Activation of Protein Kinase C-zeta in Pancreatic beta-Cells In Vivo Improves Glucose Tolerance and Induces beta-Cell Expansion via mTOR Activation

[摘要]：OBJECTIVE-PKC-zeta activation is a key signaling event for growth factor-induced beta-cell replication in vitro. However, the effect of direct PKC-zeta activation in the beta-cell in vivo is unknown. In this study, we examined the effects of PKC-zeta activation in beta-cell expansion and function in vivo in mice and the mechanisms associated with these effects. RESEARCH DESIGN AND METHODS-We characterized glucose homeostasis and beta-cell phenotype of transgenic (TG) mice with constitutive activation of PKC-zeta in the beta-cell. We also analyzed the expression and regulation of signaling pathways, G1/S cell cycle molecules, and beta-cell functional markers in TG and wild-type mouse islets. RESULTS-TG mice displayed increased plasma insulin, improved glucose tolerance, and enhanced insulin secretion with concomitant upregulation of islet insulin and glucokinase expression. In addition, TG mice displayed increased beta-cell proliferation, size, and mass compared with wild-type littermates. The increase in beta-cell proliferation was associated with upregulation of cyclins D1, D2, D3, and A and downregulation of p21. Phosphorylation of D-cyclins, known to initiate their rapid degradation, was reduced in TG mouse islets. Phosphorylation/inactivation of GSK-3 beta and phosphorylation/activation of mTOR, critical regulators of D-cyclin expression and beta-cell proliferation, were enhanced in TG mouse islets, without changes in Akt phosphorylation status. Rapamycin treatment in vivo eliminated the increases in beta-cell proliferation, size, and mass; the upregulation of cyclins Ds and A in TG mice; and the improvement in glucose tolerance identifying mTOR as a novel downstream mediator of PKC-zeta-induced beta-cell replication and expansion in vivo. CONCLUSIONS PKC-zeta, through mTOR activation, modifies the expression pattern of beta-cell cycle molecules leading to increased beta-cell replication and mass with a concomitant enhancement in beta-cell function. Approaches to enhance PKC-zeta activity may be of value as a therapeutic strategy for the treatment of diabetes. Diabetes 60:2546-2559, 2011

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