STRUCTURE AND MECHANISM OF BIOLOGICAL CHROMIUM

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Involvement of chromium in human and animal nutrition is now well established through clinical and nutritional studies. The trace element plays a role in glucose metabolism and may have other essential functions as well. Both acute and chronic human deficiencies are recognized. The elderly are especially susceptible to chromium deficiency, and a large fraction of these glucose-intelerant individuals respond to dietary chromium supplements with improved glucose tolerance. The active chromium complex (or complexes) has not yet been isolated in pure form, and the material remains structurally uncharacterized. The molecular basis of action and biosynthesis pathways are undefined. Long-term goals of this project are to isolate, characterize, synthesize, and elucidate the mechanism of action of the native chromium species. Preliminary efforts by this research group have been directed toward evaluation of the hypothesis that nicotinic acid (niacin) was a part of the active chromium complex. Model compound results provide no evidence to favor this hypothesis. Development of improved isolation methods in this laboratory has allowed purification of two yeast chromium complexes well beyond levels reported by previous investigators. The low-molecular-weight materials have been partially characterized by chemical and spectroscopic techniques. The fractionated chromium complex that is anionic at neutral pH and cationic at acid pH stimulates glucose oxidation by adipocytes, and increases the apparent number of insulin receptors by a factor of 2.5 in a Friend erythroleukemia cellular insulin binding assay. This latter finding has mechanistic significance and is highly relevant to the tiology of maturity-onset diabetes in that loss of insulin receptors and apparent chromium deficiency are common for this condition. Specific project objectives include: (1) further improvements in our chromatographic isolation procedures with extension to mammalian tissues; (2) chemical and spectroscopic characterization of isolated complexes; (3) chemical synthesis of identified low-molecular-weight chromium complexes; (4) improvement of biosynthetic yields; and (5) evalution of three cellular bioassay methods in order to gain mechanistic information and assurance that chromium activity is being measured with high specificity.