Enhancement of post‐receptor insulin signaling by trivalent chromium in hepatoma cells is associated with differential inhibition of specific protein‐tyrosine phosphatases

Abstract

Various molecular forms of chromium have been implicated in the regulation of glucose metabolism, and chromium deficiency can be associated with insulin resistance and impaired glucose tolerance. Protein-tyrosine phosphatases (PTPases), which negatively regulate signaling through the insulin receptor, are potential targets of chromium action, since this transition metal may inhibit catalysis at the thiol-dependent active sites of these enzymes. Treatment of cultured rat hepatoma cells with 0.1 mM CrCl 3 for 16 h increased the insulin-stimulated tyrosine phosphorylation of high M r insulin receptor substrate (IRS) proteins by 49% to 7.3-fold over basal (n ‫ס‬ 7; P ‫ס‬ 0.03), without altering basal insulin receptor or IRS tyrosine phosphorylation or insulin-stimulated receptor autophosphorylation, suggesting a post-receptor effect of chromium on signal transduction. PTPase activity in cell extracts of CrCl 3 -treated hepatoma cells before or after insulin stimulation was unchanged, indicating that if chromium acted via cellular PTPases, the effect was reversible and limited to the in vivo state. Chromium (Cr +3 ) ion and two organic derivatives, an oligopeptide chromium complex from bovine liver (Cr-pep), and a synthetic multinuclear complex of chromium with carboxylate ligands (Sm-Cr) were also tested for their direct in vitro inhibition of the enzymatic activity of LAR and PTP1B, two structurally variant PTPases that have been implicated in regulation of the insulin signaling pathway. PTP1B (rat and human) was strongly inhibited by CrCl 3 to 21-33% of control (n ‫ס‬ 4-6; P < 0.001). In contrast, LAR activity was actually enhanced by CrCl 3 to 47% above the control value (n ‫ס‬ 12; P < 0.001). The Cr-pep and Sm-Cr complexes had no effect on PTP1B and LAR activity at the tested concentrations using the pNPP assay. These data suggest that the metabolic effects of chromium may be mediated by inhibition of PTP1B, a PTPase that negatively modulates insulin signaling, consistent with other recent studies implicating PTP1B in the regulation of the dephosphorylation of post-insulin receptor substrate proteins.

A newly synthetic chromium complex – chromium(phenylalanine)3 improves insulin responsiveness and reduces whole body glucose tolerance

“…However, the mechanism by which chromium enhances insulin-stimulated Akt phosphorylation is unclear. One potential explanation could be the inhibition of the enzyme phosphotyrosine phosphatase (PTP-1B) by chromium, which is a known negative regulator of insulin signaling [27].…”

Evidence for Use of Chromium in Treatment of Pre-Diabetes

“…Vincent's group found that LMWCr (complete with Cr) enhanced phosphatase activity (although not necessarily PTP-1B) in adipocyte membranes but did see a significant reduction in activity with Cr in PTP-1B in rat hepatoma cells. 81,82 In addition, Wang et al saw reductions in both expression and activity of PTP-1B in the skeletal muscle of obese rats treated with Cr picolinate. 17 Insulin Receptor Substrate 1 (IRS-1) can also be phosphorylated on a specific serine residue which prevents it from activating PI3K so reducing insulin signaling.…”