Olanzapine Induced Dysmetabolic Changes Involving Tissue Chromium Mobilization in Female Rats.

Atypical antipsychotics, such as olanzapine, are commonly prescribed to patients with schizophrenic symptoms and other psychiatric disorders. However, weight gain and metabolic disturbance cause adverse effects, impair patient compliance and limit clinical utility. Thus, a better understanding of treatment-acquired adverse effects and identification of targets for therapeutic intervention are believed to offer more clinical benefits for patients with schizophrenia. Beyond its nutritional effects, studies have indicated that supplementation of chromium brings about beneficial outcomes against numerous metabolic disorders. In this study, we investigated whether olanzapine-induced weight gain and metabolic disturbance involved chromium dynamic mobilization in a female Sprague-Dawley rat model, and whether a dietary supplement of chromium improved olanzapine-acquired adverse effects. Olanzapine medicated rats experienced weight gain and adiposity, as well as the development of hyperglycemia, hyperinsulinemia, insulin resistance, hyperlipidemia, and inflammation. The olanzapine-induced metabolic disturbance was accompanied by a decrease in hepatic Akt and AMP-activated Protein Kinase (AMPK) actions, as well as an increase in serum interleukin-6 (IL-6), along with tissue chromium depletion. A daily intake of chromium supplements increased tissue chromium levels and thermogenic uncoupling protein-1 (UCP-1) expression in white adipose tissues, as well as improved both post-olanzapine weight gain and metabolic disturbance. Our findings suggest that olanzapine medicated rats showed a disturbance of tissue chromium homeostasis by inducing tissue depletion and urinary excretion. This loss may be an alternative mechanism responsible for olanzapine-induced weight gain and metabolic disturbance.

Evaluation of titanium dioxide and chromic oxide as digestibility markers in ponies fed alfalfa hay in relation to marker dosing frequency.

In equines, Cr2O3 is widely accepted as an indigestible marker, but there are health concerns regarding the carcinogenic properties of Cr2O3. Recently, TiO2 has been suggested to be an alternative digestibility marker in equines. However, a comparison between Cr2O3 and TiO2 has not been made in equines. Six Welsh pony geldings (initial BW: 254±3 kg; 7 years of age) fed chopped alfalfa hay were used to evaluate the use of TiO2 (Ti) and Cr2O3 (Cr) as markers for calculating apparent digestibility and to investigate the effect of frequency of marker administration on the measurement of digestibility values. Diets contained 4.65 kg dry matter (DM) chopped alfalfa hay supplemented with minerals, vitamins, TiO2 (3.3 g Ti/day) and Cr2O3 (3.2 g Cr/day). Ponies were dosed with either 3.3 g Ti and 3.2 g Cr once daily (DF1) or with 1.65 g Ti and 1.60 g Cr twice daily (DF2). After adaptation to the diets and procedures for 14 days, voluntary voided faeces were collected quantitatively over 7 days and analysed for moisture, ash, Ti and Cr. Apparent total tract DM digestibility (DMD) and organic matter digestibility (OMD) were calculated using the total faecal collection (TFC) and marker method (Ti and Cr). The overall mean cumulative faecal recovery of Cr and Ti (as % of intake) were 102.0% and 96.6%, respectively. Mean daily faecal recoveries of Cr as well as of Ti were not different (P=0.323; P=0.808, respectively) between treatments. Overall daily faecal recovery of Cr differed (P=0.019) from 100% when the marker was dosed once daily, whereas overall daily faecal recovery was similar to 100% for both administration frequencies when Ti was used as a marker. For both markers, the coefficient of variation of the mean faecal marker recovery between horses was lower when the markers were administrated twice per day. Across treatments, cumulative DMD and OMD estimated with Ti were similar (P=0.345; P=0.418, respectively) compared with those values determined by TFC method. When Cr was used, the calculated cumulative DMD tended (P=0.097) to be greater compared with those estimated with TFC, and cumulative OMD values were overestimated (P=0.013). Orally supplemented Ti recovery in the faeces of ponies fed chopped alfalfa hay with Ti administered once or twice daily was close to 100%, making it the preferred marker for digestibility trials in equines.

[Biological significance of chromium III for the human organism]. / Biologiczne znaczenie chromu III dla organizmu czlowieka.

Currently, chromium is probably the most controversial transition metal. In recent publications it is clearly stated that it is not an essential micronutrient and should be considered to have a pharmacological effect. Conflicting scientific reports along with a huge amount of dietary supplements, as well as dietary and sports nutrients available on the market have prompted the authors to investigate the available information on the range of possible application, efficacy and safety of products containing salts or chelates of chromium III. The authors reviewed articles in electronic databases for the years 1959-2016, and selected works describing the biochemical, physiological and toxic properties of chromium salts and chelates and the range of possible applications in medicine, dietetics and sport. A critical analysis of reports dealing with the effect of chromium on the carbohydrate and lipid metabolism, body composition, lean body mass and sports performance was carried out. The authors indicated papers analyzing the mechanism of action of chromium in the cognitive and affective disorders. Much attention has been paid to the safety use of chromium III supplements. There are still some unsolved issues. In the field of toxicology, a limited number of reports about environmental exposure to trivalent chromium in the workplace draws our attention. In the field of biochemical research, there is still a need to clarify the mechanism of psychiatric and endocrinological activity, especially in conjunction with the immune system. Med Pr 2018;69(2):211-223.

Digestibility marker and ileal amino acid digestibility in phytase-supplemented soybean or canola meals for growing pigs.

Two experiments using soybean meal (SBM) or canola meal (CM) were conducted to investigate whether the choice of digestibility marker influenced the apparent ileal digestibility (AID) or standardized ileal digestibility (SID) of N and AA in diets supplemented with phytase. In each experiment, 18 barrows fitted with T-cannulas at the ileocecal junction were assigned to 3 diets consisting of a N-free diet to determine endogenous losses of N and AA, a semipurified diet (SBM in Exp. 1 or CM in Exp. 2), and the semipurified diet supplemented with phytase at 1,000 phytase units/kg. Three digestibility markers including acid-insoluble ash (AIA), chromic oxide (Cr2O3), and titanium dioxide (TiO2) were added to each diet at 3 g/kg. Each diet was fed for 7 d, consisting of a 5-d adjustment and a 2-d collection of ileal digesta. In both studies, basal ileal endogenous losses determined with Cr2O3 as a digestibility marker were lower (P<0.01) than with those determined with AIA or TiO2 digestibility markers. Using SBM as the protein source in Exp. 1, there was no interaction between phytase and digestibility marker on AID or SID of AA. The AID of N and AA in SBM using AIA as a digestibility marker tended to be lower (P<0.1) compared with Cr2O3 or TiO2 digestibility markers. Phytase supplementation increased (P<0.001) the AID of Ca and P. The use of AIA or Cr2O3 digestibility marker tended to be associated with lower (P<0.1) SID values compared with TiO2. Phytase did not affect the SID of N or any AA in SBM except for Met, for which there was an increase (P<0.05) with phytase supplementation. Using CM as the protein source in Exp. 2, there were significant interactions between digestibility marker and phytase. Phytase supplementation had effects (P<0.01) on AID or SID when Cr2O3 or TiO2 was used as the digestibility marker. With Cr2O3 or TiO2 as the digestibility marker in the CM diets, phytase supplementation increased (P<0.05) the SID of N and all AA (except Trp). There was no SID of N or AA response to phytase supplementation of CM when AIA was used as a digestibility marker. In contrast, there were no clear improvements in AA digestibility from phytase supplementation for SBM. Phytase effects on AID or SID of AA were dependent on the digestibility marker used in diets when CM was used as the protein source but not when SBM was used as the protein source. Therefore, AA digestibility response to phytase supplementation may depend on the protein being evaluated as well as the choice of digestibility marker.

Comparison of direct and indirect estimates of apparent total tract digestibility in swine with effort to reduce variation by pooling of multiple day fecal samples.

The intent of this study was to establish a fecal sampling procedure for the indicator method (IM) to provide digestibility values similar to those obtained by the total collection (TC) method. A total of 24 pigs (52.6 ± 1.5 kg) were fed 1 of 4 diets with a 2 × 2 factorial arrangement of virginiamycin and phytase (PHY) added to a corn-soybean meal diet with no inorganic P supplement. Pigs were housed in metabolism crates for a 5-d TC period after 7 d of adaptation. Immediately after the TC, a fecal collection period followed, using the IM by including 0.25% of Cr2O3 in the feed for 10 d. Fecal collection for the IM started the day after diets containing Cr2O3 were first fed, and continued for 9 consecutive days with a single grab sample per day. Similar portions of feces from d 5 to 9 were also composited into 4 samples to evaluate multi-day pooling combinations. Highly variable means and CV among samples for apparent total tract digestibility (ATTD) were observed at d 1 and 2 using the IM. The mean ATTD for DM, GE, and nutrients appeared to be stabilized by d 5 or 6 in all dietary treatments. The TC data seemed to have lower CV than the IM data for many components. Based on the linear broken-line analysis, fecal Cr concentration plateaued at d 3.75 (P < 0.001) after the first feeding of Cr. Mean ATTD values by the IM were lower than those by the TC method for DM (P < 0.05), GE (P < 0.01), P (P < 0.01), and Ca (P < 0.001). The PHY supplementation improved ATTD of P (P < 0.001) and Ca (P < 0.001) in both collection methods, whereas the PHY effect on ATTD of DM was observed only for the IM (P < 0.05). Differences related to PHY effect on ATTD were detected from d 4 to 9 in a single grab sample for P and DM but the ATTD of DM had inconsistent P-values by day. Fecal sampling after 4 d of initial feeding of marker always allowed detection of treatment effects on ATTD of P but not on ATTD of DM. Results indicated that the IM results in lower digestibility values than the TC method and does not provide the same treatment difference as the TC digestibility for energy and nutrients that are not highly impacted by the dietary treatment. For the IM, ATTD values and fecal Cr concentration stabilize at least on d 5 after initial feeding of diets containing Cr2O3. At least 2-d pooling of feces for the IM appears to be needed to provide greater accuracy and lower variations than a single grab sample.

Chromium: is it essential, pharmacologically relevant, or toxic?

Over fifty years ago, the element chromium (as the trivalent ion) was proposed to be an essential element for mammals with a role in maintaining proper carbohydrate and lipid metabolism. Evidence for an essential role came from dietary studies with rodents, studies on the effects of chromium on subjects on total parenteral nutrition, and studies of the absorption and transport of chromium. Over the next several decades, chromium-containing nutritional supplements became so popular for weight loss and muscle development that sales were second only to calcium among mineral supplements. However, the failure to identify the responsible biomolecules(s) that bind chromium(III) and their mode of action, particularly a postulated species named glucose tolerance factor or GTF, resulted in the status of chromium being questioned in recent years, such that the question of its being essential needs to be formally readdressed. At the same time as chromium(III)'s popularity as a nutritional supplement was growing, concerns over its safety appeared. While chromium has been conclusively shown not to have beneficial effects on body mass or composition and should be removed from the list of essential trace elements, chromium(III) compounds are generally nontoxic and have beneficial pharmacological effects in rodents models of insulin insensitivity, although human studies have not conclusively shown any beneficial effects. Mechanisms have been proposed for these pharmacological effects, but all suffer from a lack of consistent supporting evidence.

Marker type but not concentration influenced apparent ileal amino acid digestibility in phytase-supplemented diets for broiler chickens and pigs.

Two experiments were conducted to investigate whether the choice of digestibility marker or marker concentration in corn-soybean meal diets influence apparent ileal AA digestibility (AIAAD) or the potential phytase-induced improvement in AIAAD in broiler chickens and pigs. One hundred ninety-two, 42-d-old, Ross 708 broilers were used in a 7-d study in Exp 1. The birds were allocated to 6 dietary treatments in a 2 × 3 factorial arrangement of treatments in a split-plot design. The factors were a combination of chromic oxide and titanium dioxide (0.3% or 0.5% of both markers, as-fed basis), and 3 levels of phytase inclusion [0, 500, or 1,000 phytase units (FTU)/kg]. In Exp. 2, 6 barrows fitted with a simple T-cannula at the distal ileum were allocated to 4 diets in a 6 × 4 Youden square design and 2 × 2 factorial arrangement of treatments. The factors were similar to Exp. 1, except the 500-FTU/kg phytase level was not used in Exp. 2. There were no marker type × marker concentration, phytase × marker type, or phytase × marker type × marker concentration interactions for any of the AA in either experiment. On average, AIAAD values calculated using Ti was greater (P < 0.05) than those calculated using Cr, regardless of the phytase inclusion level in both experiments. In Exp. 1, AIAAD values for His, Trp, Cys, and Pro were greater (P < 0.05) at the 0.3% than 0.5% marker concentration. The AIAAD values were consistently greater when calculated using Ti compared with Cr, irrespective of phytase level. It is concluded that the type of marker used does not influence whether a response to phytase supplementation, in terms of AIAAD, is observed.

Efficacy of dietary chromium (III) supplementation on tissue chromium deposition in finishing pigs.

The study was conducted to evaluate the efficacy of different forms of trivalent chromium (Cr) supplementation on tissue chromium deposition in finishing pigs. A total of 96 pigs with an initial average body mass 65.57±1.05 kg were blocked by body mass and randomly assigned to four treatments with three replicates. Pigs were offered one of four diets including a control diet or the control diet supplemented with 200 µg/kg chromium from either chromium chloride (CrCl(3)), chromium picolinate (CrPic) or chromium nanocomposite (CrNano) for 40 days. During the trial, all pigs were given free access to feed and water. After feeding trial, eight pigs from each treatment were slaughtered for samples collection. The results showed that supplemental CrNano increased Cr content in blood, longissimus muscle, heart, liver, kidney, jejunum, and ileum (P<0.05). Supplemental Cr from three sources increased Cr excretion from all feces (P<0.05). Urinary Cr excretion was increased by CrNano or CrPic supplementation significantly. These results suggested that chromium nanocomposite exhibited more effective on tissue Cr deposition in pigs, which indicated higher absorption compared with CrCl(3) and CrPic.

The effect of microelements supplementation on beta-oxidation activity in healthy and type 1 diabetic rats.

Diabetes mellitus type 1 disease changes the activity of fatty acid degradation as compared to healthy animals. Supplementation in vitro with microelements chromium Cr3+ and selenium Se4+ and Se2- in non-toxic ([96.15 pmol (5 ppm) for chromium and 6.33 micromol (0.5 ppm) for selenium] concentrations strongly stimulates the activity of this process in diabetic rats. In healthy animals only chromium Cr3+ in concentration of 96.15 micromol (5 ppm) stimulated beta-oxidation activity in lymphocytes. It may indicate the beneficial effect of supplementation of the diet with microelements, chromium Cr3 and selenium Se4+ or Se2- at concentrations as low as 100 micromol for chromium and 6 micromol for selenium, respectively.

Comparison of acute absorption of commercially available chromium supplements.

Chromium (Cr) supplements are available as picolinate, nicotinate or chloride (the latter primarily in multivitamin-mineral supplements). The picolinate form has been reported to be the best absorbed and most efficacious, but some reports question which form has superior absorption. The present study examined acute Cr absorption, based on 24h urinary Cr values, for picolinate, two types of nicotinate, and chloride in young adult, non-overweight females. College-aged women were given 200 microg of Cr as each of the four supplement types in random order accompanied by a small standardized meal, separated by at least a week washout. Cr picolinate produced significantly higher 24h urinary Cr than either of two nicotinate supplements or Cr chloride given in a multivitamin-mineral supplement. This difference was seen for absolute values of the urinary Cr and for percent increases. In conclusion, based on an indirect measure of acute absorption, Cr picolinate was superior to three other Cr complexes commonly sold as supplements.

Determination of true digestive utilization of phosphorus and the endogenous phosphorus outputs associated with soybean meal for growing pigs.

The objectives of this study were to determine true P digestibility, the gastrointestinal endogenous P outputs associated with soybean meal (SBM), and the role of the large intestine in P digestion in growing pigs. Four Yorkshire barrows, with average initial and final BW of 40 and 58 kg, were fitted with a simple T-cannula at the distal ileum and fed four diets according to a 4 x 4 Latin square design. The diets were cornstarch-based and contained four levels of P (0.098, 0.196, 0.293, and 0.391% on a DM basis) from solvent-extracted conventional SBM. Chromic oxide (3.5 g/kg of diet, as-fed basis) was included as a digestibility marker. Each experimental period consisted of 8 d with a 4-d adaptation period and a 4-d collection of representative ileal digesta (2 d) and fecal (2 d) samples. True ileal and fecal P digestibility values and the ileal and fecal endogenous P outputs associated with SBM were determined by the regression analysis technique. There were no differences (P > 0.05) in true P digestibility values (ileal, 59.0 +/- 8.3 vs. fecal, 51.3 +/- 7.9%, n = 16) and endogenous P outputs (ileal, 0.59 +/- 0.18 vs. fecal, 0.45 +/- 0.21 g/kg of DMI, n = 16) between the ileal and the fecal levels. The endogenous fecal P loss accounted for 8.1 and 17.6% of the NRC (1998) recommended total and available P requirements in growing pigs, respectively. In conclusion, approximately 51% of the total P in conventional SBM is digested in growing pigs. The large intestine does not play an important role in the digestion of P associated with SBM in the growing pig. The fecal loss of the gastrointestinal endogenous P is an important route of P excretion in the growing pig.

Cytotoxicity and oxidative mechanisms of different forms of chromium.

Chromium exists mostly in two valence states in nature: hexavalent chromium [chromium(VI)] and trivalent chromium [chromium(III)]. Chromium(VI) is commonly used in industrial chrome plating, welding, painting, metal finishes, steel manufacturing, alloy, cast iron and wood treatment, and is a proven toxin, mutagen and carcinogen. The mechanistic cytotoxicity of chromium(VI) is not completely understood, however, a large number of studies demonstrated that chromium(VI) induces oxidative stress, DNA damage, apoptotic cell death and altered gene expression. Conversely, chromium(III) is essential for proper insulin function and is required for normal protein, fat and carbohydrate metabolism, and is acknowledged as a dietary supplement. In this paper, comparative concentration- and time-dependent effects of chromium(VI) and chromium(III) were demonstrated on increased production of reactive oxygen species (ROS) and lipid peroxidation, enhanced excretion of urinary lipid metabolites, DNA fragmentation and apoptotic cell death in both in vitro and in vivo models. Chromium(VI) demonstrated significantly higher toxicity as compared with chromium(III). To evaluate the role of p53 gene, the dose-dependent effects of chromium(VI) were assessed in female C57BL/6Ntac and p53-deficient C57BL/6TSG p53 mice on enhanced production of ROS, lipid peroxidation and DNA fragmentation in hepatic and brain tissues. Chromium(VI) induced more pronounced oxidative damage in multiple target organs in p53 deficient mice. Comparative studies of chromium(III) picolinate and niacin-bound chromium(III), two popular dietary supplements, reveal that chromium(III) picolinate produces significantly more oxidative stress and DNA damage. Studies have implicated the toxicity of chromium picolinate in renal impairment, skin blisters and pustules, anemia, hemolysis, tissue edema, liver dysfunction; neuronal cell injury, impaired cognitive, perceptual and motor activity; enhanced production of hydroxyl radicals, chromosomal aberration, depletion of antioxidant enzymes, and DNA damage. Recently, chromium picolinate has been shown to be mutagenic and picolinic acid moiety appears to be responsible as studies show that picolinic acid alone is clastogenic. Niacin-bound chromium(III) has been demonstrated to be more bioavailable and efficacious and no toxicity has been reported. In summary, these studies demonstrate that a cascade of cellular events including oxidative stress, genomic DNA damage and modulation of apoptotic regulatory gene p53 are involved in chromium(VI)-induced toxicity and carcinogenesis. The safety of chromium(III) is largely dependent on the ligand, and adequate clinical studies are warranted to demonstrate the safety and efficacy of chromium(III) for human consumption.

Coconut oil as a protective carrier of dietary vitamin A fed to ruminants.

Safflower and coconut oil were compared as protective carriers of dietary vitamin A supplemented to abomasally cannulated sheep. Vitamin A, 240,000 I.U., was predissolved in 11.7 g of safflower or coconut oil and bolused directly into the rumen of mature wethers along with 4 g of chromic oxide. The vitamin A was pre-dissolved in 0, 11.7, 23.4 or 35.0 g of coconut oil in experiment 2. Determination of carrier oil protectiveness of solubilized dietary vitamin A was based on recoveries of vitamin A supplement and chromic oxide in abomasal digesta 24 h post dosage. Vitamin A recoveries were significantly higher (P < 0.05) when dissolved in coconut oil (55.6%) compared to safflower oil (35.5%). Recoveries of vitamin A in abomasal digesta increased linearly (P < 0.01) with the amount of carrier coconut oil in experiment 2. Results of these experiments support the potential use of coconut oil as a protective carrier of ruminal labile vitamin A.