Expression-Based Network Biology Identifies Alteration in Key Regulatory Pathways of Type 2 Diabetes and Associated Risk/Complications

Abstract

Type 2 diabetes mellitus (T2D) is a multifactorial and genetically heterogeneous disease which leads to impaired glucose homeostasis and insulin resistance. The advanced form of disease causes acute cardiovascular, renal, neurological and microvascular complications. Thus there is a constant need to discover new and efficient treatment against the disease by seeking to uncover various novel alternate signalling mechanisms that can lead to diabetes and its associated complications. The present study allows detection of molecular targets by unravelling their role in altered biological pathways during diabetes and its associated risk factors and complications. We have used an integrated functional networks concept by merging co-expression network and interaction network to detect the transcriptionally altered pathways and regulations involved in the disease. Our analysis reports four novel significant networks which could lead to the development of diabetes and other associated dysfunctions. (a) The first network illustrates the up regulation of TGFBRII facilitating oxidative stress and causing the expression of early transcription genes via MAPK pathway leading to cardiovascular and kidney related complications. (b) The second network demonstrates novel interactions between GAPDH and inflammatory and proliferation candidate genes i.e., SUMO4 and EGFR indicating a new link between obesity and diabetes. (c) The third network portrays unique interactions PTPN1 with EGFR and CAV1 which could lead to an impaired vascular function in diabetic nephropathy condition. (d) Lastly, from our fourth network we have inferred that the interaction of β-catenin with CDH5 and TGFBR1 through Smad molecules could contribute to endothelial dysfunction. A probability of emergence of kidney complication might be suggested in T2D condition. An experimental investigation on this aspect may further provide more decisive observation in drug target identification and better understanding of the pathophysiology of T2D and its complications.

PUFAs from Stem Bark of Alstonia boonei Synergistically Modulates Diabetic, Hepatic and Androgenic Damage by Low Expression of COX-2 and iNOS in Rats

“…Similarly, as observed, there was a significant rise in hepatic and testicular MDA contents in diabetic induced rat. This result is in agreement with previous investigations where animals suffering from insulin dependent diabetics (type 1) showed increased lipid peroxidation [21,33]. It was also reported that diabetic patients are more susceptible to membrane damage [32,34].…”

Association of SUMO4 Met55Val variation with increased insulin resistance in newly diagnosed type 2 diabetes in a Chinese population

“…SUMO4 can also suppress STAT1 DNA binding activity via direct sumoylation [23] , which suggested the possibility of SUMO4 modification in JAK/STAT pathway contributing to the development of inflammation and/or insulin resistance [24] . A recently published paper showed that SUMO4 can interact with GAPDH via its ubiquitin domain under conditions of stress and obesity, indicating that the interaction between SUMO4 and GAPDH may affect insulin sensitivity regulation [25] . Additionally, SUMO4 sumoylation may play a role in the regulation of intracellular stress [26] .…”

Understanding Genetic Heterogeneity in Type 2 Diabetes by Delineating Physiological Phenotypes:SIRT1and its Gene Network in Impaired Insulin Secretion

“…After the network analysis, we observed that the hub proteins are communicating with many other significant proteins involved in several pathways that are reported to be affected in T2D. We propose that further biochemical investigations need to be conducted on the removal of these hub proteins to provide better understanding of the roles played by these proteins in the pathophysiology of T2D [60].…”