Background

Insulin resistance is the decreased effectiveness of insulin receptor function during signaling of glucose uptake. Insulin receptors are regulated by endocytosis, a process that removes receptors from the cell surface to be marked for degradation or for re-use.

Objectives

Our goal was to discover insulin-resistance-related genes that play key roles in endocytosis which could serve as potential biological targets to enhance insulin sensitivity.

Methods

The gene mutations related to insulin resistance were elucidated from ClinVar. These were used as the seed set. Using the GeneFriends program, the genes associated with this set were elucidated and used as an enriched set for the next step. The enriched gene set network was visualized by Cytoscape. After that, using the VisANT program, the most significant cluster of genes was identified. With the help of the DAVID program, the most important KEGG pathway corresponding to the gene cluster and insulin resistance was found. Eleven genes part of the KEGG endocytosis pathway were identified. Finally, using the ChEA3 program, seven transcription factors managing these genes were defined.

Results

Thirty-two genes of pathogenic significance in insulin resistance were elucidated, and then co-expression data for these genes were utilized. These genes were organized into clusters, one of which was singled out for its high node count of 58 genes and low p-value (p = 4.117 × 10⁻⁷). DAVID Pathways, a functional annotation tool, helped identify a set of 11 genes from a single cluster associated with the endocytosis pathway related to insulin resistance. These genes (AMPH, BIN1, CBL, DNM1, DNM2, DNM3, ITCH, SH3GL1, SH3GL2, SH3GL3, and SH3KBP1) are all involved in either clathrin-mediated endocytosis of the insulin receptor (IR) or clathrin-independent endocytosis of insulin-resistance-related G protein-coupled receptors (GPCR). They represent prime therapeutic targets to improve insulin sensitivity through modulation of transmembrane cell signaling. Using the ChEA3 database, we also found seven transcription factors (REST, MYPOP, CAMTA2, MYT1L, ZBTB18, NKX6–2, and CXXC5) that control the expression of these 11 genes. Inhibiting these key transcription factors would be another strategy to downregulate endocytosis.

Conclusion

We believe that delaying removal of insulin receptors from the cell surface would prolong signaling of glucose uptake and counteract the symptoms of insulin resistance.

中文翻译：

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靶向胰岛素受体内吞作用作为胰岛素抵抗的治疗方法

背景

胰岛素抵抗是指葡萄糖摄取信号期间胰岛素受体功能的有效性降低。胰岛素受体受到内吞作用的调节，内吞作用是从细胞表面去除受体以标记降解或再利用的过程。

目标

我们的目标是发现在内吞作用中发挥关键作用的胰岛素抵抗相关基因，这些基因可以作为增强胰岛素敏感性的潜在生物靶标。

方法

ClinVar 阐明了与胰岛素抵抗相关的基因突变。这些被用作种子集。使用 GeneFriends 程序，阐明了与该组相关的基因，并将其用作下一步的富集组。通过 Cytoscape 可视化富集的基因集网络。之后，使用 VisANT 程序，鉴定出最重要的基因簇。在DAVID程序的帮助下，找到了与基因簇和胰岛素抵抗相对应的最重要的KEGG通路。已鉴定出 KEGG 内吞途径的 11 个基因部分。最后，使用 ChEA3 程序，定义了管理这些基因的七个转录因子。

结果

阐明了在胰岛素抵抗中具有致病意义的 32 个基因，然后利用了这些基因的共表达数据。这些基因被组织成簇，其中一个簇因其 58 个基因的高节点数和低p值 ( p  = 4.117 × 10 ^-7 ) 而被挑选出来。DAVID Pathways 是一种功能注释工具，帮助从与胰岛素抵抗相关的内吞作用途径相关的单个簇中识别出一组 11 个基因。这些基因（AMPH、BIN1、CBL、DNM1、DNM2、DNM3、ITCH、SH3GL1、SH3GL2、SH3GL3和SH3KBP1）均参与网格蛋白介导的胰岛素受体 (IR) 内吞作用或网格蛋白独立的胰岛素受体内吞作用。耐药相关的 G 蛋白偶联受体 (GPCR)。它们代表了通过调节跨膜细胞信号传导来提高胰岛素敏感性的主要治疗靶点。使用 ChEA3 数据库，我们还发现了控制这 11 个基因表达的 7 个转录因子（REST、MYPOP、CAMTA2、MYT1L、ZBTB18、NKX6-2 和 CXXC5）。抑制这些关键转录因子将是下调内吞作用的另一种策略。

结论

我们相信，延迟从细胞表面去除胰岛素受体将延长葡萄糖摄取的信号传导并抵消胰岛素抵抗的症状。