Endoplasmic reticulum (ER) stress has been shown to play an important role in beta cell loss in diabetes. However, the factors involved in this process are still not fully understood. Growth differentiation factor 15 (GDF15), a member of the transforming growth factor beta (TGFβ) family, is a stress response gene and is involved in various diseases. GDF15 is expressed in adult human beta cells; however, its role in beta cells and diabetes had not been elucidated. Interestingly, we now have identified GDF15 as a key factor involved in ER stress-induced beta cell loss. We found that GDF15 mRNA, protein levels and promoter activity were significantly induced by ER stress in INS-1 cells, Akita beta cells, and primary human islets and we identified the transcription factor involved. Moreover, we discovered that overexpression of GDF15 exacerbated, while knockdown of GDF15 inhibited ER stress-induced beta cell apoptosis, at least in part by regulating the pro-apoptotic factor CHOP. Most importantly, we found that GDF15 knockout mice were protected from STZ-induced diabetes, maintained insulin producing beta cells and exhibited improved serum insulin levels. Taken together, our findings suggest that GDF15 plays an important role in ER stress-induced beta cell death and that inhibition of GDF15 may represent a novel strategy to reduce beta cell loss and treat diabetes.
G. Xu: None. S. Jo: None. J. Chen: None. T. Grayson: None. A. Shalev: None.