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Altered bcl-2 and bax Expression and Intracellular Ca²⁺ Signaling in Apoptosis of Pancreatic Cells and the Impairment of Glucose-Induced Insulin Secretion¹

Department of Metabolism and Clinical Nutrition, Kyoto University School of Medicine, Kyoto; and the Division of Molecular Medicine, Center for Biomedical Science, Chiba University School of Medicine (H.Y., H.K., S.S.), Chiba, Japan

Address all correspondence and requests for reprints to: Nobuhisa Mizuno, M.D., Department of Metabolism and Clinical Nutrition, Kyoto University School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606–01, Japan. E-mail: mizuno{at}metab.kuhp.kyoto-u.ac.jp

Apoptosis is the process of cellular self-destruction, and genes such as bcl-2 and bax are known to inhibit and promote apoptosis, respectively. In this study, we show that apoptosis can be induced in pancreatic ß-cell lines, and we investigate the apoptotic pathways through the bcl-2 and bax genes and intracellular Ca²⁺. Serum deprivation induces apoptosis in the MIN6 and RINm5F pancreatic ß-cell lines, and alters the bcl-2 messenger RNA (mRNA) and protein. KCl, BayK, A23187, and ionomycin elicit an elevation of cytosolic/nuclear Ca²⁺, which, however, is insufficient to evoke apoptosis or to alter bcl-2 or bax mRNA expression in MIN6 cells. The extracellular Ca²⁺ chelators, EGTA and 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, tetrapotassium salt, hydrate, evoke apoptosis and also alter the ratio of bcl-2 to bax mRNA and protein concomitantly with the depletion of cytosolic/nuclear Ca²⁺. This indicates that there are at least two apoptotic pathways in pancreatic ß-cells: through serum deprivation and through a decrease in cytosolic/nuclear Ca²⁺. MIN6 cells exhibit reduced insulin secretion induced by glucose regardless of the molecular pathway of apoptosis. Apoptosis in pancreatic ß-cells, therefore, may be closely related to the impairment of insulin secretion in certain pathological conditions such as diabetes mellitus.

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