Hypoglycemia, Vascular Disease and Cognitive Dysfunction in Diabetes: Insights from Text Mining-Based Reconstruction and Bioinformatics Analysis of the Gene Networks.

Olga V Saik,Vadim V Klimontov

doi:10.3390/ijms222212419

Abstract

Hypoglycemia has been recognized as a risk factor for diabetic vascular complications and cognitive decline, but the molecular mechanisms of the effect of hypoglycemia on target organs are not fully understood. In this work, gene networks of hypoglycemia and cardiovascular disease, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, cognitive decline, and Alzheimer’s disease were reconstructed using ANDSystem, a text-mining-based tool. The gene network of hypoglycemia included 141 genes and 2467 interactions. Enrichment analysis of Gene Ontology (GO) biological processes showed that the regulation of insulin secretion, glucose homeostasis, apoptosis, nitric oxide biosynthesis, and cell signaling are significantly enriched for hypoglycemia. Among the network hubs, INS, IL6, LEP, TNF, IL1B, EGFR, and FOS had the highest betweenness centrality, while GPR142, MBOAT4, SLC5A4, IGFBP6, PPY, G6PC1, SLC2A2, GYS2, GCGR, and AQP7 demonstrated the highest cross-talk specificity. Hypoglycemia-related genes were overrepresented in the gene networks of diabetic complications and comorbidity; moreover, 14 genes were mutual for all studied disorders. Eleven GO biological processes (glucose homeostasis, nitric oxide biosynthesis, smooth muscle cell proliferation, ERK1 and ERK2 cascade, etc.) were overrepresented in all reconstructed networks. The obtained results expand our understanding of the molecular mechanisms underlying the deteriorating effects of hypoglycemia in diabetes-associated vascular disease and cognitive dysfunction.

Highlights

Laboratory of Endocrinology, Research Institute of Clinical and Experimental Lymphology—Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences
In our previous work [28], we have reconstructed a gene network associated with hypoglycemia in individuals with diabetes
As the ANDSystem (ICG SB RAS, Novosibirsk, Russia) [22,23,24] was updated in 2021, the gene network related to hypoglycemia (Figure 1) has been expanded to include 141 genes/proteins and 5525 interactions (Table S1)

Summary

Introduction

Biological processes showed that the regulation of insulin secretion, glucose homeostasis, apoptosis, nitric oxide biosynthesis, and cell signaling are significantly enriched for hypoglycemia. Hypoglycemia-related genes were overrepresented in the gene networks of diabetic complications and comorbidity; 14 genes were mutual for all studied disorders. Eleven GO biological processes (glucose homeostasis, nitric oxide biosynthesis, smooth muscle cell proliferation, ERK1 and ERK2 cascade, etc.) were overrepresented in all reconstructed networks. The long-term consequences of hypoglycemia include cardiovascular events, as well as cognitive and psychological problems [2]. In both type 1 and type 2 diabetes, self-reported episodes of severe hypoglycemia are related to increased risk of death [3]. In turn, increases the risk of hypoglycemia [11]

Methods

Results

Conclusion