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

From the Laboratory of Molecular Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts

Address correspondence and reprint requests to Joel F. Habener, MD, Laboratory of Molecular Endocrinology, 55 Fruit St., Thier 306, Massachusetts General Hospital, Boston, MA 02114. E-mail: jhabener{at}partners.org

Abbreviations: CREB, cAMP-responsive element binding protein; CXCR, CX chemokine receptor; GLP, glucagon-like peptide; PI, phosphatidylinositol; ROS, reactive oxygen species; SDF, stromal cell–derived factor; siRNA, small interfering RNA; SMA, smooth muscle actin; STZ, streptozotocin; TUNEL, transferase-mediated dUTP nick-end labeling

OBJECTIVE—Diabetes is caused by a deficiency of pancreatic ß-cells that produce insulin. Approaches to enhance ß-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 ß-cells.

RESEARCH DESIGN AND METHODS—Mouse pancreata and clonal ß-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 ß-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 ß-cells (RIP-SDF-1 mice) are resistant to STZ-induced ß-cell apoptosis and diabetes. In MIN6 ß-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 ß-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 ß-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 ß-cell survival via activation of Akt, suggesting that SDF-1 agonists may prove beneficial for treatment of diabetes.

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