FIG. 1. Proposed model for leucine's role in mitogenic signaling. α-KG,α-ketoglutarate; AOAA, aminooxyacetic acid; AT, aminotransferase; BCKDH,branched-chain α—keto-acid dehydrogenase; GDH, glutamate dehydrogenase; IR, insulin receptor; IRS, insulin receptor substrate;p70^s6k, p70 S6 kinase; PHAS-I, phosphorylated heat- and acid-stable protein regulated by insulin; PKB, protein kinase B. FIG. 1. Proposed model for leucine's role in mitogenic signaling. α-KG,α-ketoglutarate; AOAA, aminooxyacetic acid; AT, aminotransferase; BCKDH,branched-chain α—keto-acid dehydrogenase; GDH, glutamate dehydrogenase; IR, insulin receptor; IRS, insulin receptor substrate;p70s6k, p70 S6 kinase; PHAS-I, phosphorylated heat- and acid-stable protein regulated by insulin; PKB, protein kinase B. More

FIG. 2. The three nutrient-sensing pathways, mTOR, AMPK, and SIRT1, may be independently and coordinately involved in the pathogenesis of diabetic nephropathy. 4E-BP, 4E-binding protein; COX2, cyclooxygenase-2; eNOS, endothelial nitric oxide synthase; EPO, erythropoietin; FoxO, forkhead box class ... More

Figure 4 Schema depicting roles of SS ceramides in insulin resistance under postabsorptive conditions. There are two possible explanations for the data regarding SS ceramide concentrations and de novo synthesis of ceramides to insulin resistance. One model depicts the circumstance in which, when p... More

FIG. 4. Integration of the metabolomics with transcriptomics data and their superimposition to build metabolic networks. A: Metabolic network of PPAR transcription pathway, which is connected to other metabolic processes such as lipid homeostasis, glucose, fatty acid metabolism, and inflammatory response. B: Network model of downstream of insulin-signaling pathways. The metabolites and the gene names shown in red are upregulated, and the same shown in blue are downregulated during insulin deficiency. B, binding; C, cleavage; CoA, coenzyme A; Erk, extracellular signal–related kinase; HPODE, hydroperoxylinoleic acid; IE, influence on expression; MAP, mitogen-activated protein; MAPK, MAP kinase; PDGF, platelet-derived growth factor; PI3K, phosphatidylinositol 3-kinase; PKA, cAMP-dependent protein kinase; PKB, protein kinase B; P-, dephosphorylation; RXR, retinoid X receptor; SREBP1c, sterol regulatory element–binding protein 1c; T, transformation; TGF, transforming growth factor; TR, transcription regulation; +P, phosphorylation; Z, catalysis; GPCR, G protein-coupled receptor; 15d-PGJ2, deoxy-delta prostaglandin J₂; PDK/PDK1, 3-phosphoinositide-dependent protein kinase -1; ACACA, acetyl-CoA carboxylase; ACSL, acyl-CoA synthetase long-chain family members; ACLY, ATP citrate lyase; BCAA, branch chain amino acid; CISY, citrate synthase; DAG, diacylglycerol; ELOVL, elongation-of-very-long-chain-fatty acids; EMT, epithelial-mesenchymal transition; BEH, ethylene-bridged hybrid; 4E-BP1, eukaryotic translation initiation factor 4E binding protein 1; FADS1, fatty acid desaturase 1; FASN, fatty acid synthase; GSK3β, glycogen synthase kinase 3; GNAS, G protein αs- dependent adenylate cyclase; GRB2, growth factor receptor-bound protein 2; H-Ras, Harvey rat sarcoma viral oncogene homolog; HGF, hepatocyte growth factor; HXK, hexokinase; HSS, high-strength silica; HODE, hydroxyoctadecadienoic acid; INSIG2, insulin-induced gene 2; IRS-1 and IRS-2, insulin receptor substrates-1 and -2; TRIP, mediator complex subunit 1; MEK/MAP1, mitogen-activated protein kinase kinase 1; NCOA1, nuclear receptor coactivator 1; NRC1/SRC1, nuclear receptor coactivator 1; N-CoR, nuclear receptor corepressor; SMRT, nuclear receptor corepressors; NUDT1, nudix (nucleoside diphosphate-linked moiety X)-type motif 1; PtdIns(3,4,5)P₃, phosphatidylinositol 3,4,5-triphosphate; P13K, phospatidylinositol 3-kinase; PtdIns(4,5)P₂, phosphatidylinositol 4,5-biphosphate; PGE, prostaglandin; PTGIS, prostaglandin I₂ (prostacyclin) synthase; PDGHS, prostaglandin-endoperoxide synthase 2 prostaglandin G/H synthase; COX2, cyclooxygenase 2; PDHA, pyruvate dehydrogenase (lipoamide) α1; QCs, quality controls; RARs, retinoic acid receptors; RXRA, retinoid X nuclear receptor (α; SHC, Src homology 2 domain containing transforming protein 1; SHP, small heterodimer partner; SOS, son of sevenless protein homologs 1 and 2; c-Raf-1, gene homolog 1; XIAP, X-linked inhibitor of apoptosis. FIG. 4. Integration of the metabolomics with transcriptomics data and their superimposition to build metabolic networks. A: Metabolic network of PPAR transcription pathway, which is connected to other metabolic processes such as lipid homeostasis, glucose, fatty acid metabolism, and inflammatory response. B: Network model of downstream of insulin-signaling pathways. The metabolites and the gene names shown in red are upregulated, and the same shown in blue are downregulated during insulin deficiency. B, binding; C, cleavage; CoA, coenzyme A; Erk, extracellular signal–related kinase; HPODE, hydroperoxylinoleic acid; IE, influence on expression; MAP, mitogen-activated protein; MAPK, MAP kinase; PDGF, platelet-derived growth factor; PI3K, phosphatidylinositol 3-kinase; PKA, cAMP-dependent protein kinase; PKB, protein kinase B; P-, dephosphorylation; RXR, retinoid X receptor; SREBP1c, sterol regulatory element–binding protein 1c; T, transformation; TGF, transforming growth factor; TR, transcription regulation; +P, phosphorylation; Z, catalysis; GPCR, G protein-coupled receptor; 15d-PGJ2, deoxy-delta prostaglandin J2; PDK/PDK1, 3-phosphoinositide-dependent protein kinase -1; ACACA, acetyl-CoA carboxylase; ACSL, acyl-CoA synthetase long-chain family members; ACLY, ATP citrate lyase; BCAA, branch chain amino acid; CISY, citrate synthase; DAG, diacylglycerol; ELOVL, elongation-of-very-long-chain-fatty acids; EMT, epithelial-mesenchymal transition; BEH, ethylene-bridged hybrid; 4E-BP1, eukaryotic translation initiation factor 4E binding protein 1; FADS1, fatty acid desaturase 1; FASN, fatty acid synthase; GSK3β, glycogen synthase kinase 3; GNAS, G protein αs- dependent adenylate cyclase; GRB2, growth factor receptor-bound protein 2; H-Ras, Harvey rat sarcoma viral oncogene homolog; HGF, hepatocyte growth factor; HXK, hexokinase; HSS, high-strength silica; HODE, hydroxyoctadecadienoic acid; INSIG2, insulin-induced gene 2; IRS-1 and IRS-2, insulin receptor substrates-1 and -2; TRIP, mediator complex subunit 1; MEK/MAP1, mitogen-activated protein kinase kinase 1; NCOA1, nuclear receptor coactivator 1; NRC1/SRC1, nuclear receptor coactivator 1; N-CoR, nuclear receptor corepressor; SMRT, nuclear receptor corepressors; NUDT1, nudix (nucleoside diphosphate-linked moiety X)-type motif 1; PtdIns(3,4,5)P3, phosphatidylinositol 3,4,5-triphosphate; P13K, phospatidylinositol 3-kinase; PtdIns(4,5)P2, phosphatidylinositol 4,5-biphosphate; PGE, prostaglandin; PTGIS, prostaglandin I2 (prostacyclin) synthase; PDGHS, prostaglandin-endoperoxide synthase 2 prostaglandin G/H synthase; COX2, cyclooxygenase 2; PDHA, pyruvate dehydrogenase (lipoamide) α1; QCs, quality controls; RARs, retinoic acid receptors; RXRA, retinoid X nuclear receptor (α; SHC, Src homology 2 domain containing transforming protein 1; SHP, small heterodimer partner; SOS, son of sevenless protein homologs 1 and 2; c-Raf-1, gene homolog 1; XIAP, X-linked inhibitor of apoptosis. 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FIG. 4. Integration of the metabolomics with transcriptomics data and their superimposition to build metabolic networks. A: Metabolic network of PPAR transcription pathway, which is connected to other metabolic processes such as lipid homeostasis, glucose, fatty acid metabolism, and inflammatory response. B: Network model of downstream of insulin-signaling pathways. The metabolites and the gene names shown in red are upregulated, and the same shown in blue are downregulated during insulin deficiency. B, binding; C, cleavage; CoA, coenzyme A; Erk, extracellular signal–related kinase; HPODE, hydroperoxylinoleic acid; IE, influence on expression; MAP, mitogen-activated protein; MAPK, MAP kinase; PDGF, platelet-derived growth factor; PI3K, phosphatidylinositol 3-kinase; PKA, cAMP-dependent protein kinase; PKB, protein kinase B; P-, dephosphorylation; RXR, retinoid X receptor; SREBP1c, sterol regulatory element–binding protein 1c; T, transformation; TGF, transforming growth factor; TR, transcription regulation; +P, phosphorylation; Z, catalysis; GPCR, G protein-coupled receptor; 15d-PGJ2, deoxy-delta prostaglandin J₂; PDK/PDK1, 3-phosphoinositide-dependent protein kinase -1; ACACA, acetyl-CoA carboxylase; ACSL, acyl-CoA synthetase long-chain family members; ACLY, ATP citrate lyase; BCAA, branch chain amino acid; CISY, citrate synthase; DAG, diacylglycerol; ELOVL, elongation-of-very-long-chain-fatty acids; EMT, epithelial-mesenchymal transition; BEH, ethylene-bridged hybrid; 4E-BP1, eukaryotic translation initiation factor 4E binding protein 1; FADS1, fatty acid desaturase 1; FASN, fatty acid synthase; GSK3β, glycogen synthase kinase 3; GNAS, G protein αs- dependent adenylate cyclase; GRB2, growth factor receptor-bound protein 2; H-Ras, Harvey rat sarcoma viral oncogene homolog; HGF, hepatocyte growth factor; HXK, hexokinase; HSS, high-strength silica; HODE, hydroxyoctadecadienoic acid; INSIG2, insulin-induced gene 2; IRS-1 and IRS-2, insulin receptor substrates-1 and -2; TRIP, mediator complex subunit 1; MEK/MAP1, mitogen-activated protein kinase kinase 1; NCOA1, nuclear receptor coactivator 1; NRC1/SRC1, nuclear receptor coactivator 1; N-CoR, nuclear receptor corepressor; SMRT, nuclear receptor corepressors; NUDT1, nudix (nucleoside diphosphate-linked moiety X)-type motif 1; PtdIns(3,4,5)P₃, phosphatidylinositol 3,4,5-triphosphate; P13K, phospatidylinositol 3-kinase; PtdIns(4,5)P₂, phosphatidylinositol 4,5-biphosphate; PGE, prostaglandin; PTGIS, prostaglandin I₂ (prostacyclin) synthase; PDGHS, prostaglandin-endoperoxide synthase 2 prostaglandin G/H synthase; COX2, cyclooxygenase 2; PDHA, pyruvate dehydrogenase (lipoamide) α1; QCs, quality controls; RARs, retinoic acid receptors; RXRA, retinoid X nuclear receptor (α; SHC, Src homology 2 domain containing transforming protein 1; SHP, small heterodimer partner; SOS, son of sevenless protein homologs 1 and 2; c-Raf-1, gene homolog 1; XIAP, X-linked inhibitor of apoptosis. FIG. 4. Integration of the metabolomics with transcriptomics data and their superimposition to build metabolic networks. A: Metabolic network of PPAR transcription pathway, which is connected to other metabolic processes such as lipid homeostasis, glucose, fatty acid metabolism, and inflammatory response. B: Network model of downstream of insulin-signaling pathways. The metabolites and the gene names shown in red are upregulated, and the same shown in blue are downregulated during insulin deficiency. B, binding; C, cleavage; CoA, coenzyme A; Erk, extracellular signal–related kinase; HPODE, hydroperoxylinoleic acid; IE, influence on expression; MAP, mitogen-activated protein; MAPK, MAP kinase; PDGF, platelet-derived growth factor; PI3K, phosphatidylinositol 3-kinase; PKA, cAMP-dependent protein kinase; PKB, protein kinase B; P-, dephosphorylation; RXR, retinoid X receptor; SREBP1c, sterol regulatory element–binding protein 1c; T, transformation; TGF, transforming growth factor; TR, transcription regulation; +P, phosphorylation; Z, catalysis; GPCR, G protein-coupled receptor; 15d-PGJ2, deoxy-delta prostaglandin J2; PDK/PDK1, 3-phosphoinositide-dependent protein kinase -1; ACACA, acetyl-CoA carboxylase; ACSL, acyl-CoA synthetase long-chain family members; ACLY, ATP citrate lyase; BCAA, branch chain amino acid; CISY, citrate synthase; DAG, diacylglycerol; ELOVL, elongation-of-very-long-chain-fatty acids; EMT, epithelial-mesenchymal transition; BEH, ethylene-bridged hybrid; 4E-BP1, eukaryotic translation initiation factor 4E binding protein 1; FADS1, fatty acid desaturase 1; FASN, fatty acid synthase; GSK3β, glycogen synthase kinase 3; GNAS, G protein αs- dependent adenylate cyclase; GRB2, growth factor receptor-bound protein 2; H-Ras, Harvey rat sarcoma viral oncogene homolog; HGF, hepatocyte growth factor; HXK, hexokinase; HSS, high-strength silica; HODE, hydroxyoctadecadienoic acid; INSIG2, insulin-induced gene 2; IRS-1 and IRS-2, insulin receptor substrates-1 and -2; TRIP, mediator complex subunit 1; MEK/MAP1, mitogen-activated protein kinase kinase 1; NCOA1, nuclear receptor coactivator 1; NRC1/SRC1, nuclear receptor coactivator 1; N-CoR, nuclear receptor corepressor; SMRT, nuclear receptor corepressors; NUDT1, nudix (nucleoside diphosphate-linked moiety X)-type motif 1; PtdIns(3,4,5)P3, phosphatidylinositol 3,4,5-triphosphate; P13K, phospatidylinositol 3-kinase; PtdIns(4,5)P2, phosphatidylinositol 4,5-biphosphate; PGE, prostaglandin; PTGIS, prostaglandin I2 (prostacyclin) synthase; PDGHS, prostaglandin-endoperoxide synthase 2 prostaglandin G/H synthase; COX2, cyclooxygenase 2; PDHA, pyruvate dehydrogenase (lipoamide) α1; QCs, quality controls; RARs, retinoic acid receptors; RXRA, retinoid X nuclear receptor (α; SHC, Src homology 2 domain containing transforming protein 1; SHP, small heterodimer partner; SOS, son of sevenless protein homologs 1 and 2; c-Raf-1, gene homolog 1; XIAP, X-linked inhibitor of apoptosis. More