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Department of Internal Medicine I, University of Lübeck, Ratzeburger Allee 160, D- 23538 Lübeck, Germany
¹ Department of Internal Medicine, University Clinic Bergmannsheil, Ruhr-University Bochum, Bochum, Germany
² Curschmann-Klinik, Timmendorfer Strand, Germany

(Requests for offprints should be addressed to M Meier; Email: markus.meier{at}uni-luebeck.de)

Calpains are a family of non-lysosomal cytoplasmatic cysteine proteases. Since calpain 10 (CAPN10), a member of the calpain family of proteases, has been found to represent a putative diabetes susceptibility gene, it was argued that calpains may be involved in the development of type 2 diabetes. The functional role of calpains in insulin signaling and/or insulin action is, however, not clear. We investigated the effects of the calpains 1 and 2 inhibitor PD151746 on insulin signaling and insulin action in human hepatoma G2 cells (HepG2). HepG2 cells were incubated without (–PD) or with (+PD) 5.33 µmol/l PD151746 for different times and then stimulated with 100 nmol/l insulin for 0 (t₀), 5 (t₅), 15 (t₁₅), 30 (t₃₀), 45 (t₄₅), and 60 (t₆₀) min. After solubilization of the cells, insulin receptor kinase activity, tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1), IRS-1-associated phosphatidylinositol-3 kinase (PI3-kinase), PI3-kinase activity, Thr³⁰⁸ phosphorlyation of Akt, amount of protein tyrosine phosphatase- (PTP), and glycogen synthase activity were determined. Incubation with PD151746 resulted in a significant reduction of insulin-stimulated glycogen synthesis compared with cells not pre-incubated with the calpain inhibitor (–PD: t₀, 4.90 ± 1.20%; t₅, 5.90 ± 1.02%; t₁₅, 5.29 ± 0.95%; t₃₀, 5.60 ± 1.10%; t₄₅, 5.52 ± 0.90%; t₆₀, 5.67 ± 0.97%;+PD: t₀, 4.56 ± 1.10%; t₅, 6.16 ± 1.05%; t₁₅, 7.52 ± 1.09%; t₃₀, 7.68 ± 1.10%; t₄₅, 8.28 ± 0.89%; t₆₀, 7.69 ± 0.98%; P < 0.05). Incubation with PD151746 significantly increased the protein amount of PTP in the cells after 12 h (–PD: t₁, 0.85 ± 0.18 RU (Relative unit); t₈, 0.87 ± 0.18 RU; t₁₂, 0.9 ± 0.13 RU; +PD: t₁, 0.92 ± 0.21 RU; t₈, 1.1 ± 0.15 RU; t₁₂, 1.34 ± 0.16 RU; P < 0.05). Calpain inhibition with PD151746 had no effect on the insulin stimulation of the investigated insulin signaling parameters. These results in HepG2 cells suggest that calpains play a role in the hepatic regulation of insulin-stimulated glycogen synthesis independent of the PI3-kinase/Akt signaling pathway.