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J. Biol. Chem., Vol. 281, Issue 6, 3261-3267, February 10, 2006

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Glucose-stimulated DNA Synthesis through Mammalian Target of Rapamycin (mTOR) Is Regulated by K_ATP Channels

EFFECTS ON CELL CYCLE PROGRESSION IN RODENT ISLETS^*

Guim Kwon, Connie A. Marshall, Hui Liu, Kirk L. Pappan, Maria S. Remedi^¶, and Michael L. McDaniel¹

From the Departments of Pathology and Immunology and ^¶Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110 and the School of Pharmacy, Southern Illinois University, Edwardsville, Illinois 62026

The aim of this study was to define metabolic signaling pathways that mediate DNA synthesis and cell cycle progression in adult rodent islets to devise strategies to enhance survival, growth, and proliferation. Since previous studies indicated that glucose-stimulated activation of mammalian target of rapamycin (mTOR) leads to [³H]thymidine incorporation and that mTOR activation is mediated, in part, through the K_ATP channel and changes in cytosolic Ca²⁺, we determined whether glyburide, an inhibitor of K_ATP channels that stimulates Ca²⁺ influx, modulates [³H]thymidine incorporation. Glyburide (10–100 nM) at basal glucose stimulated [³H]thymidine incorporation to the same magnitude as elevated glucose and further enhanced the ability of elevated glucose to increase [³H]thymidine incorporation. Diazoxide (250 µM), an activator of K_ATP channels, paradoxically potentiated glucose-stimulated [³H]thymidine incorporation 2–4-fold above elevated glucose alone. Cell cycle analysis demonstrated that chronic exposure of islets to basal glucose resulted in a typical cell cycle progression pattern that is consistent with a low level of proliferation. In contrast, chronic exposure to elevated glucose or glyburide resulted in progression from G₀/G₁ to an accumulation in S phase and a reduction in G₂/M phase. Rapamycin (100 nM) resulted in an 62% reduction of S phase accumulation. The enhanced [³H]thymidine incorporation with chronic elevated glucose or glyburide therefore appears to be associated with S phase accumulation. Since diazoxide significantly enhanced [³H]thymidine incorporation without altering S phase accumulation under chronic elevated glucose, this increase in DNA synthesis also appears to be primarily related to an arrest in S phase and not cell proliferation.

Received for publication, August 10, 2005 , and in revised form, December 8, 2005.

^* This work was supported by National Institutes of Health Grant DK-06181 (to M. L. M.), an American Diabetes Association Mentor-based Postdoctoral Fellowship (to M. L. M), and an American Diabetes Association/Takeda Pharmaceuticals Mentor-based Minority Postdoctoral Fellowship (to M. L. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pathology & Immunology, Washington University School of Medicine, Campus Box 8118, 660 South Euclid Ave., St. Louis, MO 63110. Tel.: 314-362-7435; Fax: 314-362-4096; E-mail: mmcdaniel{at}wustl.edu.

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