Stromal Cell–Derived Factor-1 (SDF-1)/CXCL12 Attenuates Diabetes in Mice and Promotes Pancreatic β-Cell Survival by Activation of the Prosurvival Kinase Akt

Abstract

OBJECTIVE—Diabetes is caused by a deficiency of pancreatic β-cells that produce insulin. Approaches to enhance β-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 β-cells. RESEARCH DESIGN AND METHODS—Mouse pancreata and clonal β-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 β-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 β-cells (RIP-SDF-1 mice) are resistant to STZ-induced β-cell apoptosis and diabetes. In MIN6 β-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 β-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 β-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 β-cell survival via activation of Akt, suggesting that SDF-1 agonists may prove beneficial for treatment of diabetes.