31 Yano, T. Liu, Z. Donovan, J. Thomas, M. K. Habener, J. F. 2007 Diabetes 56 12 2946-57 Dec 1939-327X (Electronic) 17878289 Diabetes Mellitus, Experimental/prevention & control Chemokine CXCL12/*genetics Cell Survival Animals Receptors, CXCR4/genetics Rats Proto-Oncogene Proteins c-akt/*metabolism Promoter Regions, Genetic Mice, Transgenic Mice Insulin-Secreting Cells/*cytology Insulin/genetics Enzyme Activation Diabetes Mellitus Receptors Promoter Regions Genetic Transgenic Experimental/prevention & control CXCR4/genetics OBJECTIVE: Diabetes is caused by a deficiency of pancreatic beta-cells that produce insulin. Approaches to enhance beta-cell mass by increasing proliferation and survival are desirable. We determined whether stromal cell-derived factor (SDF)-1/CXCL12 and its receptor, CX chemokine receptor (CXCR)4, are important for the survival of beta-cells. RESEARCH DESIGN AND METHODS: Mouse pancreata and clonal beta-cells were examined for expression of SDF-1 and CXCR4, activation of AKT and downstream signaling pathways by SDF-1, and protection against apoptosis and diabetes induced by streptozotocin (STZ). RESULTS: CXCR4 is expressed in beta-cells, and SDF-1 is expressed in microvascular endothelial cells within the islets and in surrounding interstitial stromal tissue. Transgenic mice overexpressing SDF-1 within their beta-cells (RIP-SDF-1 mice) are resistant to STZ-induced beta-cell apoptosis and diabetes. In MIN6 beta-cells, a CXCR4 antagonist (AMD3100) induces apoptosis, increases reactive oxygen species, decreases expression levels of the anti-apoptotic protein Bcl-2, and reduces phosphorylation of the proapoptotic protein Bad. Active phosphorylated prosurvival kinase Akt is increased both in the beta-cells of RIP-SDF-1 mice and in INS-1 cells treated with SDF-1 and sensitive to AMD3100. Inhibition of AKT expression by small interfering RNA attenuates the ameliorative effects of SDF-1 on caspase-dependent apoptosis induced by thapsigargin or glucose deprivation in INS-1 beta-cells. Specific inhibition of Akt activation by a soluble inhibitor (SH-5) reverses the anti-apoptotic effects of SDF-1 in INS-1 cells and mouse islets. CONCLUSIONS: SDF-1 promotes pancreatic beta-cell survival via activation of Akt, suggesting that SDF-1 agonists may prove beneficial for treatment of diabetes. DK55365/DK/NIDDK NIH HHS/United StatesDK61251/DK/NIDDK NIH HHS/United StatesP30DK057521/DK/NIDDK NIH HHS/United StatesJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tUnited States http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17878289