Effect of insulin on the phosphoproteome of skeletal muscles in normal conditions and with insulin resistance

Abstract

The skeletal muscles are the main site of insulin-dependent glucose uptake, and the development of insulin resistance in skeletal muscles is the main factor in the progression of insulin resistance in the whole organism. This disorder is associated with defects in the canonical insulin cascade regulating glucose uptake; however, the specific molecular mechanisms are still debatable. Global mass spectrometry-based phosphoproteomic analysis appears to be an optimal approach to studying complex signaling networks.

The review summarizes data from phosphoproteomic studies investigating changes in intracellular signaling in skeletal muscles upon insulin stimulation under normal conditions and insulin resistance. In vitro and in vivo studies have shown that insulin stimulation/food intake causes large-scale changes in the phosphoproteome (hundreds of phosphosites). These changes affect not only the canonical insulin cascades but also other signaling pathways and proteins with different functions (enzymes of carbohydrate and fat metabolism, sarcomeric and mitochondrial proteins, transcription factors, chaperones, etc.) and cause transcriptomic changes. Insulin resistance impairs the phosphoproteomic response to insulin; however, these changes only slightly affect the canonical insulin cascade regulating glucose uptake. The causes of impairments in insulin-dependent glucose uptake are hypothesized to be related primarily by a combination of multiple defects in various signaling molecules that regulate glucose uptake directly or indirectly; however, they are not associated with the canonical insulin cascade.

Keywords

insulin / skeletal muscle / type 2 diabetes mellitus / kinases / phosphorylation

References

[1] Khan MAB, Hashim MJ, King JK, et al. Epidemiology of type 2 diabetes — global burden of disease and forecasted trends. J Epidemiol Glob Health. 2020;10(1):107–111. doi: 10.2991/jegh.k.191028.001

[2] Khan M.A.B., Hashim M.J., King J.K., et al. Epidemiology of type 2 diabetes — global burden of disease and forecasted trends // J Epidemiol Glob Health. 2020. Vol. 10, N 1. P. 107–111. doi: 10.2991/jegh.k.191028.001

[3] Gray N, Picone G, Sloan F, Yashkin A. Relation between BMI and diabetes mellitus and its complications among US older adults. South Med J. 2015;108(1):29–36. doi: 10.14423/SMJ.0000000000000214

[4] Gray N., Picone G., Sloan F., Yashkin A. Relation between BMI and diabetes mellitus and its complications among US older adults // South Med J. 2015. Vol. 108, N 1. P. 29–36. doi: 10.14423/SMJ.0000000000000214

[5] Karin A, Jon E, Martin A, et al. Body mass index in adolescence, risk of type 2 diabetes and associated complications: a nationwide cohort study of men. EClinicalMedicine. 2022;46:101356. doi: 10.1016/j.eclinm.2022.101356

[6] Karin A., Jon E., Martin A., et al. Body mass index in adolescence, risk of type 2 diabetes and associated complications: a nationwide cohort study of men // EClinicalMedicine. 2022. Vol. 46. P. 101356. doi: 10.1016/j.eclinm.2022.101356

[7] Merz KE, Thurmond DC. Role of skeletal muscle in insulin resistance and glucose uptake. Compr Physiol. 2020;10(3):785–809. doi: 10.1002/cphy.c190029

[8] Merz K.E., Thurmond D.C. Role of skeletal muscle in insulin resistance and glucose uptake // Compr Physiol. 2020. Vol. 10, N 3. P. 785–809. doi: 10.1002/cphy.c190029

[9] DeFronzo RA, Gunnarsson R, Björkman O, et al. Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. J Clin Invest. 1985;76(1):149–155. doi: 10.1172/JCI111938

[10] DeFronzo R.A., Gunnarsson R., Bjorkman O., et al. Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus // J Clin Invest. 1985. Vol. 76, N 1. P. 149–155. doi: 10.1172/JCI111938

[11] Petersen MC, Shulman GI. Mechanisms of insulin action and insulin resistance. Physiol Rev. 2018;98(4):2133–2223. doi: 10.1152/physrev.00063.2017

[12] Petersen M.C., Shulman G.I. Mechanisms of insulin action and insulin resistance // Physiol Rev. 2018. Vol. 98, N 4. P. 2133–2223. doi: 10.1152/physrev.00063.2017

[13] James DE, Stöckli J, Birnbaum MJ. The aetiology and molecular landscape of insulin resistance. Nat Rev Mol Cell Biol. 2021;22(11):751–771. doi: 10.1038/s41580-021-00390-6

[14] James D.E., Stöckli J., Birnbaum M.J. The aetiology and molecular landscape of insulin resistance // Nat Rev Mol Cell Biol. 2021. Vol. 22, N 11. P. 751–771. doi: 10.1038/s41580-021-00390-6

[15] Needham EJ, Parker BL, Burykin T, et al. Illuminating the dark phosphoproteome. Sci Signal. 2019;12(565):eaau8645. doi: 10.1126/scisignal.aau8645

[16] Needham E.J., Parker B.L., Burykin T., et al. Illuminating the dark phosphoproteome // Sci Signal. 2019. Vol. 12, N 565. P. eaau8645. doi: 10.1126/scisignal.aau8645

[17] Batista TM, Jayavelu AK, Wewer Albrechtsen NJ, et al. A cell-autonomous signature of dysregulated protein phosphorylation underlies muscle insulin resistance in type 2 diabetes. Cell Metab. 2020;32(5):844–859.e5. doi: 10.1016/j.cmet.2020.08.007

[18] Batista T.M., Jayavelu A.K., Wewer Albrechtsen N.J., et al. A cell-autonomous signature of dysregulated protein phosphorylation underlies muscle insulin resistance in type 2 diabetes // Cell Metab. 2020. Vol. 32, N 5. P. 844–859. doi: 10.1016/j.cmet.2020.08.007

[19] Haider N, Lebastchi J, Jayavelu AK, et al. Signaling defects associated with insulin resistance in nondiabetic and diabetic individuals and modification by sex. J Clin Invest. 2021;131(21):e151818. doi: 10.1172/JCI151818

[20] Haider N., Lebastchi J., Jayavelu A.K., et al. Signaling defects associated with insulin resistance in nondiabetic and diabetic individuals and modification by sex // J Clin Invest. 2021. Vol. 131, N 21. P. e151818. doi: 10.1172/JCI151818

[21] Kettenbach AN, Sano H, Keller SR, et al. SPECHT — single-stage phosphopeptide enrichment and stable-isotope chemical tagging: quantitative phosphoproteomics of insulin action in muscle. J Proteomics. 2015;114:48–60. doi: 10.1016/j.jprot.2014.11.001

[22] Kettenbach A.N., Sano H., Keller S.R., et al. SPECHT — single-stage phosphopeptide enrichment and stable-isotope chemical tagging: quantitative phosphoproteomics of insulin action in muscle // J Proteomics. 2015. Vol. 114. P. 48–60. doi: 10.1016/j.jprot.2014.11.001

[23] Small L, Brandon AE, Parker BL, et al. Reduced insulin action in muscle of high fat diet rats over the diurnal cycle is not associated with defective insulin signaling. Mol Metab. 2019;25:107–118. doi: 10.1016/j.molmet.2019.04.006

[24] Small L., Brandon A.E., Parker B.L., et al. Reduced insulin action in muscle of high fat diet rats over the diurnal cycle is not associated with defective insulin signaling // Mol Metab. 2019. Vol. 25. P. 107–118. doi: 10.1016/j.molmet.2019.04.006

[25] van Gerwen J, Masson SWC, Cutler HB, et al., The genetic and dietary landscape of the muscle insulin signalling network. Elife. 2024;12:RP89212. doi: 10.7554/eLife.89212

[26] van Gerwen J., Masson S.W.C., Cutler H.B., et al. The genetic and dietary landscape of the muscle insulin signalling network // Elife. 2024. Vol. 12. P. RP89212. doi: 10.7554/eLife.89212

[27] Needham EJ, Hingst JR, Parker BL, et al. Personalized phosphoproteomics identifies functional signaling. Nat Biotechnol. 2022;40(4):576–584. doi: 10.1038/s41587-021-01099-9

[28] Needham E.J., Hingst J.R., Parker B.L., et al. Personalized phosphoproteomics identifies functional signaling // Nat Biotechnol. 2022. Vol. 40, N 4. P. 576–584. doi: 10.1038/s41587-021-01099-9

[29] Zhao X, Bak S, Pedersen AJ, et al. Insulin increases phosphorylation of mitochondrial proteins in human skeletal muscle in vivo. J Proteome Res. 2014;13(5):2359–2369. doi: 10.1021/pr401163t

[30] Zhao X., Bak S., Pedersen A.J., et al. Insulin increases phosphorylation of mitochondrial proteins in human skeletal muscle in vivo // J Proteome Res. 2014. Vol. 13, N 5. P. 2359–2369. doi: 10.1021/pr401163t

[31] Needham EJ, Hingst JR, Onslev JD, et al. Personalized phosphoproteomics of skeletal muscle insulin resistance and exercise links MINDY1 to insulin action. medRxiv. 2024. doi: 10.1101/2024.03.11.24304084

[32] Needham E.J., Hingst J.R., Onslev J.D., et al. Personalized phosphoproteomics of skeletal muscle insulin resistance and exercise links MINDY1 to insulin action // medRxiv. 2024. doi: 10.1101/2024.03.11.24304084

[33] Yadav Y, Dey CS. Ser/Thr phosphatases: one of the key regulators of insulin signaling. Rev Endocr Metab Disord. 2022;23(5):905–917. doi: 10.1007/s11154-022-09727-8

[34] Yadav Y., Dey C.S. Ser/Thr phosphatases: one of the key regulators of insulin signaling // Rev Endocr Metab Disord. 2022. Vol. 23, N 5. P. 905–917. doi: 10.1007/s11154-022-09727-8

[35] Boucher J, Kleinridders A, Kahn CR. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol. 2014;6(1):a009191. doi: 10.1101/cshperspect.a009191

[36] Boucher J., Kleinridders A., Kahn C.R. Insulin receptor signaling in normal and insulin-resistant states // Cold Spring Harb Perspect Biol. 2014. Vol. 6, N 1. P. a009191. doi: 10.1101/cshperspect.a009191

[37] White MF, Kahn CR. Insulin action at a molecular level — 100 years of progress. Mol Metab. 2021;52:101304. doi: 10.1016/j.molmet.2021.101304

[38] White M.F., Kahn C.R. Insulin action at a molecular level — 100 years of progress // Mol Metab. 2021. Vol. 52. P. 101304. doi: 10.1016/j.molmet.2021.101304

[39] Hubbard SR. The insulin receptor: both a prototypical and atypical receptor tyrosine kinase. Cold Spring Harb Perspect Biol. 2013;5(3):a008946. doi: 10.1101/cshperspect.a008946

[40] Hubbard S.R. The insulin receptor: both a prototypical and atypical receptor tyrosine kinase // Cold Spring Harb Perspect Biol. 2013. Vol. 5, N 3. P. a008946. doi: 10.1101/cshperspect.a008946

[41] Sasaoka T, Kobayashi M. The functional significance of Shc in insulin signaling as a substrate of the insulin receptor. Endocr J. 2000;47(4):373–381. doi: 10.1507/endocrj.47.373

[42] Sasaoka T., Kobayashi M. The functional significance of Shc in insulin signaling as a substrate of the insulin receptor // Endocr J. 2000. Vol. 47, N 4. P. 373–381. doi: 10.1507/endocrj.47.373

[43] Zhang J, Liu F. Tissue-specific insulin signaling in the regulation of metabolism and aging. IUBMB Life. 2014;66(7):485–495. doi: 10.1002/iub.1293

[44] Zhang J., Liu F. Tissue-specific insulin signaling in the regulation of metabolism and aging // IUBMB Life. 2014. Vol. 66, N 7. P. 485–495. doi: 10.1002/iub.1293

[45] Beeson M, Sajan MP, Dizon M, et al. Activation of protein kinase C-zeta by insulin and phosphatidylinositol-3,4,5-(PO4)3 is defective in muscle in type 2 diabetes and impaired glucose tolerance: amelioration by rosiglitazone and exercise. Diabetes. 2003;52(8):1926–1934. doi: 10.2337/diabetes.52.8.1926

[46] Beeson M., Sajan M.P., Dizon M., et al. Activation of protein kinase C-zeta by insulin and phosphatidylinositol-3,4,5-(PO4)3 is defective in muscle in type 2 diabetes and impaired glucose tolerance: amelioration by rosiglitazone and exercise // Diabetes. 2003. Vol. 52, N 8. P. 1926–1934. doi: 10.2337/diabetes.52.8.1926

[47] Higaki, Y, Wojtaszewski JF, Hirshman MF, et al. Insulin receptor substrate-2 is not necessary for insulin- and exercise-stimulated glucose transport in skeletal muscle. J Biol Chem. 1999;274(30):20791–20795. doi: 10.1074/jbc.274.30.20791

[48] Higaki Y., Wojtaszewski J.F., Hirshman M.F., et al. Insulin receptor substrate-2 is not necessary for insulin- and exercise-stimulated glucose transport in skeletal muscle // J Biol Chem. 1999. Vol. 274, N 30. P. 20791–20795. doi: 10.1074/jbc.274.30.20791

[49] Gao X, Lowry PR, Zhou X, et al. PI3K/Akt signaling requires spatial compartmentalization in plasma membrane microdomains. Proc Natl Acad Sci U S A. 2011;108(35):14509–14514. doi: 10.1073/pnas.1019386108

[50] Gao X., Lowry P.R., Zhou X., et al. PI3K/Akt signaling requires spatial compartmentalization in plasma membrane microdomains // Proc Natl Acad Sci U S A. 2011. Vol. 108, N 35. P. 14509–14514. doi: 10.1073/pnas.1019386108

[51] Demir S, Nawroth PP, Herzig S, Ekim Üstünel B. Emerging targets in type 2 diabetes and diabetic complications. Adv Sci (Weinh). 2021;8(18):e2100275. doi: 10.1002/advs.202100275

[52] Demir S., Nawroth P.P., Herzig S., Ekim Üstünel B. Emerging targets in type 2 diabetes and diabetic complications // Adv Sci (Weinh). 2021. Vol. 8, N 18. P. e2100275. doi: 10.1002/advs.202100275

[53] Cho H, Mu J, Kim JK, et al. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science. 2001;292(5522):1728–1731. doi: 10.1126/science.292.5522.1728

[54] Cho H., Mu J., Kim J.K., et al. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta) // Science. 2001. Vol. 292, N 5522. P. 1728–1731. doi: 10.1126/science.292.5522.1728

[55] Cho H, Thorvaldsen JL, Chu Q, et al. Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J Biol Chem. 2001;276(42):38349–38352. doi: 10.1074/jbc.C100462200

[56] Cho H., Thorvaldsen J.L., Chu Q., et al. Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice // J Biol Chem. 2001. Vol. 276, N 42. P. 38349–38352. doi: 10.1074/jbc.C100462200

[57] Sano H, Eguez L, Teruel MN, et al. Rab10, a target of the AS160 Rab GAP, is required for insulin-stimulated translocation of GLUT4 to the adipocyte plasma membrane. Cell Metab. 2007;5(4):293–303. doi: 10.1016/j.cmet.2007.03.001

[58] Sano H., Eguez L., Teruel M.N., et al. Rab10, a target of the AS160 Rab GAP, is required for insulin-stimulated translocation of GLUT4 to the adipocyte plasma membrane // Cell Metab. 2007. Vol. 5, N 4. P. 293–303. doi: 10.1016/j.cmet.2007.03.001

[59] Friedrichsen M, Birk JB, Richter EA, et al. Akt2 influences glycogen synthase activity in human skeletal muscle through regulation of NH₂-terminal (sites 2 + 2a) phosphorylation. Am J Physiol Endocrinol Metab. 2013;304(6):E631–E639. doi: 10.1152/ajpendo.00494.2012

[60] Friedrichsen M., Birk J.B., Richter E.A., et al. Akt2 influences glycogen synthase activity in human skeletal muscle through regulation of NH(2)-terminal (sites 2 + 2a) phosphorylation // Am J Physiol Endocrinol Metab. 2013. Vol. 304, N 6. P. E631–E639. doi: 10.1152/ajpendo.00494.2012

[61] Manning BD, Toker A. AKT/PKB signaling: navigating the network. Cell. 2017;169(3):381–405. doi: 10.1016/j.cell.2017.04.001

[62] Manning B.D., Toker A. AKT/PKB signaling: navigating the network // Cell. 2017. Vol. 169, N 3. P. 381–405. doi: 10.1016/j.cell.2017.04.001

[63] Sakaguchi M, Cai W, Wang CH, et al. FoxK1 and FoxK2 in insulin regulation of cellular and mitochondrial metabolism. Nat Commun. 2019;10(1):1582. doi: 10.1038/s41467-019-09418-0

[64] Sakaguchi M., Cai W., Wang C.H., et al. FoxK1 and FoxK2 in insulin regulation of cellular and mitochondrial metabolism // Nat Commun. 2019. Vol. 10, N 1. P. 1582. doi: 10.1038/s41467-019-09418-0

[65] Karlsson HKR, Kasahara A, Ikeda M, et al. Quantitative phosphoproteomic analysis of IRS1 in skeletal muscle from men with normal glucose tolerance or type 2 diabetes: a case-control study. Metabolism. 2021;118:154726. doi: 10.1016/j.metabol.2021.154726

[66] Karlsson H.K.R., Kasahara A., Ikeda M., et al. Quantitative phosphoproteomic analysis of IRS1 in skeletal muscle from men with normal glucose tolerance or type 2 diabetes: a case-control study // Metabolism. 2021. Vol. 118. P. 154726. doi: 10.1016/j.metabol.2021.154726

[67] Langlais P, Yi Z, Finlayson J, et al. Global IRS-1 phosphorylation analysis in insulin resistance. Diabetologia. 2011;54(11):2878–2889. doi: 10.1007/s00125-011-2271-9

[68] Langlais P., Yi Z., Finlayson J., et al. Global IRS-1 phosphorylation analysis in insulin resistance // Diabetologia. 2011. Vol. 54, N 11. P. 2878–2889. doi: 10.1007/s00125-011-2271-9

[69] Eshima H. Influence of obesity and type 2 diabetes on calcium handling by skeletal muscle: spotlight on the sarcoplasmic reticulum and mitochondria. Front Physiol. 2021;12:758316. doi: 10.3389/fphys.2021.758316

[70] Eshima H. Influence of obesity and type 2 diabetes on calcium handling by skeletal muscle: spotlight on the sarcoplasmic reticulum and mitochondria // Front Physiol. 2021. Vol. 12. P. 758316. doi: 10.3389/fphys.2021.758316

[71] Bijur GN, Jope RS. Rapid accumulation of Akt in mitochondria following phosphatidylinositol 3-kinase activation. J Neurochem. 2003;87(6):1427–1435. doi: 10.1046/j.1471-4159.2003.02113.x

[72] Bijur G.N., Jope R.S. Rapid accumulation of Akt in mitochondria following phosphatidylinositol 3-kinase activation // J Neurochem. 2003. Vol. 87, N 6. P. 1427–1435. doi: 10.1046/j.1471-4159.2003.02113.x

[73] Yang JY, Yeh HY, Lin K, Wang PH. Insulin stimulates Akt translocation to mitochondria: implications on dysregulation of mitochondrial oxidative phosphorylation in diabetic myocardium. J Mol Cell Cardiol. 2009;46(6):919–926. doi: 10.1016/j.yjmcc.2009.02.015

[74] Yang J.Y., Yeh H.Y., Lin K., Wang P.H. Insulin stimulates Akt translocation to mitochondria: implications on dysregulation of mitochondrial oxidative phosphorylation in diabetic myocardium // J Mol Cell Cardiol. 2009. Vol. 46, N 6. P. 919–926. doi: 10.1016/j.yjmcc.2009.02.015

[75] Makhnovskii PA, Lednev EM, Gavrilova AO, et al. Dysregulation of early gene response to a mixed meal in skeletal muscle in obesity and type 2 diabetes. Physiol Genomics. 2023;55(10):468–477. doi: 10.1152/physiolgenomics.00046.2023

[76] Makhnovskii P.A., Lednev E.M., Gavrilova A.O., et al. Dysregulation of early gene response to a mixed meal in skeletal muscle in obesity and type 2 diabetes // Physiol Genomics. 2023. Vol. 55, N 10. P. 468–477. doi: 10.1152/physiolgenomics.00046.2023

[77] Coletta DK, Balas B, Chavez AO, et al. Effect of acute physiological hyperinsulinemia on gene expression in human skeletal muscle in vivo. Am J Physiol Endocrinol Metab. 2008;294(5):E910–E917. doi: 10.1152/ajpendo.00607.2007

[78] Coletta D.K., Balas B., Chavez A.O., et al. Effect of acute physiological hyperinsulinemia on gene expression in human skeletal muscle in vivo // Am J Physiol Endocrinol Metab. 2008. Vol. 294, N 5. P. E910–E917. doi: 10.1152/ajpendo.00607.2007

[79] Rome S, Clément K, Rabasa-Lhoret R, et al. Microarray profiling of human skeletal muscle reveals that insulin regulates approximately 800 genes during a hyperinsulinemic clamp. J Biol Chem. 2003;278(20):18063–18068. doi: 10.1074/jbc.M300293200

[80] Rome S., Clement K., Rabasa-Lhoret R., et al. Microarray profiling of human skeletal muscle reveals that insulin regulates approximately 800 genes during a hyperinsulinemic clamp // J Biol Chem. 2003. Vol. 278, N 20. P. 18063–18068. doi: 10.1074/jbc.M300293200

[81] Wu X, Wang J, Cui X, et al. The effect of insulin on expression of genes and biochemical pathways in human skeletal muscle. Endocrine. 2007;31(1):5–17. Corrected and republished from: Endocrine. 2007;32(3):356. doi: 10.1007/s12020-007-0007-x

[82] Wu X., Wang J., Cui X., et al. The effect of insulin on expression of genes and biochemical pathways in human skeletal muscle // Endocrine. 2007. Vol. 31, N 1. P. 5–17. Corrected and republished from: Endocrine. 2007. Vol. 32, N 3. P. 356. doi: 10.1007/s12020-007-0007-x

[83] Archer AE, Von Schulze AT, Geiger PC. Exercise, heat shock proteins and insulin resistance. Philos Trans R Soc Lond B Biol Sci. 2018;373(1738):20160529. doi: 10.1098/rstb.2016.0529

[84] Archer A.E., Von Schulze A.T., Geiger P.C. Exercise, heat shock proteins and insulin resistance // Philos Trans R Soc Lond B Biol Sci. 2018. Vol. 373, N 1738. P. 20160529. doi: 10.1098/rstb.2016.0529

[85] Timofeev YS, Kiselev AR, Dzhioeva ON, Drapkina OM. Heat shock proteins (HSPs) and cardiovascular complications of obesity: searching for potential biomarkers. Curr Issues Mol Biol. 2023;45(12):9378–9389. doi: 10.3390/cimb45120588

[86] Timofeev Y.S., Kiselev A.R., Dzhioeva O.N., Drapkina O.M. Heat shock proteins (HSPs) and cardiovascular complications of obesity: searching for potential biomarkers // Curr Issues Mol Biol. 2023. Vol. 45, N 12. P. 9378–9389. doi: 10.3390/cimb45120588

[87] Krook A, Roth RA, Jiang XJ, et al. Insulin-stimulated Akt kinase activity is reduced in skeletal muscle from NIDDM subjects. Diabetes. 1998;47(8):1281–1286. doi: 10.2337/diab.47.8.1281

[88] Krook A., Roth R.A., Jiang X.J., et al. Insulin-stimulated Akt kinase activity is reduced in skeletal muscle from NIDDM subjects // Diabetes. 1998. Vol. 47, N 8. P. 1281–1286. doi: 10.2337/diab.47.8.1281

[89] Tonks KT, Ng Y, Miller S, et al. Impaired Akt phosphorylation in insulin-resistant human muscle is accompanied by selective and heterogeneous downstream defects. Diabetologia. 2013;56(4):875–885. doi: 10.1007/s00125-012-2811-y

[90] Tonks K.T., Ng Y., Miller S., et al. Impaired Akt phosphorylation in insulin-resistant human muscle is accompanied by selective and heterogeneous downstream defects // Diabetologia. 2013. Vol. 56, N 4. P. 875–885. doi: 10.1007/s00125-012-2811-y

[91] Albers PH, Pedersen AJ, Birk JB, et al. Human muscle fiber type-specific insulin signaling: impact of obesity and type 2 diabetes. Diabetes. 2015;64(2):485–497. doi: 10.2337/db14-0590

[92] Albers P.H., Pedersen A.J., Birk J.B., et al. Human muscle fiber type-specific insulin signaling: impact of obesity and type 2 diabetes // Diabetes. 2015. Vol. 64, N 2. P. 485–497. doi: 10.2337/db14-0590

[93] Vind BF, Birk JB, Vienberg SG, et al. Hyperglycaemia normalises insulin action on glucose metabolism but not the impaired activation of AKT and glycogen synthase in the skeletal muscle of patients with type 2 diabetes. Diabetologia. 2012;55(5):1435–1445. doi: 10.1007/s00125-012-2482-8

[94] Vind B.F., Birk J.B., Vienberg S.G., et al. Hyperglycaemia normalises insulin action on glucose metabolism but not the impaired activation of AKT and glycogen synthase in the skeletal muscle of patients with type 2 diabetes // Diabetologia. 2012. Vol. 55, N 5. P. 1435–1445. doi: 10.1007/s00125-012-2482-8

[95] Kim YB, Kotani K, Ciaraldi TP, et al. Insulin-stimulated protein kinase C lambda/zeta activity is reduced in skeletal muscle of humans with obesity and type 2 diabetes: reversal with weight reduction. Diabetes. 2003;52(8):1935–1942. doi: 10.2337/diabetes.52.8.1935

[96] Kim Y.B., Kotani K., Ciaraldi T.P., et al. Insulin-stimulated protein kinase C lambda/zeta activity is reduced in skeletal muscle of humans with obesity and type 2 diabetes: reversal with weight reduction // Diabetes. 2003. Vol. 52, N 8. P. 1935–1942. doi: 10.2337/diabetes.52.8.1935

[97] Kim YB, Nikoulina SE, Ciaraldi TP, et al. Normal insulin-dependent activation of Akt/protein kinase B, with diminished activation of phosphoinositide 3-kinase, in muscle in type 2 diabetes. J Clin Invest. 1999;104(6):733–741. doi: 10.1172/JCI6928

[98] Kim Y.B., Nikoulina S.E., Ciaraldi T.P., et al. Normal insulin-dependent activation of Akt/protein kinase B, with diminished activation of phosphoinositide 3-kinase, in muscle in type 2 diabetes // J Clin Invest. 1999. Vol. 104, N 6. P. 733–741. doi: 10.1172/JCI6928

[99] Bandyopadhyay GK, Yu JG, Ofrecio J, Olefsky JM. Increased p85/55/50 expression and decreased phosphotidylinositol 3-kinase activity in insulin-resistant human skeletal muscle. Diabetes. 2005;54(8):2351–2359. doi: 10.2337/diabetes.54.8.2351

[100] Bandyopadhyay G.K., Yu J.G., Ofrecio J., Olefsky J.M. Increased p85/55/50 expression and decreased phosphotidylinositol 3-kinase activity in insulin-resistant human skeletal muscle // Diabetes. 2005. Vol. 54, N 8. P. 2351–2359. doi: 10.2337/diabetes.54.8.2351

[101] Karlsson HK, Zierath JR, Kane S, et al. Insulin-stimulated phosphorylation of the Akt substrate AS160 is impaired in skeletal muscle of type 2 diabetic subjects. Diabetes. 2005;54(6):1692–1697. doi: 10.2337/diabetes.54.6.1692

[102] Karlsson H.K., Zierath J.R., Kane S., et al. Insulin-stimulated phosphorylation of the Akt substrate AS160 is impaired in skeletal muscle of type 2 diabetic subjects // Diabetes. 2005. Vol. 54, N 8. P. 2351–2359. doi: 10.2337/diabetes.54.8.2351

[103] Krook A, Björnholm M, Galuska D, et al. Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients. Diabetes. 2000;49(2):284–292. doi: 10.2337/diabetes.49.2.284

[104] Krook A., Bjornholm M., Galuska D., et al. Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients // Diabetes. 2000. Vol. 49, N 2. P. 284–292. doi: 10.2337/diabetes.49.2.284

[105] Cusi K, Maezono K, Osman A, et al. Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J Clin Invest. 2000;105(3):311–320. doi: 10.1172/JCI7535

[106] Cusi K., Maezono K., Osman A., et al. Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle // J Clin Invest. 2000. Vol. 105, N 3. P. 311–320. doi: 10.1172/JCI7535

[107] Højlund K, Staehr P, Hansen BF, et al. Increased phosphorylation of skeletal muscle glycogen synthase at NH2-terminal sites during physiological hyperinsulinemia in type 2 diabetes. Diabetes. 2003;52(6):1393–1402. doi: 10.2337/diabetes.52.6.1393

[108] Højlund K., Staehr P., Hansen B.F., et al. Increased phosphorylation of skeletal muscle glycogen synthase at NH2-terminal sites during physiological hyperinsulinemia in type 2 diabetes // Diabetes. 2003. Vol. 52, N 6. P. 1393–1402. doi: 10.2337/diabetes.52.6.1393

[109] Meyer MM, Levin K, Grimmsmann T, et al. Insulin signalling in skeletal muscle of subjects with or without type II-diabetes and first degree relatives of patients with the disease. Diabetologia. 2002;45(6):813–822. doi: 10.1007/s00125-002-0830-9

[110] Meyer M.M., Levin K., Grimmsmann T., et al. Insulin signalling in skeletal muscle of subjects with or without type II-diabetes and first degree relatives of patients with the disease // Diabetologia. 2002. Vol. 45, N 6. P. 813–822. doi: 10.1007/s00125-002-0830-9

[111] Guridi M, Tintignac LA, Lin S, et al. Activation of mTORC1 in skeletal muscle regulates whole-body metabolism through FGF21. Sci Signal. 2015;8(402):ra113. doi: 10.1126/scisignal.aab3715

[112] Guridi M., Tintignac L.A., Lin S., et al. Activation of mTORC1 in skeletal muscle regulates whole-body metabolism through FGF21 // Sci Signal. 2015. Vol. 8, N 402. P. ra113. doi: 10.1126/scisignal.aab3715

RIGHTS & PERMISSIONS

Eco-Vector