期刊
DIABETES
卷 58, 期 3, 页码 663-672出版社
AMER DIABETES ASSOC
DOI: 10.2337/db07-1208
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资金
- NIDDK NIH HHS [DK-07296, R56 DK006181, T32 DK007296, DK-56341, R01 DK006181, P30 DK056341-07, P30 DK056341, P30 DK056341-08, DK-006181] Funding Source: Medline
OBJECTIVE-Our previous studies demonstrated that nutrient, regulation of mammalian target of rapamycin (mTOR) signaling promotes regenerative processes in rodent islets but rarely in human islets. Our objective was to extend these findings by using therapeutic agents to determine whether the regulation of glycogen synthase kinase-3 (GSK-3)/beta-catenin and mTOR signaling represent, key components necessary for effecting a positive impact on human P-cell mass relevant to type 1 and 2 diabetes. RESEARCH DESIGN AND METHODS-Primary adult human and rat islets were treated with the GSK-3 inhibitors, LiCl and the highly potent 1-azakenpaullone (1-Akp), and with nutrients. DNA synthesis, cell cycle progression, and proliferation of beta-cells were assessed. Measurement of insulin secretion and content and Western blot analysis of GSK-3 mid mTOR signaling components were performed. RESULTS-Human islets treated for 4 days with LiCl or 1-Akp exhibited significant increases in DNA synthesis' cell cycle progression, and proliferation of beta-cells that displayed varying degrees of sensitivity to rapamycin. Intermediate glucose (8 mmol/l) produced a striking degree of synergism in combination with GSK-3 inhibition to enhance bromodeoxyruidine (BrdU) incorporation mid Ki-67 expression in human beta-cells. Nuclear translocation of beta-catenin responsible for cell proliferation was found to be particularly sensitive to rapamycin. CONCLUSIONS-A combination of GSK-3 inhibition and nutrient activation of mTOR contributes to enhanced DNA synthesis, cell cycle progression, and proliferation of human beta-cells. Identification of therapeutic agents that appropriately regulate GSK-3 and mTOR signaling may provide a feasible and available approach to enhance human islet growth and proliferation. Diabetes 58:663-672, 2009
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