MOA Chromium is an essential nutrient involved in the metabolism of glucose, insulin and blood lipids. Its role in potentiating insulin signalling cascades has been implicated in several studies. Chromium upregulates insulin-stimulated insulin signal transduction via affecting effector molecules downstream of the insulin receptor (IR). IR-mediated signalling pathway involves phoshorylation of multiple intracellular domains and protein kinases, and downstream effector molecules [A32353]. Upon activation by ligands, intracellular β-subunit of IR autophosphorylates and activates tyrosine kinase domain of the IR, followed by activation and phosphorylation of regulatory proteins and downstream signalling effectors including phosphatidylinositol 2-kinase (PI3K). PI3K activates further downstream reaction cascades to activate protein kinase B (Akt) to ultimately promote translocation of glucose transporter-4 (Glut4)-vesicles from the cytoplasm to the cell surface and regulate glucose uptake [A32353]. Chromium enhances the kinase activity of insulin receptor β and increases the activity of downstream effectors, pI3-kinase and Akt. ; ; Under insulin-resistant conditions, chromium also promotes GLUT-4 transporter translocation that is independent of activity of IR, IRS-1, PI3-kinase, or Akt; chromium mediates cholesterol efflux from the membranes via increasing fluidity of the membrane by decreasing the membrane cholesterol and upregulation of sterol regulatory element-binding protein [A32353]. As a result, intracellular GLUT-4 transporters are stimulated to translocate from intracellular to the plasma membrane, leading to enhanced glucose uptake in muscle cells [L1990]. Chromium attenuates the activity of PTP-1B _in vitro,_ which is a negative regulator of insulin signaling. It also alleviates ER stress that is observed to be elevated the suppression of insulin signaling. ER stress is thought to activate c-Jun N-terminal kinase (JNK), which subsequently induces serine phosphorylation of IRS and aberration of insulin signalling [A32353]. Transient upregulation of AMPK by chromium also leads to increased glucose uptake [A32353].

ABSORPTION Chromium compounds are both absorbed by the lung and the gastrointestinal tract. Oral absorption of chromium compounds in humans can range between 0.5% and 10%, with the hexavalent (VI) chromium more easily absorbed than the trivalent (III) form [L1982]. Absorption of chromium from the intestinal tract is low, ranging from less than 0.4% to 2.5% of the amount consumed [L1986]. Vitamin C and the vitamin B niacin is reported to enhance chromium absorption [L1986].; ; Most hexavalent Cr (VI) undergoes partial intragastric reduction to Cr (III) upon absorption, which is an action mainly mediated by sulfhydryl groups of amino acids [L1982]. Cr (VI) readily penetrates cell membranes and chromium can be found in both erythrocytes and plasma after gastrointestinal absorption of Cr (IV). In comparison, the presence of chromium is limited to the plasma as Cr (III) displays poor cell membrane penetration [L1982]. Once transported through the cell membrane, Cr (VI) is rapidly reduced to Cr (III), which subsequently binds to macromolecules or conjugate with proteins. Cr (III) may be bound to transferrin or other plasma proteins, or as complexes, such as glucose tolerance factor (GTF).

TOXICITY Oral LD50 for Cr (VI) is 135 - 175 mg/kg in mouse and 46 - 113 mg/kg in rat [L1982]. Oral LD50 for Cr (III) in rat is >2000 mg/kg [L1982]. LD50 of chromium (III) oxide in rats is reported to be > 5g/kg [L1983]. Other LD50 values reported for rats include: 3.5 g/kg (CI 3.19-3.79 g/kg) for chromium sulphate; 11.3 g/kg for chromium (III) acetate; 3.3 g/kg for chromium nitrate; and 1.5 g/kg for chromium nitrate nonahydrate [L1983]. ; ; Acute overdose of chromium is rare and seriously detrimental effects of hexavalent chromium are primarily the result of chronic low-level exposure [L1982]. In case of overdose with minimal toxicity following acute ingestion, treatment should be symptomatic and supportive [L1982]. There is no known antidote for chromium toxicity. ; ; Hexavalent chromium is a Class A carcinogen by the inhalation route of exposure and Class D by the oral route [L1982]. The oral lethal dose in humans has been estimated to be 1-3 g of Cr (VI); oral toxicity most likely involves gastrointestinal bleeding rather than systemic toxicity [L1982]. Chronic exposure may cause damage to the following organs: kidneys, lungs, liver, upper respiratory tract [MSDS]. Soluble chromium VI compounds are human carcinogens. Hexavalent chromium compounds were mutagenic in bacteria assays and caused chromosome aberrations in mammalian cells. There have been associations of increased frequencies of chromosome aberrations in lymphocytes from chromate production workers [L1981]. In human cells _in vitro_, Cr (VI) caused chromosomal aberrations, sister chromatid exchanges and oxidative DNA damage [L1982].