title: 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 beta-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.
authors.affiliation: Institute of Bioinformatics and Applied Biotechnology, Bangalore, Karnataka, India.
authors.forename: Urmi
authors.initials: U
authors.lastname: Sengupta
authors.forename: Sanchaita
authors.initials: S
authors.lastname: Ukil
authors.forename: Nevenka
authors.initials: N
authors.lastname: Dimitrova
authors.forename: Shipra
authors.initials: S
authors.lastname: Agrawal
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000235:genetics*; D003925:Diabetic Angiopathies / Q000150:complications / Q000201:enzymology; D003928:Diabetic Nephropathies / Q000150:complications / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis; D053263:Gene Regulatory Networks / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000235:genetics*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D005227:Fatty Acids; D007328:Insulin; D016760:Proto-Oncogene Proteins c-fos; D017382:Reactive Oxygen Species; D018125:Receptors, Transforming Growth Factor beta; C489647:SUMO4 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II