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

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.

Impairment of Mitochondrial Respiration in Metabolic Diseases: An Overview

“…Hypoglycemia is the most common acute complication associated with the treatment of diabetes and has a strong impact on brain metabolism and function [ 70 , 71 , 72 ]. Hippocampal homogenate was used as a source of brain mitochondria by He et al who reported that recurrent hypoglycemia in diabetic rats caused a drop in NADH-linked OXPHOS, OXPHOS capacity, ET capacity and succinate-dependent ET capacity compared with diabetic controls without recurrent drops in glycemia.…”

Gene Networks of Hyperglycemia, Diabetic Complications, and Human Proteins Targeted by SARS-CoV-2: What Is the Molecular Basis for Comorbidity?

“…The CTS is calculated as a number of neighbors of a particular node (molecule) in a network divided by the number of all neighbors of the node in the global human gene network of the ANDSystem. A higher CTS value means that a node is closely and specifically related to a studied network [24,[26][27][28]. The highest crosstalk specificity (CTS) values (Table S3) were demonstrated by uncoupling protein 2 (UCP2), hydroxisteroid 11-beta dehydrohenase-1 (HSD11B1), interleukin-19 (IL19), fatty acid binding protein 1 (FABP1), pyroglutamylated RFamide peptide (QRFP), resistin (RETN), solute carrier family 2 member 2 (SLC2A2), leptin receptor overlapping transport (LEPROT), endothelial cell-specific molecule 1 (ESM1), and cholecystokinin (CCK) genes.…”

“…In this work, we operated on gene networks associated with cardiovascular disease (CVD), diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy that have been reconstructed and described previously [27,28]. These networks include 494, 685, 424, and 130 genes/proteins, respectively (Table S5).…”

“…The system can be used for the analysis of molecular mechanisms of human diseases and their associations [25,26]. Recently, we applied this tool to reconstruct and analyze the gene networks of diabetic complications, glucose variability, and hypoglycemia [27,28].…”

Uncovering the genes linking glucose variability with endothelial dysfunction in diabetes by the analysis of gene networks

“…Background: High glucose variability (GV) is recognized as a contributor for diabetic microvascular and macrovascular complications, including diabetic retinopathy, chronic kidney disease, diabetic neuropathy, and macrovascular disease [1][2][3]. The results of numerous studies have pointed to the role of endothelial dysfunction in the development of these complications [1,4].…”