title: Network signatures link hepatic effects of anti-diabetic interventions with systemic disease parameters.
abstract: BACKGROUND
  Multifactorial diseases such as type 2 diabetes mellitus (T2DM), are driven by a complex network of interconnected mechanisms that translate to a diverse range of complications at the physiological level. To optimally treat T2DM, pharmacological interventions should, ideally, target key nodes in this network that act as determinants of disease progression.
  
  
  RESULTS
  We set out to discover key nodes in molecular networks based on the hepatic transcriptome dataset from a preclinical study in obese LDLR-/- mice recently published by Radonjic et al. Here, we focus on comparing efficacy of anti-diabetic dietary (DLI) and two drug treatments, namely PPARA agonist fenofibrate and LXR agonist T0901317. By combining knowledge-based and data-driven networks with a random walks based algorithm, we extracted network signatures that link the DLI and two drug interventions to dyslipidemia-related disease parameters.
  
  
  CONCLUSIONS
  This study identified specific and prioritized sets of key nodes in hepatic molecular networks underlying T2DM, uncovering pathways that are to be modulated by targeted T2DM drug interventions in order to modulate the complex disease phenotype.
authors.affiliation: TNO, Research Group Microbiology & Systems Biology, Zeist, The Netherlands. thomas@edgeleap.com.|Current address: EdgeLeap B.V, Utrecht, The Netherlands. thomas@edgeleap.com.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kelder
authors.affiliation: TNO, Research Group Microbiology & Systems Biology, Zeist, The Netherlands. lars.verschuren@tno.nl.
authors.forename: Lars
authors.initials: L
authors.lastname: Verschuren
authors.affiliation: TNO, Research Group Microbiology & Systems Biology, Zeist, The Netherlands. ben.vanommen@tno.nl.
authors.forename: Ben
authors.initials: B
authors.lastname: van Ommen
authors.affiliation: TNO, Research Group Microbiology & Systems Biology, Zeist, The Netherlands. alain.vangool@tno.nl.|Department of Laboratory Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. alain.vangool@tno.nl.|Faculty of Physics, Mathematics and Informatics, Radboud University Nijmegen, Nijmegen, The Netherlands. alain.vangool@tno.nl.
authors.forename: Alain J
authors.initials: AJ
authors.lastname: van Gool
authors.affiliation: TNO, Research Group Microbiology & Systems Biology, Zeist, The Netherlands. marijana@edgeleap.com.|Current address: EdgeLeap B.V, Utrecht, The Netherlands. marijana@edgeleap.com.
authors.forename: Marijana
authors.initials: M
authors.lastname: Radonjic
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000178:diet therapy / Q000188:drug therapy*; D018450:Disease Progression; D011345:Fenofibrate / Q000494:pharmacology; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D011973:Receptors, LDL / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D059467:Transcriptome / Q000235:genetics*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D011345:Fenofibrate; D006845:Hydrocarbons, Fluorinated; D011973:Receptors, LDL; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides