Involvement of Ca²+/Calmodulin Kinase Ⅱ (CaMK Ⅱ) in Genistein-Induced Potentiation of Leucine/Glutamine-Stimulated Insulin Secretion
2009
Lee, S.J. (Ajou University School of Medicine, Suwon, Republic of Korea) | Kim, H.E. (Ajou University School of Medicine, Suwon, Republic of Korea) | Choi, S.E. (Ajou University School of Medicine, Suwon, Republic of Korea) | Shin, H.C. (Ajou University School of Medicine, Suwon, Republic of Korea) | Kwag, W.J. (Yuhan Pharmaceutical Research Center, Yongin, Republic of Korea) | Lee, B.K. (Yuhan Pharmaceutical Research Center, Yongin, Republic of Korea) | Cho, K.W. (Anyang University, Incheon, Republic of Korea) | Kang, Y. (Ajou University School of Medicine, Suwon, Republic of Korea), E-mail: [email protected]
Genistein has been reported to potentiate glucose-stimulated insulin secretion (GSIS). Inhibitory activity on tyrosine kinase or activation of protein kinase A (PKA) was shown to play a role in the genistein-induced potentiation effect on GSIS. The aim of the present study was to elucidate the mechanism of genistein-induced potentiation of insulin secretion. Genistein augmented insulin secretion in INS-1 cells stimulated by various energy-generating nutrients such as glucose, pyruvate, or leucine/glutamine (Leu/Gln), but not the secretion stimulated by depolarizing agents such as KCl and tolbutamide, or Ca²+ channel opener Bay K8644. Genistein at a concentration of 50 μM showed a maximum potentiation effect on Leu/Gln-stimulated insulin secretion, but this was not sufficient to inhibit the activity of tyrosine kinase. Inhibitor studies as well as immunoblotting analysis demonstrated that activation of PKA was little involved in genistein-induced potentiation of Leu/Gln-stimulated insulin secretion. On the other hand, all the inhibitors of Ca²+/calmodulin kinase Ⅱ tested, significantly diminished genistein-induced potentiation. Genistein also elevated the levels of [Ca²+]∧i and phospho-CaMK Ⅱ. Furthermore, genistein augmented Leu/Gln-stimulated insulin secretion in CaMK Ⅱ-overexpressing INS-1 cells. These data suggest that the activation of CaMK Ⅱ played a role in genistein-induced potentiation of insulin secretion.
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