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2 Chromium and Metabolism Chromium (Cr) potentiates the action of insulin via the glucose tolerance factor (GTF) (Mertz, 1993a). Although the way in which this potentiation occurs has not been determined, Mertz et al. (1974) hypothesized that chromium forms a complex with insulin and insulin receptors to facilitate the response of insulin-sensitive tissues. Anderson et al. (1990) demonstrated that suboptimal intake of chromium by humans leads to detrimental changes in glucose, insulin, and glucagon status of subjects with slightly impaired glucose tolerance. Re- search results presented by Govindaraju et al. (1989) did not support the postulate that trivalent Cr+3 serves to assemble insulin and its receptor through metal-sulfur bonding, but indicated that chromium stabilizes the structure of insulin and af- fects its state of aggregation to influence the biopotency of the hormone. In summarizing results of several experiments with humans, rats, mice, and other species, Anderson (1994) presented a list of physiological and biochemical symptoms of chromium deficiencies that strongly suggest chromium is an essen- tial nutrient (Table 2-1~. Other indications suggesting that chromium is essential in the diets of food- producing animals are presented later in this report. Because there is no accurate measure of chromium status, daily chromium requirements for animals, includ- ing humans, have been difficult to define. One measure of sufficiency has been to determine whether glucose tolerance is improved with chromium supplemen- tation. Moreover, the form of dietary chromium determines biological activity, and GTF in brewer's yeast has the highest bioavailability (Toepfer et al., 1973~. A range of chromium intake between 50 and 200 ,ug/day is recommended for adult humans (National Research Council, 1989~. 10
CHROMIUM AND MEIA:BOLISM TABLE 2-1. Signs and Symptoms of Chromium Deficiency Species 11 Function Impaired glucose tolerance Elevated circulating insulin Glycosuria Fasting hyperglycemia Impaired growth Hypoglycemia Elevated serum cholesterol and triacylglycerols Increased incidence of aortic plaques Increased aortic intimal plaque area Neuropathy Encephalopathy Corneal lesion Ocular eye pressure Decreased fertility and sperm count Decreased longevity Decreased insulin binding Decreased insulin receptor number Decreased lean body mass Elevated percentage body fat Enhanced humoral immune response Morbidity Human, rat, mouse, squirrel 1 · . monkey, guinea pig Human, rat, pig Human, rat Human, rat, mouse Human, rat, mouse, turkey Human Human, rat, mouse, cattle, pig Rabbit, rat, mouse Rabbit Human Human Rat, squirrel monkey Human Rat Rat, mouse Human Human Human, pig, rat Human, pig Cattle Cattle Source: Anderson, 1994 CARBOHYDRATE METABOLISM The first suggestion that chromium participates in carbohydrate metabolism in animals was the report of Schwarz and Mertz (1957~. They observed that GTF, which was shown later to contain chromium (Schwarz and Mertz, 1959), was deficient in animals with impaired glucose tolerance, and that supplemental chro- mium improved glucose tolerance (Schwarz and Mertz, 1959~. Although GTF seems to contain nicotinic acid, glycine, glutamic acid, and cysteine in addition to chromium, synthetic complexes have markedly less insulin-potentiating activity than does the naturally occurring complex (Anderson et al., 1978~. Thus, the exact structure of the native insulin-potentiating complex has not been deter- mined. Glucose uptake, glucose use for lipogenesis, glucose oxidation to carbon dioxide, and glycogenesis increase because of the addition of chromium plus insulin to animal tissues (Anderson, 1987~. Chromium alone was ineffective. Also, the low-molecular-weight, chromium-binding substance present in milk enhanced glucose oxidation and lipogenesis from glucose (Yamamoto et al., 1988, 1989~. The effect of the substance on glucose metabolism was decreased markedly when chromium was removed.
12 THE ROLE OF CHROMIUM INANIMA:L NUTRITION Chromium supplementation of several human patients receiving total parenteral nutrition and afflicted with a variety of disorders in glucose metabo- lism, such as diabetes-like symptoms, caused glucose metabolism to return to normal (Jeejeebhoy et al., 1977~. Because of this benefit of supplemental chro- mium, the American Medical Association recommends daily supplementation of total parenteral nutrition solutions with 10 to 15 ,ug of Cr+3 to stable adults with intestinal fluid losses. There also have been observations of a syndrome resem- bling diabetes mellitus being cured by chromium supplementation, indicating that a decreased sensitivity of peripheral tissues to insulin is the primary bio- chemical lesion in chromium deficiency (Anderson et al., 1996a). Chromium increases or potentiates the activity of insulin but does not substitute for the anabolic hormone. Anderson (1987) cited numerous case studies with humans in which glucose tolerance and other measures of glucose metabolism were improved with chro- mium supplementation. Moreover, supplemental dietary chromium (200 or 1,000 ,ug/day) had beneficial effects on cholesterol, glycosylated hemoglobin, glucose, and insulin in blood of humans with type II diabetes (Anderson et al., 1996a). Improvements were not always observed, probably because chromium status was adequate without chromium supplementation or because other Biological factors were involved. LIPID METABOLISM Numerous studies suggest that chromium is necessary for normal lipid metabolism and for minimizing rates of atherogenesis. For example, rats and rabbits fed low-chromium diets had greater concentrations of serum cholesterol and aortic lipids and exhibited greater plaque formation (Abraham et al., 1982a,b). Chromium supplementation decreased cholesterol concentrations. Newman et al. (1978) reported that humans who died of coronary artery disease had low chromium concentration in aortae but not in other tissues. Increases in high-density lipoprotein (HDL) cholesterol (Anderson, 1 995; Riales and Albrink, 1981~; and decreases in total cholesterol, low density lipoprotein (LDL) cholesterol, and triacylglycerols (Anderson, 1995; Lefavi et al., 1993) in humans have been reported to occur after chromium supplementation. Ander- son (1987) indicates that the effects of chromium supplementation on blood lipids in humans are not always consistent; effects on lipid metabolism seem independent of effects on glucose metabolism (Lefavi et al., 1993~. Blood lipids of humans with the greatest concentrations of blood cholesterol and triacylglycerols decrease the most after chromium supplementation. Because many factors cause elevated blood lipids, only those hyperlipemic individuals with marginal chromium status would be candidates for improvements in clini- cal status by chromium supplementation.
CHROMIUM AND MEIA:BOLISM 13 PROTEIN METABOLISM Because of the role of insulin in amino acid uptake by animal tissues, chro- mium is predicted to interact with protein biosynthesis. Roginski and Mertz (1969) reported that chromium supplementation increased amino acid incorpora- tion into heart proteins and amino acid uptake into tissues of rats. No other studies of an effect of chromium on protein synthesis or turnover have been reported. NUCLEIC ACID METABOLISM Chromium in the trivalent oxidation state seems to be involved in the struc- tural integrity and expression of genetic information in animals. The bonding of chromium to nucleic acids is tighter than is that of other metal ions (Okada et al., 1982~. Chromium protects ribonucleic acid (RNA) against heat denaturation. Moreover, chromium seems to concentrate in the nuclei of animal cells. Support- ing the hypothesis that it affects gene function, chromium has been shown to enhance RNA synthesis in mice in vitro (Okada et al., 1982) and in vivo (Okada et al., 1983~. With the use of the regenerating rat liver model, nucleic-acid- enhancing activity was associated with a 70,000 dalton protein that contained 5 to 6 chromium ions (Okada et al., 1984~. STRESS Chromium status of animals seems to be influenced by physiological, patho- logical, and nutritional stresses. For example, exercise (Anderson et al., 1982) and trauma (Borer and Anderson, 1984) increased urinary chromium of humans and thereby could contribute to chromium deficiency. Symptoms of chromium deficiency are aggravated by a low-protein diet, exercise, blood loss, and infec- tion (Mertz and Roginski, 1969; Roginski and Mertz, 1969~. The intriguing possibility that supplemental chromium increases longevity and retards aging by improving immune function and enhancing resistance to infectious diseases is being investigated (Burton et al., 1996~. Several studies summarized by Burton (1995) indicate that supplemental dietary chromium for market-transit-stressed feedlot calves and periparturient and early-lactation dairy cows improves milk production, immune status, and health. CHROMIUM TOXICITY Chromium salts are strong oxidizing agents used, for example, in alloying and tanning, and in the manufacture of rust- and corrosion-resistant paints. Work- ers exposed to high concentrations of these compounds suffer from chromium toxicity, and their symptoms include eczematous dermatitis, ulceration of skin,
4 THE ROLE OF CHROMIUM IN ANIMAL NUTRITION lung cancer, gastroenteritis, nephritis, and hepatitis. Chromium toxicity is prima- rily associated with exposure to hexavalent Cr+6 compounds rather than to Cr+3 compounds, which have relatively low toxicity. The difference in toxicity be- tween the two forms arises because of the relative ease with which Cr+6 is ab- sorbed by cells. Unlike Cr+3, Cr+6 is taken up easily, probably through an ion transport system (Jennette, 1979~. Thus, extracellular reduction of Cr+6 to Cr+3 currently is perceived as a protective action (DeFlora and Wetterhahn, 1989~. Inside the cell, reduction of Cr+6 could be a mechanism for detoxification as well as for activation (Alexander, 1993~. Some of the chromium species formed become long-lived coordinated complexes that can migrate from the cytoplasm to the nucleus and damage the deoxyribonucleic acid (DNA) therein. Several enzymes and low-molecular-weight compounds participate in the reduction pro- cess (Alexander, 1993~. Ascorbate and thiol-reducing-containing reductants, such as glutathione and cysteine, are likely nonenzymatic reductants (Alcedo and Wetterhahn, 1990; DeFlora and Wetterhahn, 1989; Standeven and Wetterhahn, 1991~. Among enzymatic proteins, the endoplasmic P450 and the ethanol- inducible P450IIE1 have been shown to reduce Cr+6 in vitro (Mikalsen et al., 1991~. Hexavalent chromium also can penetrate the mitochondrial membrane and be reduced (Ryberg and Alexander, 1984, 1990~. Although Cr+6 can react at several places within the cell, the toxic effects seem specific. Excess cellular Cr+6 causes a dramatic depression of mitochondrial oxygen consumption, evi- dently because of an inhibition of the oc-ketoglutarate dehydrogenase that sup- plies the respiratory chain with reduced nicotinamide adenine dinucleotide (Ryberg and Alexander, 1990~. Several DNA lesions also can be observed after Cr+6 exposure; for example, DNA strand breaks, DNA interstrand cross-links, DNA-protein cross-links, and nucleotide derivatives caused by reactive oxygen species can be formed and cause abnormal phenotypes (Alexander, 1993~. For livestock, the National Research Council (1980) set the maximum toler- able concentrations of chromium in the diet at 3,000 ppm for the oxide and 1,000 ppm for the chloride form. Both forms are present as Cr+3. Hexavalent forms are more soluble than are Cr+3 forms, and they are at least five times more toxic.