Schematic flow chart of the generation and evaluation of the MITIN network.

<p>The different sources of functional interaction are combined to generate a functional interactome. The resulting network is used to identify the direct and indirect interactions between the insulin signaling and mitochondria systems. The relevance of the MITIN network is tested analyzing gene expression data of models perturbing either insulin signaling or mitochondria function, and testing the variability within or near the MITIN network genes using GWA meta-analyses from DIAGRAM consortium. *In all PPIhigh and PPIcorr, both pair of interacting proteins have to be simultaneously expressed in any of the insulin-targeted tissues (adipose tissue, muscle, liver and heart).</p

Gene set enrichment analysis.

<p>Gene set enrichment analysis of models with impaired Insulin (a, c) or mitochondrial (b) function. In all cases there was enrichment of upregulated genes within the internodes, except for the case when internodes were generated from a random network (d).</p

Strong candidates linking both insulin and mitochondria genes.

<p>The internode genes listed in the table have at least three lines of evidence that link them to the mitochondria and three to insulin signaling.</p>#<p>Above 95% percentile of T2D association gene scores based on DIAGRAM meta-analysis (see <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003046#pgen-1003046-t002" target="_blank">Table 2</a>).</p>*<p>Associated to HOMA-IR(9.74E–6) <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003046#pgen.1003046-Dupuis1" target="_blank">[42]</a>.</p

Internode genes that fall in the 95% percentile of T2D association gene scores based on DIAGRAM meta-analysis using MAGENTA, and putative associations with T2D-related traits.

<p>Associations were looked-up in GWAS meta-analyses from the MAGIC, GIANT and ICBP consortiums for SNPs within 500 kb from the internode gene boundaries.</p>*<p>upregulated in our chronic insulin treatment (fold change = 1.4; FDR = 0.004) and in the Dor RNAi experiment (fold change = 1.33; FDR = 0.1).</p>**<p>Chromosome position based on genome build 36 (hg18).</p>#<p>Within the high confidence internode set.</p><p>BMI: Body Mass Index; HDL: High Density Lipoprotein; LDL: Low Density Lipoprotein; 2 hrGluc: 2 hours glucose challenge; TC: total Cholesterol; WHR: Waist to Hip Ratio; TG: Triglycerides; DBP:Diastolic Blood Pressure; SBP: Systolic Blood Pressure; HbA1C: Glycaeted Hemoglobin; FastGluc: Fasting Glucose levels; HGNC: HUGO Gene Nomenclature committee.</p

Connections of two internode genes, TRAF2 and NFKB1, with insulin genes and mitochondria genes.

<p>Two strong candidates linking both insulin and mitochondria genes from <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003046#pgen-1003046-t001" target="_blank">Table 1</a> were chosen and their connections to insulin genes and mitochondria genes verified using literature published in the PubMed. See main text for detailed description. A) TRAF2 has been reported to be connected to MAP3K1 (MEKK1) and CAV1 (caveolin 1) insulin genes, and to MAP3K5 (ASK1) and CASP8 (caspase-8) mitochondrial genes. A possible connection to MTOR (mTOR) has also to be considered. MAP3K5 = ASK1; MAP3K1 = MEKK1. B) NFKB1 (NF-κB1) is connected to IKBKB (IKKβ), AKT2, MAP3K1 and SOCS3 insulin genes, and BCL2 and BCL2L1 mitochondrial genes. NFKB1 = NFKBp50; IKBKB = IKKβ = IKK2; MAP3K1 = MEKK1; P65 = RelA. Green boxes represent insulin genes reported to interact with TRAF2 or NFKB1 according to our network; and light-blue represents mitochondrial genes reported to interact with TRAF2 or NFKB1 according to our network. Yellow boxes represent insulin signaling genes.</p