EXOC6 (Exocyst Complex Component 6) Is Associated with the Risk of Type 2 Diabetes and Pancreatic β-Cell Dysfunction

SIMPLE SUMMARY: EXOC6 and EXOC6B (EXOC6/6B) are components of the exocyst complex involved in the secretory granule docking. The exact role of EXOC6/6B in pancreatic β-cell function and risk of type 2 diabetes (T2D) required further investigations. Herein, we showed that EXOC6/6B is associated with the risk of T2D and is essential to maintain the function of pancreatic β-cell. Our study suggests that EXOC6/6B are crucial regulators for insulin secretion and for exocytosis machinery in β-cells. ABSTRACT: EXOC6 and EXOC6B (EXOC6/6B) components of the exocyst complex are involved in the secretory granule docking. Recently, EXOC6/6B were anticipated as a molecular link between dysfunctional pancreatic islets and ciliated lung epithelium, making diabetic patients more prone to severe SARS-CoV-2 complications. However, the exact role of EXOC6/6B in pancreatic β-cell function and risk of T2D is not fully understood. Herein, microarray and RNA-sequencing (RNA-seq) expression data demonstrated the expression of EXOC6/6B in human pancreatic islets. Expression of EXOC6/6B was not affected by diabetes status. Exploration of the using the translational human pancreatic islet genotype tissue-expression resource portal (TIGER) revealed three genetic variants (rs947591, rs2488071 and rs2488073) in the EXOC6 gene that were associated (p < 2.5 × 10(−20)) with the risk of T2D. Exoc6/6b silencing in rat pancreatic β-cells (INS1-832/13) impaired insulin secretion, insulin content, exocytosis machinery and glucose uptake without cytotoxic effect. A significant decrease in the expression Ins1, Ins1, Pdx1, Glut2 and Vamp2 was observed in Exoc6/6b-silenced cells at the mRNA and protein levels. However, NeuroD1, Gck and InsR were not influenced compared to the negative control. In conclusion, our data propose that EXOC6/6B are crucial regulators for insulin secretion and exocytosis machinery in β-cells. This study identified several genetic variants in EXOC6 associated with the risk of T2D. Therefore, EXOC6/6B could provide a new potential target for therapy development or early biomarkers for T2D.