title: Genetic variation in insulin-induced kinase signaling.
abstract: Individual differences in sensitivity to insulin contribute to disease susceptibility including diabetes and metabolic syndrome. Cellular responses to insulin are well studied. However, which steps in these response pathways differ across individuals remains largely unknown. Such knowledge is needed to guide more precise therapeutic interventions. Here, we studied insulin response and found extensive individual variation in the activation of key signaling factors, including ERK whose induction differs by more than 20-fold among our subjects. This variation in kinase activity is propagated to differences in downstream gene expression response to insulin. By genetic analysis, we identified cis-acting DNA variants that influence signaling response, which in turn affects downstream changes in gene expression and cellular phenotypes, such as protein translation and cell proliferation. These findings show that polymorphic differences in signal transduction contribute to individual variation in insulin response, and suggest kinase modulators as promising therapeutics for diseases characterized by insulin resistance.
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA ixwang@umich.edu vgcheung@umich.edu.
authors.forename: Isabel Xiaorong
authors.initials: IX
authors.lastname: Wang
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, MD, USA.
authors.forename: Girish
authors.initials: G
authors.lastname: Ramrattan
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA Howard Hughes Medical Institute, Chevy Chase, MD, USA Departments of Pediatrics and Genetics, University of Michigan, Ann Arbor, MI, USA ixwang@umich.edu vgcheung@umich.edu.
authors.forename: Vivian G
authors.initials: VG
authors.lastname: Cheung
mesh_terms: D002352:Carrier Proteins / Q000235:genetics; D052816:Foreskin / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000235:genetics; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006801:Humans; D007231:Infant, Newborn; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D020935:MAP Kinase Signaling System; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: C446513:ARAP1 protein, human; D002352:Carrier Proteins; D020690:GTPase-Activating Proteins; D007328:Insulin; D009363:Neoplasm Proteins; C477698:THADA protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt
keywords: DNA variants; individual variation; insulin response; signal transduction; type 2 diabetes