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The Role of Ca²⁺ Influx for Insulin-Mediated Glucose Uptake in Skeletal Muscle

¹ Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
² Department of Physiology and Biocenter Oulu, University of Oulu, Oulun Yliopisto, Finland
³ Biovitrum, Stockholm, Sweden

Address correspondence and reprint requests to Håkan Westerblad, Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77, Stockholm, Sweden. E-mail: hakan.westerblad{at}ki.se

Abbreviations: 2-APB, 2-aminoethoxydiphenyl borate; 2-DG, 2-deoxyglucose; 2-NBDG, 2-(N-[7-nitrobenz-2-oxa-1,3-diazol-4-yl]amino)-2-deoxyglucose; [Ca²⁺]_i, intracellular calcium concentration; [Ca²⁺]_mem, calcium concentration close to cell membrane; EDL, extensor digitorum longus; ERK, extracellular signal–related kinase; FDB, flexor digitorum brevis; MDL, cis-N-(2-phenylcyclopentyl)azacyclotridec-1-en-2-amine; OAG, 1-oleyl-2-acetyl-sn-glycerol; PKB, protein kinase B

The involvement of Ca²⁺ in insulin-mediated glucose uptake is uncertain. We measured Ca²⁺ influx (as Mn²⁺ quenching or Ba²⁺ influx) and 2-deoxyglucose (2-DG) uptake in single muscle fibers isolated from limbs of adult mice; 2-DG uptake was also measured in isolated whole muscles. Exposure to insulin increased the Ca²⁺ influx in single muscle cells. Ca²⁺ influx in the presence of insulin was decreased by 2-aminoethoxydiphenyl borate (2-APB) and increased by the membrane-permeable diacylglycerol analog 1-oleyl-2-acetyl-sn-glycerol (OAG), agents frequently used to block and activate, respectively, nonselective cation channels. Maneuvers that decreased Ca²⁺ influx in the presence of insulin also decreased 2-DG uptake, whereas increased Ca²⁺ influx was associated with increased insulin-mediated glucose uptake in isolated single cells and whole muscles from both normal and insulin-resistant obese ob/ob mice. 2-APB and OAG affected neither basal nor hypoxia- or contraction-mediated 2-DG uptake. 2-APB did not inhibit the insulin-mediated activation of protein kinase B or extracellular signal–related kinase 1/2 in whole muscles. In conclusion, alterations in Ca²⁺ influx specifically modulate insulin-mediated glucose uptake in both normal and insulin-resistant skeletal muscle. Moreover, the present results indicate that Ca²⁺ acts late in the insulin signaling pathway, for instance, in the GLUT4 translocation to the plasma membrane.

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