeast were studied. 51Cr was taken up by yeast cells most rapidly during the logarithmic growth period in Sabouraud's liquid medium containing 5% glucose. Cells grown in a medium containing only 0.5% glucose at the beginning of cultivation incorporated very little 51Cr, and incorporation ceased when the glucose concentration was reduced to less than 0.1%. Addition of 5% glucose into this culture resulted in a very rapid increase in the 51Cr uptake. The second glucose addition did not notably increase the rate of 51Cr uptake by the yeast. Chromium, reduced yeast growth slightly, however, was not clearly toxic.