Abstract
Simple SummaryEXOC6 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. 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.
Highlights
Diabetes mellitus is a major health problem, diagnosed in more than 500 million individuals worldwide
We used our to investigate the EXOC6/6B expression compared to some key functional genes for huprevious microarray and RNA-seq expression data from human islets man pancreatic β-cell, such as KCNJ11 and GLUT1
This study showed portant role that are play the pathophysiology of but Thisexpression study showed that expressed ininhuman pancreatic islets, was that not are expressed in human pancreatic islets, but their expression was not influenced by diabetes or hyperglycemia status
Summary
Diabetes mellitus is a major health problem, diagnosed in more than 500 million individuals worldwide (www.idf.org, accessed on 6 January 2022). Accounts for approximately 90% of all diabetes cases described by elevated blood sugar levels due to inappropriate insulin secretion levels in pancreatic β-cells, action in target tissues, or both [1]. Insulin is a 51-amino acid protein synthesized in pancreatic β-cells and is governed by different molecules, including sugar, Ca2+ , ATP, phospholipids, cAMP and hormones [2–5]. Elevated ATP concentration closes the sensitive K+ -channels in response to glucose stimulation [6] and opens the voltage-gated Ca2+ channels to permit. Ca2+ influx and trigger the exocytosis of insulin granules. Exocytosis machinery of insulin granules is a well-organized process involving tethering, docking, and fusion of granules to a specific site on the plasma membrane [7]. Despite the increased knowledge about the exocytosis of insulin granules, genes and molecules involved in the mechanism remain to be discovered
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