Department of Endocrinology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Department of Orthopedics, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.
Biochem Biophys Res Commun. 2020 Jan 29;522(1):14-20. doi: 10.1016/j.bbrc.2019.11.051. Epub 2019 Nov 15.
Diabetes mellitus is a metabolic disease characterized by an increase in blood glucose levels due to lack of insulin secretion. Previous studies have confirmed that PICK1 is critical for both β-cell function and glucose homeostasis. The aim of this study was to investigate the role of PICK1 in response to high glucose-induced β-cell dysfunction and the molecular mechanism of regulation of PICK1. We found that overexpression of PICK1 in db/db diabetic mice significantly improved glucose tolerance and increased insulin release. High glucose treatment of Min6 cells inhibited PICK1 expression, and overexpression of PICK1 protected against high glucose-induced pancreatic cell dysfunction. Activation of the PI3K/Akt pathway by PICK1 in Min6 cells resulted in increased GLUT2 expression and this increase was abolished by treatment with a PI3K-specific inhibitor. Further, we showed that expression of PICK1 is negatively regulated by miR-139-5p through directly targeting its 3'UTR. These data suggested that PICK1 may participate in the functional protection of pancreatic β-cells through PI3K/Akt signaling, promote insulin secretion, and delay the progression of diabetes, and is negatively regulated by miR-139-5p, further clarifying the regulation of pancreatic β-cell function.
糖尿病是一种代谢性疾病，其特征是由于胰岛素分泌不足导致血糖水平升高。先前的研究已经证实，PICK1 对于β细胞功能和葡萄糖稳态都至关重要。本研究旨在探讨 PICK1 在高糖诱导的β细胞功能障碍中的作用及其调控 PICK1 的分子机制。我们发现，在 db/db 糖尿病小鼠中过表达 PICK1 可显著改善葡萄糖耐量并增加胰岛素释放。高葡萄糖处理 Min6 细胞抑制 PICK1 表达，而过表达 PICK1 可防止高葡萄糖诱导的胰岛细胞功能障碍。PICK1 在 Min6 细胞中激活 PI3K/Akt 通路导致 GLUT2 表达增加，而这种增加可被 PI3K 特异性抑制剂处理所消除。此外，我们表明 PICK1 的表达受 miR-139-5p 的负调控，通过直接靶向其 3'UTR。这些数据表明，PICK1 可能通过 PI3K/Akt 信号通路参与胰腺β细胞的功能保护，促进胰岛素分泌，延缓糖尿病的进展，并受 miR-139-5p 的负调控，进一步阐明了胰腺β细胞功能的调节。
