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

Abstract

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-1 (SDF-1/CXCL12) and its receptor CXCR4 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.

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 streptozotocin-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 pro-apoptotic 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, sensitive to AMD3100. Inhibition of AKT expression by siRNA 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 the activation of Akt suggesting that SDF-1 agonists may prove beneficial for the treatment of diabetes.