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.
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.


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.
Yano
Tatsuya
T
Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Liu
Zhengyu
Z
Donovan
Jennifer
J
Thomas
Melissa K
MK
Habener
Joel F
JF
D000818:Animals; D002470:Cell Survival; D054377:Chemokine CXCL12 / Q000235:genetics*; D003921:Diabetes Mellitus, Experimental / Q000517:prevention & control; D004789:Enzyme Activation; D007328:Insulin / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000166:cytology*; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D019718:Receptors, CXCR4 / Q000235:genetics
C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D007328:Insulin; D019718:Receptors, CXCR4; D051057:Proto-Oncogene Proteins c-akt