A newly synthetic chromium complex—Chromium (d-phenylalanine)3 activates AMP-activated protein kinase and stimulates glucose transport

We synthesized the chromium (phenylalanine)3 [Cr(d-phe)3] by chelating chromium(III) with d-phenylalanine ligand in aqueous solution to improve the bioavailability of chromium, and reported that Cr(d-phe)3 improved insulin sensitivity. AMP-activated protein kinase (AMPK) is a key mediator for glucose uptake and insulin sensitivity. To address the molecular mechanisms by which Cr(d-phe)3 increases insulin sensitivity, we investigated whether Cr(d-phe)3 stimulates glucose uptake via activation of AMPK signaling pathway. H9c2 myoblasts and isolated cardiomyocytes were treated with Cr(d-phe)3 (25 μM). Western blotting was used for signaling determination. The glucose uptake was determined by 2-deoxy-d-glucose-3H accumulation. HPLC measured concentrations of AMP. The mitochondrial membrane potential (Δψ) was detected by JC-1 fluorescence assay. Cr(d-phe)3 stimulated the phosphorylation of α catalytic subunit of AMPK at Thr172, as well the downstream targets of AMPK, acetyl-CoA carboxylase (ACC, Ser212) and eNOS (Ser1177). Moreover, Cr(d-phe)3 significantly stimulated glucose uptake in both H9c2 cells and cardiomyocytes. AMPK inhibitor compound C (10 μM) dramatically inhibited the glucose uptake stimulated by Cr(d-phe)3, while it did not affect insulin stimulation of glucose uptake. Furthermore, in vivo studies showed that Cr(d-phe)3 also activated cardiac AMPK signaling pathway. The increase of cardiac AMP concentration and the decrease of mitochondrial membrane potential (Δψ) may contribute to the activation of AMPK induced by Cr(d-phe)3. Cr(d-phe)3 is a novel compound that activates AMPK signaling pathway, which contributes to the regulation of glucose transport during stress conditions that may be associated the role of AMPK in increasing insulin sensitivity.