Centre for Biomolecular Interactions Bremen, University of Bremen, 28359 Bremen, Germany.
Int J Mol Sci. 2018 Mar 24;19(4):975. doi: 10.3390/ijms19040975.
Loss of pancreatic β-cell function and/or mass is a central hallmark of all forms of diabetes but its molecular basis is incompletely understood. β-cell apoptosis contributes to the reduced β-cell mass in diabetes. Therefore, the identification of important signaling molecules that promote β-cell survival in diabetes could lead to a promising therapeutic intervention to block β-cell decline during development and progression of diabetes. In the present study, we identified F-box protein 28 (FBXO28), a substrate-recruiting component of the Skp1-Cul1-F-box (SCF) ligase complex, as a regulator of pancreatic β-cell survival. FBXO28 was down-regulated in β-cells and in isolated human islets under diabetic conditions. Consistently, genetic silencing of FBXO28 impaired β-cell survival, and restoration of FBXO28 protected β-cells from the harmful effects of the diabetic milieu. Although FBXO28 expression positively correlated with β-cell transcription factor and FBXO28 depletion also reduced insulin mRNA expression, neither FBXO28 overexpression nor depletion had any significant impact on insulin content, glucose-stimulated insulin secretion (GSIS) or on other genes involved in glucose sensing and metabolism or on important β-cell transcription factors in isolated human islets. Consistently, FBXO28 overexpression did not further alter insulin content and GSIS in freshly isolated islets from patients with type 2 diabetes (T2D). Our data show that FBXO28 improves pancreatic β-cell survival under diabetogenic conditions without affecting insulin secretion, and its restoration may be a novel therapeutic tool to promote β-cell survival in diabetes.
胰岛 β 细胞功能和/或数量的丧失是所有类型糖尿病的一个核心特征，但它的分子基础尚未完全被理解。β 细胞凋亡导致糖尿病中 β 细胞数量减少。因此，鉴定在糖尿病中促进 β 细胞存活的重要信号分子，可能会导致一种有前途的治疗干预措施，以阻止糖尿病发展和进展过程中 β 细胞的衰退。在本研究中，我们发现 F-box 蛋白 28（FBXO28）是 Skp1-Cul1-F-box（SCF）连接酶复合物的底物募集成分，是胰腺 β 细胞存活的调节剂。FBXO28 在β 细胞和分离的人类胰岛中在糖尿病条件下下调。一致地，FBXO28 的基因沉默损害了 β 细胞的存活，而 FBXO28 的恢复保护了β 细胞免受糖尿病环境的有害影响。尽管 FBXO28 的表达与β 细胞转录因子呈正相关，并且 FBXO28 的耗竭也降低了胰岛素 mRNA 的表达，但 FBXO28 的过表达或耗竭对胰岛素含量、葡萄糖刺激的胰岛素分泌（GSIS）或对其他涉及葡萄糖感应和代谢的基因或对分离的人类胰岛中的重要β 细胞转录因子均没有显著影响。一致地，FBXO28 的过表达并没有进一步改变 2 型糖尿病（T2D）患者新鲜分离的胰岛中的胰岛素含量和 GSIS。我们的数据表明，FBXO28 在致糖尿病条件下改善了胰岛 β 细胞的存活，而不影响胰岛素分泌，其恢复可能是促进糖尿病中β 细胞存活的一种新的治疗工具。
