糖脂毒性对胰腺β细胞的功能损伤作用及机制

现在关于高糖高脂对胰腺β细胞的毒性机制已经有了明显的进展,但还不完全清楚。实际上,β细胞响应过量营养物质的过程是一个连续的过程,包括β细胞补偿和β细胞功能失调。在早期,β细胞应对高糖高脂的反应是一个积极主动的过程;而到后期,过量的糖脂会导致胰岛素分泌下降,削弱胰岛素基因表达量,并促进胰岛β细胞凋亡。最终对2型糖尿病的发展有促进作用。综述了近年来细胞水平和分子水平,在葡萄糖存在的条件下,脂肪酸对胰腺β细胞的损伤作用及其机制的研究进展,重在说明葡萄糖和脂肪酸在2型糖尿病发展中的共同作用。     

A ubiquitin-dependent mitophagy complex maintains mitochondrial function and insulin secretion in beta cells

Mitochondrial autophagy or mitophagy is a key component of mitochondrial quality control, which is necessary to maintain cellular bioenergetics. Pancreatic islet β-cells, which release insulin in response to circulating blood glucose levels, are particularly susceptible to mitochondrial dysfunction due to their high metabolic activity and energy requirements for insulin processing, maturation, and secretion. Therefore, dysregulated mitophagy has drawn interest in the etiology of β-cell failure in diabetes. We demonstrate that the pivotal β-cell mitophagy regulator, CLEC16A, is an E3 ligase that forms a ubiquitin-dependent tripartite complex with RNF41/NRDP1 and USP8. Maintenance of the CLEC16A-RNF41-USP8 mitophagy complex is necessary for maximal cellular respiration and insulin secretion. Further, we observe that diabetogenic metabolic stressors, including elevated glucose and fatty acids, destabilize the CLEC16A-RNF41-USP8 complex and lead to β-cell apoptosis. Thus, the β-cell mitophagy pathway requires ubiquitin signals to stabilize the CLEC16A-RNF41-USP8 complex and maintain mitochondrial quality control.