Hyperglycemia-Induced Dysregulated Fusion Intermediates in Insulin-Secreting Cells Visualized by Super-Resolution Microscopy

Frontiers in Cell and Developmental Biology

Kuo Liang²  Yanmei Liu³  Liangyi Chen⁵  Lisi Wei⁶  Liuju Li⁶  Guoyi Yang⁶ 

[1] Beijing Academy of Artificial Intelligence, Beijing, China;Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China;Institute for Brain Research and Rehabilitation, Key Laboratory of Brain, Cognition and Education Science, South China Normal University, Guangzhou, China;PKU-IDG/McGovern Institute for Brain Research, Beijing, China;Shenzhen Bay Laboratory, Shenzhen, China;State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, School of Future Technology, Peking University, Beijing, China;

关键词: fusion pore;    exocytosis;    SNARE;    secretory vesicle;    insulin;    glucotoxicity;   

DOI  :  10.3389/fcell.2021.650167

来源: DOAJ

【 摘 要 】

Impaired insulin release is a hallmark of type 2 diabetes and is closely related to chronically elevated glucose concentrations, known as “glucotoxicity.” However, the molecular mechanisms by which glucotoxicity impairs insulin secretion remain poorly understood. In addition to known kiss-and-run and kiss-and-stay fusion events in INS-1 cells, ultrafast Hessian structured illumination microscopy (Hessian SIM) enables full fusion to be categorized according to the newly identified structures, such as ring fusion (those with enlarged pores) or dot fusion (those without apparent pores). In addition, we identified four fusion intermediates during insulin exocytosis: initial pore opening, vesicle collapse, enlarged pore formation, and final pore dilation. Long-term incubation in supraphysiological doses of glucose reduced exocytosis in general and increased the occurrence of kiss-and-run events at the expense of reduced full fusion. In addition, hyperglycemia delayed pore opening, vesicle collapse, and enlarged pore formation in full fusion events. It also reduced the size of apparently enlarged pores, all of which contributed to the compromised insulin secretion. These phenotypes were mostly due to the hyperglycemia-induced reduction in syntaxin-1A (Stx-1A) and SNAP-25 protein, since they could be recapitulated by the knockdown of endogenous Stx-1A and SNAP-25. These findings suggest essential roles for the vesicle fusion type and intermediates in regulating insulin secretion from pancreatic beta cells in normal and disease conditions.

【 授权许可】

Unknown