GDF15 in ER stress, β cell, and diabetes

Guanlan Xu, Junqin Chen, SeongHo Jo, Truman B Grayson, Sasanka Ramanadham, Akio Koizumi, Emily L Germain-Lee, Se-Jin Lee, Anath Shalev
Endocrinology, Volume 163, Issue 5, May 2022, bqac030
https://doi.org/10.1210/endocr/bqac030

Abstract

Endoplasmic reticulum (ER) stress contributes to pancreatic β-cell apoptosis in diabetes, but the factors involved are still not fully elucidated. Growth differentiation factor 15 (GDF15) is a stress response gene and has been reported to be increased and play an important role in various diseases. However, the role of GDF15 in β cells in the context of ER stress and diabetes is still unclear. In this study, we have discovered that GDF15 promotes ER stress-induced β-cell apoptosis and that downregulation of GDF15 has beneficial effects on β-cell survival in diabetes. Specifically, we found that GDF15 is induced by ER stress in β cells and human islets, and that the transcription factor C/EBPβ is involved in this process. Interestingly, ER stress-induced apoptosis was significantly reduced in INS-1 cells with Gdf15 knockdown and in isolated Gdf15 knockout mouse islets. In vivo, we found that Gdf15 deletion attenuates streptozotocin-induced diabetes by preserving β cells and insulin levels. Moreover, deletion of Gdf15 significantly delayed diabetes development in spontaneous ER stress-prone Akita mice. Thus, our findings suggest that GDF15 contributes to ER stress-induced β-cell apoptosis and that inhibition of GDF15 may represent a novel strategy to promote β-cell survival and treat diabetes.

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