{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T01:27:45Z","timestamp":1788917265558,"version":"build-2803163510"},"reference-count":214,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T00:00:00Z","timestamp":1724284800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The incidence of diabetes, including type 2 diabetes (T2DM), is increasing sharply worldwide. To reverse this, more effective approaches in prevention and treatment are needed. In our review, we sought to summarize normal insulin action and the pathways that primarily influence the development of T2DM. Normal insulin action involves mitogenic and metabolic pathways, as both are important in normal metabolic processes, regeneration, etc. However, through excess energy, both can be hyperactive or attenuated\/inactive leading to disturbances in the cellular and systemic regulation with the consequence of cellular stress and systemic inflammation. In this review, we detailed the beneficial molecular changes caused by some important components of nutrition and by exercise, which act in the same molecular targets as the developed drugs, and can revert the damaged pathways. Moreover, these induce entire networks of regulatory mechanisms and proteins to restore unbalanced homeostasis, proving their effectiveness as preventive and complementary therapies. These are the main steps for success in prevention and treatment of developed diseases to rid the body of excess energy, both from stored fats and from overnutrition, while facilitating fat burning with adequate, regular exercise in healthy people, and together with necessary drug treatment as required in patients with insulin resistance and T2DM.<\/jats:p>","DOI":"10.3390\/ijms25169113","type":"journal-article","created":{"date-parts":[[2024,8,26]],"date-time":"2024-08-26T05:16:24Z","timestamp":1724649384000},"page":"9113","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Molecular Aspects in the Development of Type 2 Diabetes and Possible Preventive and Complementary Therapies"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-9543-2663","authenticated-orcid":false,"given":"Laura","family":"Simon-Szab\u00f3","sequence":"first","affiliation":[{"name":"Department of Molecular Biology, Semmelweis University, Tuzolto u. 37-47, 1094 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Be\u00e1ta","family":"Liz\u00e1k","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Semmelweis University, Tuzolto u. 37-47, 1094 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00e1bor","family":"Sturm","sequence":"additional","affiliation":[{"name":"Directorate of Information Technology Basic Infrastructure and Advanced Applications, Semmelweis University, \u00dcll\u0151i \u00fat 78\/b, 1082 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anik\u00f3","family":"Somogyi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Hematology, Semmelweis University, Baross u., 1085 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Istv\u00e1n","family":"Tak\u00e1cs","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Oncology, Semmelweis University, Koranyi S. u 2\/a, 1083 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2586-6639","authenticated-orcid":false,"given":"Zsuzsanna","family":"N\u00e9meth","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Oncology, Semmelweis University, Koranyi S. u 2\/a, 1083 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,22]]},"reference":[{"key":"ref_1","first-page":"373","article-title":"History of diabetes mellitus","volume":"23","author":"Ahmed","year":"2002","journal-title":"Saudi Med. J."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"El-Seedi, H.R., Yosri, N., El-Aarag, B., Mahmoud, S.H., Zayed, A., Du, M., Saeed, A., Musharraf, S.G., El-Garawani, I.M., and Habib, M.R. (2022). Chemistry and the Potential Antiviral, Anticancer, and Anti-Inflammatory Activities of Cardiotonic Steroids Derived from Toads. Molecules, 27.","DOI":"10.3390\/molecules27196586"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Messina, G., Alioto, A., Parisi, M.C., Mingrino, O., Di Corrado, D., Crescimanno, C., Kuli\u015b, S., Nese Sahin, F., Padua, E., and Canzone, A. (2023). Experimental study on physical exercise in diabetes: Pathophysiology and therapeutic effects. Eur. J. Transl. Myol.","DOI":"10.4081\/ejtm.2023.11560"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"108819","DOI":"10.1016\/j.diabres.2021.108819","article-title":"The history of the Nobel prize for the discovery of insulin","volume":"175","author":"Lindsten","year":"2021","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4239\/wjd.v7.i1.1","article-title":"Milestones in the history of diabetes mellitus: The main contributors","volume":"7","author":"Karamanou","year":"2016","journal-title":"World J. Diabetes"},{"key":"ref_6","first-page":"139","article-title":"Paul Langerhans: A prilgrim \u201ctraveling\u201d from functional histology to marine biology","volume":"15","author":"Raica","year":"2017","journal-title":"Acta Med. Hist. Adriat."},{"key":"ref_7","first-page":"855","article-title":"Paul Langerhans, 1847\u20131888","volume":"79","author":"Campbell","year":"1958","journal-title":"Can. Med. Assoc. J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1093\/jhmas\/48.3.253","article-title":"Rewriting medical history: Charles Best and the Banting and Best myth","volume":"48","author":"Bliss","year":"1993","journal-title":"J. Hist. Med. Allied Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"S67","DOI":"10.2337\/dc13-S067","article-title":"Diagnosis and classification of diabetes mellitus","volume":"36","year":"2013","journal-title":"Diabetes Care"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1677\/JOE-09-0260","article-title":"Current views on type 2 diabetes","volume":"204","author":"Lin","year":"2010","journal-title":"J. Endocrinol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"46","DOI":"10.5897\/JPAP2013.0001","article-title":"The pathogenesis and pathophysiology of type 1 and type 2 diabetes mellitus","volume":"4","author":"Ozougwu","year":"2013","journal-title":"J. Physiol. Pathophysiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/nrendo.2017.151","article-title":"Global aetiology and epidemiology of type 2 diabetes mellitus and its complications","volume":"14","author":"Zheng","year":"2018","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"279","DOI":"10.2337\/dc07-1327","article-title":"Sensitivity and Specificity of Death Certificates for Diabetes","volume":"31","author":"Cheng","year":"2008","journal-title":"Diabetes Care"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Fan, R., Zhang, N., Yang, L., Ke, J., Zhao, D., and Cui, Q. (2020). AI-based prediction for the risk of coronary heart disease among patients with type 2 diabetes mellitus. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-71321-2"},{"key":"ref_15","first-page":"442","article-title":"Type 2 Diabetes and its Impact on the Immune System","volume":"16","author":"Berbudi","year":"2020","journal-title":"Curr. Diabetes Rev."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Holl, J., Kowalewski, C., Zimek, Z., Fiedor, P., Kaminski, A., Oldak, T., Moniuszko, M., and Eljaszewicz, A. (2021). Chronic Diabetic Wounds and Their Treatment with Skin Substitutes. Cells, 10.","DOI":"10.3390\/cells10030655"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1016\/S0140-6736(22)01655-5","article-title":"Type 2 diabetes","volume":"400","author":"Ahmad","year":"2022","journal-title":"Lancet"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Lemieux, I., and Despres, J.P. (2020). Metabolic Syndrome: Past, Present and Future. Nutrients, 12.","DOI":"10.3390\/nu12113501"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Nemeth, Z., Kiss, E., and Takacs, I. (2022). The Role of Epigenetic Regulator SIRT1 in Balancing the Homeostasis and Preventing the Formation of Specific \u201cSoil\u201d of Metabolic Disorders and Related Cancers. Front. Biosci., 27.","DOI":"10.31083\/j.fbl2709253"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Nemeth, Z., Patonai, A., Simon-Szabo, L., and Takacs, I. (2023). Interplay of Vitamin D and SIRT1 in Tissue-Specific Metabolism-Potential Roles in Prevention and Treatment of Non-Communicable Diseases Including Cancer. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24076154"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.2337\/diab.37.12.1595","article-title":"Banting lecture 1988. Role of insulin resistance in human disease","volume":"37","author":"Reaven","year":"1988","journal-title":"Diabetes"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Ambroselli, D., Masciulli, F., Romano, E., Catanzaro, G., Besharat, Z.M., Massari, M.C., Ferretti, E., Migliaccio, S., Izzo, L., and Ritieni, A. (2023). New Advances in Metabolic Syndrome, from Prevention to Treatment: The Role of Diet and Food. Nutrients, 15.","DOI":"10.3390\/nu15030640"},{"key":"ref_23","first-page":"1","article-title":"Metabolic syndrome and insulin resistance: Underlying causes and modification by exercise training","volume":"3","author":"Roberts","year":"2013","journal-title":"Compr. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1038\/s41440-024-01622-w","article-title":"The WHO Global report 2023 on hypertension warning the emerging hypertension burden in globe and its treatment strategy","volume":"47","author":"Kario","year":"2024","journal-title":"Hypertens. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/S0140-6736(07)61299-9","article-title":"Essential hypertension","volume":"370","author":"Messerli","year":"2007","journal-title":"Lancet"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/0895-4356(88)90149-7","article-title":"Risk factors for hypertension: Results from a cross sectional survey","volume":"41","author":"Mao","year":"1988","journal-title":"J. Clin. Epidemiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/s41581-019-0244-2","article-title":"The global epidemiology of hypertension","volume":"16","author":"Mills","year":"2020","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s12933-018-0703-2","article-title":"Diabetes, cardiovascular disease and the microcirculation","volume":"17","author":"Strain","year":"2018","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2153","DOI":"10.1097\/00004872-200411000-00018","article-title":"Glucose level is a major determinant of carotid intima-media thickness in patients with hypertension and hyperglycemia","volume":"22","author":"Tropeano","year":"2004","journal-title":"J. Hypertens."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.molmet.2013.11.006","article-title":"Vascular effects of advanced glycation endproducts: Clinical effects and molecular mechanisms","volume":"3","author":"Stirban","year":"2014","journal-title":"Mol. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1001\/jama.295.14.1681","article-title":"Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes","volume":"295","author":"Monnier","year":"2006","journal-title":"JAMA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4782344","DOI":"10.1155\/2022\/4782344","article-title":"Dyslipidemia Diagnosis and Treatment: Risk Stratification in Children and Adolescents","volume":"2022","author":"Mosca","year":"2022","journal-title":"J. Nutr. Metab."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1007\/s11883-023-01167-2","article-title":"Obesity and Dyslipidemia","volume":"25","author":"Nussbaumerova","year":"2023","journal-title":"Curr. Atheroscler. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1016\/j.metabol.2014.08.010","article-title":"Diabetic dyslipidemia","volume":"63","author":"Wu","year":"2014","journal-title":"Metabolism"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1111\/j.1365-2796.2010.02325.x","article-title":"The metabolic syndrome: Time to get off the merry-go-round?","volume":"269","author":"Reaven","year":"2011","journal-title":"J. Intern. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1016\/S0140-6736(05)66378-7","article-title":"The metabolic syndrome","volume":"365","author":"Eckel","year":"2005","journal-title":"Lancet"},{"key":"ref_37","unstructured":"Nutrition Physical Activity & Obesity (NAO), and Office for Prevention & Control of NCDs (MOS) (2022). WHO European Regional Obesity Report 2022, WHO."},{"key":"ref_38","unstructured":"Townsend, N., and Scriven, A. (2014). Public Health Mini-Guides: Obesity, Churchill Livingstone. [1st ed.]."},{"key":"ref_39","unstructured":"World Health Organization (1995). Physical status: The Use and Interpretation of Anthropometry, Report of a WHO Expert Committee, World Health Organization."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/0002-9149(94)90676-9","article-title":"Waist circumference and abdominal sagittal diameter: Best simple anthropometric indexes of abdominal visceral adipose tissue accumulation and related cardiovascular risk in men and women","volume":"73","author":"Pouliot","year":"1994","journal-title":"Am. J. Cardiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.jclinepi.2007.08.012","article-title":"Indices of abdominal obesity are better discriminators of cardiovascular risk factors than BMI: A meta-analysis","volume":"61","author":"Lee","year":"2008","journal-title":"J. Clin. Epidemiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1038\/sj.ijo.0800377","article-title":"Waist circumference reduction and cardiovascular benefits during weight loss in women","volume":"21","author":"Han","year":"1997","journal-title":"Int. J. Obes. Relat. Metab. Disord."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e183788","DOI":"10.1001\/jamanetworkopen.2018.3788","article-title":"Association Between Obesity and Cardiovascular Outcomes: A Systematic Review and Meta-analysis of Mendelian Randomization Studies","volume":"1","author":"Riaz","year":"2018","journal-title":"JAMA Netw. Open"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Le, T.K.C., Dao, X.D., Nguyen, D.V., Luu, D.H., Bui, T.M.H., Le, T.H., Nguyen, H.T., Le, T.N., Hosaka, T., and Nguyen, T.T.T. (2023). Insulin signaling and its application. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1226655"},{"key":"ref_45","first-page":"213","article-title":"Insulin Through the Ages: Phylogeny of a Growth Promoting and Metabolic Regulatory Hormone","volume":"40","author":"Steiner","year":"2000","journal-title":"Am. Zool."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.mce.2015.08.013","article-title":"Metabolic, anabolic, and mitogenic insulin responses: A tissue-specific perspective for insulin receptor activators","volume":"415","author":"Bedinger","year":"2015","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e142241","DOI":"10.1172\/JCI142241","article-title":"Insulin signaling in health and disease","volume":"131","author":"Saltiel","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Lipson, K.E., Kolhatkar, A.A., and Donner, D.B. (1989). Insulin stimulates proteolysis of the alpha-subunit, but not the beta-subunit, of its receptor at the cell surface in rat liver. Biochem. J., 261.","DOI":"10.1042\/bj2610333"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1038\/298667a0","article-title":"Insulin stimulates tyrosine phosphorylation of the insulin receptor in a cell-free system","volume":"298","author":"Kasuga","year":"1982","journal-title":"Nature"},{"key":"ref_50","first-page":"6","article-title":"The first structure of a receptor tyrosine kinase domain: A further step in understanding the molecular basis of insulin action","volume":"15","author":"McDonald","year":"1995","journal-title":"Structure"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1021\/bi00428a056","article-title":"Relationship between insulin receptor subunit association and protein kinase activation: Insulin-dependent covalent and Mn\/MgATP-dependent noncovalent association of alpha beta heterodimeric insulin receptors into an alpha 2 beta 2 heterotetrameric state","volume":"28","author":"Wilden","year":"1989","journal-title":"Biochemistry"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/nature26153","article-title":"Structure of the insulin receptor-insulin complex by single-particle cryo-EM analysis","volume":"556","author":"Scapin","year":"2018","journal-title":"Nature"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Gutmann, T., Schafer, I.B., Poojari, C., Brankatschk, B., Vattulainen, I., Strauss, M., and Coskun, U. (2020). Cryo-EM structure of the complete and ligand-saturated insulin receptor ectodomain. J. Cell Biol., 219.","DOI":"10.1083\/jcb.201907210"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1038\/s12276-023-01101-1","article-title":"A stepwise activation model for the insulin receptor","volume":"55","author":"Yunn","year":"2023","journal-title":"Exp. Mol. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2565","DOI":"10.1007\/s00125-012-2644-8","article-title":"Regulation of insulin sensitivity by serine\/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2","volume":"55","author":"Copps","year":"2012","journal-title":"Diabetologia"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"29829","DOI":"10.1074\/jbc.272.47.29829","article-title":"Insulin receptor substrate-2 (IRS-2) can mediate the action of insulin to stimulate translocation of GLUT4 to the cell surface in rat adipose cells","volume":"272","author":"Zhou","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Takeuchi, H., Matsuda, M., Yamamoto, T., Kanematsu, T., Kikkawa, U., Yagisawa, H., Watanabe, Y., and Hirata, M. (1998). PTB domain of insulin receptor substrate-1 binds inositol compounds. Biochem. J., 334.","DOI":"10.1042\/bj3340211"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/0092-8674(92)90167-B","article-title":"The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling","volume":"70","author":"Lowenstein","year":"1992","journal-title":"Cell"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1038\/ncomms2173","article-title":"Sos-mediated cross-activation of wild-type Ras by oncogenic Ras is essential for tumorigenesis","volume":"3","author":"Jeng","year":"2012","journal-title":"Nat. Commun."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/s41392-023-01705-z","article-title":"Targeting the RAS\/RAF\/MAPK pathway for cancer therapy: From mechanism to clinical studies","volume":"8","author":"Bahar","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/nrm.2017.89","article-title":"Biochemical and cellular properties of insulin receptor signalling","volume":"19","author":"Haeusler","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1002\/med.21867","article-title":"Glycogen synthesis and beyond, a comprehensive review of GSK3 as a key regulator of metabolic pathways and a therapeutic target for treating metabolic diseases","volume":"42","author":"Wang","year":"2022","journal-title":"Med. Res. Rev."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Wang, X., Janmaat, M., Beugnet, A., Paulin, F.E.M., and Proud, C.G. (2002). Evidence that the dephosphorylation of Ser(535) in the \u220a-subunit of eukaryotic initiation factor (eIF) 2B is insufficient for the activation of eIF2B by insulin. Biochem. J., 367.","DOI":"10.1042\/bj20020677"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1172\/JCI200112876","article-title":"The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression","volume":"108","author":"Nakae","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1016\/j.bbamcr.2011.03.010","article-title":"Akt, FoxO and regulation of apoptosis","volume":"1813","author":"Zhang","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"R113","DOI":"10.1016\/j.cub.2007.01.008","article-title":"FOXO transcription factors","volume":"17","author":"Carter","year":"2007","journal-title":"Curr. Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1042\/BCJ20210073","article-title":"GLUT4 On the move","volume":"479","author":"Fazakerley","year":"2022","journal-title":"Biochem. J."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0014-5793(98)01149-1","article-title":"Insulin-independent glucose transport regulates insulin sensitivity","volume":"436","author":"Ebeling","year":"1998","journal-title":"FEBS Lett."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1042\/BJ20050887","article-title":"AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain","volume":"391","author":"Miinea","year":"2005","journal-title":"Biochem. J."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"11369","DOI":"10.1074\/jbc.REV119.008351","article-title":"Thirty sweet years of GLUT4","volume":"294","author":"Klip","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"C377","DOI":"10.1152\/ajpcell.00297.2009","article-title":"Identification of a novel phosphorylation site on TBC1D4 regulated by AMP-activated protein kinase in skeletal muscle","volume":"298","author":"Treebak","year":"2010","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"9787","DOI":"10.1074\/jbc.M708839200","article-title":"Discovery of TBC1D1 as an insulin-, AICAR-, and contraction-stimulated signaling nexus in mouse skeletal muscle","volume":"283","author":"Taylor","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"4892","DOI":"10.1128\/MCB.23.14.4892-4900.2003","article-title":"Insulin-induced GLUT4 translocation involves protein kinase C-lambda-mediated functional coupling between Rab4 and the motor protein kinesin","volume":"23","author":"Imamura","year":"2003","journal-title":"Mol. Cell Biol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1083\/jcb.200102078","article-title":"Lipid raft microdomain compartmentalization of TC10 is required for insulin signaling and GLUT4 translocation","volume":"154","author":"Watson","year":"2001","journal-title":"J. Cell Biol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1007\/s00125-013-2849-5","article-title":"Ras-related C3 botulinum toxin substrate 1 (RAC1) regulates glucose-stimulated insulin secretion via modulation of F-actin","volume":"56","author":"Asahara","year":"2013","journal-title":"Diabetologia"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"15","DOI":"10.4093\/dmj.2021.0280","article-title":"Insulin Resistance: From Mechanisms to Therapeutic Strategies","volume":"46","author":"Lee","year":"2022","journal-title":"Diabetes Metab. J."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.tibs.2003.11.007","article-title":"TSC2: Filling the GAP in the mTOR signaling pathway","volume":"29","author":"Li","year":"2004","journal-title":"Trends Biochem. Sci."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/s41580-019-0199-y","article-title":"mTOR at the nexus of nutrition, growth, ageing and disease","volume":"21","author":"Liu","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Zhou, H., Li, X.-M., Meinkoth, J., and Pittman, R.N. (2000). Akt Regulates Cell Survival and Apoptosis at a Postmitochondrial Level. J. Cell Biol., 151.","DOI":"10.1083\/jcb.151.3.483"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"6063","DOI":"10.1111\/j.1742-4658.2009.07330.x","article-title":"Apoptosis and autophagy: Regulation of caspase-9 by phosphorylation","volume":"276","author":"Allan","year":"2009","journal-title":"FEBS J."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.cmet.2008.07.007","article-title":"SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth","volume":"8","author":"Porstmann","year":"2008","journal-title":"Cell Metab."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1194\/jlr.M004234","article-title":"Protein kinase Cbeta mediates hepatic induction of sterol-regulatory element binding protein-1c by insulin","volume":"51","author":"Yamamoto","year":"2010","journal-title":"J. Lipid Res."},{"key":"ref_83","unstructured":"Eyth, E., Basit, H., and Swift, C. (2024). Glucose Tolerance Test. StatPearls [Internet], StatPearls Publishing."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"E182","DOI":"10.1152\/ajpendo.00278.2023","article-title":"An extended minimal model of OGTT: Estimation of alpha- and beta-cell dysfunction, insulin resistance, and the incretin effect","volume":"326","author":"Subramanian","year":"2024","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"102581","DOI":"10.1016\/j.dsx.2022.102581","article-title":"Challenges in the diagnosis of insulin resistance: Focusing on the role of HOMA-IR and Tryglyceride\/glucose index","volume":"16","author":"Tahapary","year":"2022","journal-title":"Diabetes Metab. Syndr."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/j.molcel.2017.05.032","article-title":"AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance","volume":"66","author":"Garcia","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1152\/physiol.00050.2013","article-title":"AMPK: Regulating energy balance at the cellular and whole body levels","volume":"29","author":"Hardie","year":"2014","journal-title":"Physiology"},{"key":"ref_88","first-page":"265","article-title":"The adiponectin to leptin ratio, a still unrecognized biomarker of insulin resistance and cardiometabolic risk","volume":"78","author":"Vatier","year":"2020","journal-title":"Ann. Biol. Clin."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"E115","DOI":"10.1152\/ajpendo.00273.2022","article-title":"Decreased adiponectin\/leptin ratio relates to insulin resistance in adults with obesity","volume":"324","author":"Castela","year":"2023","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1097\/MOL.0b013e328328d0a4","article-title":"PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure","volume":"20","author":"Canto","year":"2009","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"S157","DOI":"10.2337\/dc09-S302","article-title":"Skeletal muscle insulin resistance is the primary defect in type 2 diabetes","volume":"32","author":"DeFronzo","year":"2009","journal-title":"Diabetes Care"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"R99","DOI":"10.1530\/JOE-16-0021","article-title":"PGC-1alpha, glucose metabolism and type 2 diabetes mellitus","volume":"229","author":"Wu","year":"2016","journal-title":"J. Endocrinol."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Simon-Szabo, L., Kokas, M., Mandl, J., Keri, G., and Csala, M. (2014). Metformin attenuates palmitate-induced endoplasmic reticulum stress, serine phosphorylation of IRS-1 and apoptosis in rat insulinoma cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0097868"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"550","DOI":"10.4254\/wjh.v5.i10.550","article-title":"Lipotoxicity in the liver","volume":"5","author":"Zambo","year":"2013","journal-title":"World J. Hepatol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1161\/HYPERTENSIONAHA.121.17981","article-title":"Hypertension in Diabetes: An Update of Basic Mechanisms and Clinical Disease","volume":"78","author":"Jia","year":"2021","journal-title":"Hypertension"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/s11892-003-0018-9","article-title":"Molecular and physiologic actions of insulin related to production of nitric oxide in vascular endothelium","volume":"3","author":"Vincent","year":"2003","journal-title":"Curr. Diab Rep."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1161\/01.HYP.25.4.774","article-title":"Fatty acids enhance vascular alpha-adrenergic sensitivity","volume":"25","author":"Stepniakowski","year":"1995","journal-title":"Hypertension"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"H2472","DOI":"10.1152\/ajpheart.00516.2002","article-title":"Alterations in KATP and KCa channel function in cerebral arteries of insulin-resistant rats","volume":"283","author":"Erdos","year":"2002","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2702","DOI":"10.1016\/j.biocel.2008.06.012","article-title":"c-Jun N-terminal kinase pathways in diabetes","volume":"40","author":"Yang","year":"2008","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/s41392-022-01073-0","article-title":"Trends in insulin resistance: Insights into mechanisms and therapeutic strategy","volume":"7","author":"Li","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Eo, H., and Valentine, R.J. (2022). Saturated Fatty Acid-Induced Endoplasmic Reticulum Stress and Insulin Resistance Are Prevented by Imoxin in C2C12 Myotubes. Front. Physiol., 13.","DOI":"10.3389\/fphys.2022.842819"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1038\/s41401-020-0482-7","article-title":"DGAT1 inhibitors protect pancreatic beta-cells from palmitic acid-induced apoptosis","volume":"42","author":"Huang","year":"2021","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.bmcl.2015.11.099","article-title":"Novel compounds reducing IRS-1 serine phosphorylation for treatment of diabetes","volume":"26","author":"Kokas","year":"2016","journal-title":"Bioorg Med. Chem. Lett."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1038\/nrd1344","article-title":"AMP kinase and malonyl-CoA: Targets for therapy of the metabolic syndrome","volume":"3","author":"Ruderman","year":"2004","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1172\/JCI29069","article-title":"Inflammation and insulin resistance","volume":"116","author":"Shoelson","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/nature21363","article-title":"Inflammation, metaflammation and immunometabolic disorders","volume":"542","author":"Hotamisligil","year":"2017","journal-title":"Nature"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/j.biocel.2006.09.007","article-title":"Apoptosis in the pathophysiology of diabetes mellitus","volume":"39","author":"Lee","year":"2007","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.tem.2009.01.003","article-title":"Endoplasmic reticulum: Nutrient sensor in physiology and pathology","volume":"20","author":"Mandl","year":"2009","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1016\/j.cell.2010.02.034","article-title":"Endoplasmic reticulum stress and the inflammatory basis of metabolic disease","volume":"140","author":"Hotamisligil","year":"2010","journal-title":"Cell"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1038\/s41392-023-01570-w","article-title":"Endoplasmic reticulum stress: Molecular mechanism and therapeutic targets","volume":"8","author":"Chen","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1038\/sj.cdd.4401840","article-title":"From acute ER stress to physiological roles of the Unfolded Protein Response","volume":"13","author":"Wu","year":"2006","journal-title":"Cell Death Differ."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"7448","DOI":"10.1128\/MCB.23.21.7448-7459.2003","article-title":"XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response","volume":"23","author":"Lee","year":"2003","journal-title":"Mol. Cell Biol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"4809","DOI":"10.1074\/jbc.M110.152900","article-title":"Endoplasmic reticulum stress response mediated by the PERK-eIF2\u03b1-ATF4 pathway is involved in osteoblast differentiation induced by BMP2","volume":"286","author":"Saito","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1128\/MCB.00408-06","article-title":"Role of disulfide bridges formed in the luminal domain of ATF6 in sensing endoplasmic reticulum stress","volume":"27","author":"Nadanaka","year":"2007","journal-title":"Mol. Cell Biol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"9047","DOI":"10.1074\/jbc.275.12.9047","article-title":"The c-Jun NH2-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser307","volume":"275","author":"Aguirre","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"7","DOI":"10.2337\/diabetes.50.1.24","article-title":"Serine\/threonine phosphorylation of IRS-1 triggers its degradation: Possible regulation by tyrosine phosphorylation","volume":"50","author":"Pederson","year":"2001","journal-title":"Diabetes"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1007\/s00125-003-1097-5","article-title":"IRS1 degradation and increased serine phosphorylation cannot predict the degree of metabolic insulin resistance induced by oxidative stress","volume":"46","author":"Potashnik","year":"2003","journal-title":"Diabetologia"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"2308","DOI":"10.1242\/jcs.026062","article-title":"Initiation and execution of lipotoxic ER stress in pancreatic beta-cells","volume":"121","author":"Cunha","year":"2008","journal-title":"J. Cell Sci."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Lair, B., Laurens, C., Van Den Bosch, B., and Moro, C. (2020). Novel Insights and Mechanisms of Lipotoxicity-Driven Insulin Resistance. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176358"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.bbrc.2011.11.073","article-title":"Metformin prevents endoplasmic reticulum stress-induced apoptosis through AMPK-PI3K-c-Jun NH2 pathway","volume":"417","author":"Jung","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"251","DOI":"10.3109\/08923970903252220","article-title":"Metformin regulates palmitate-induced apoptosis and ER stress response in HepG2 liver cells","volume":"32","author":"Kim","year":"2010","journal-title":"Immunopharmacol. Immunotoxicol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1210\/en.2009-0711","article-title":"Functional role of c-Jun-N-terminal kinase in feeding regulation","volume":"151","author":"Unger","year":"2010","journal-title":"Endocrinology"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1172\/JCI10934","article-title":"Insulin\/IGF-1 and TNF-alpha stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways","volume":"107","author":"Rui","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"S53","DOI":"10.1038\/sj.ijo.0802502","article-title":"Inflammatory pathways and insulin action","volume":"27","author":"Hotamisligil","year":"2003","journal-title":"Int. J. Obes. Relat. Metab. Disord."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1079\/PNS2004405","article-title":"Fatty acids and the metabolic syndrome","volume":"64","author":"Roche","year":"2005","journal-title":"Proc. Nutr. Soc."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"13740","DOI":"10.1074\/jbc.M210689200","article-title":"Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes","volume":"278","author":"Senn","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"23780","DOI":"10.1074\/jbc.270.40.23780","article-title":"Tumor necrosis factor alpha-induced phosphorylation of insulin receptor substrate-1 (IRS-1). Possible mechanism for suppression of insulin-stimulated tyrosine phosphorylation of IRS-1","volume":"270","author":"Kanety","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Yung, J.H.M., and Giacca, A. (2020). Role of c-Jun N-terminal Kinase (JNK) in Obesity and Type 2 Diabetes. Cells, 9.","DOI":"10.3390\/cells9030706"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.cmet.2006.05.003","article-title":"Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1","volume":"3","author":"Um","year":"2006","journal-title":"Cell Metab."},{"key":"ref_130","doi-asserted-by":"crossref","unstructured":"Sokolowska, E., and Blachnio-Zabielska, A. (2019). The Role of Ceramides in Insulin Resistance. Front. Endocrinol., 10.","DOI":"10.3389\/fendo.2019.00577"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1046\/j.1460-9568.2000.00933.x","article-title":"Anisomycin uses multiple mechanisms to stimulate mitogen-activated protein kinases and gene expression and to inhibit neuronal differentiation in PC12 phaeochromocytoma cells","volume":"12","author":"Torocsik","year":"2000","journal-title":"Eur. J. Neurosci."},{"key":"ref_132","doi-asserted-by":"crossref","unstructured":"Liu, Z., Gao, H., Zhao, Z., Huang, M., Wang, S., and Zhan, J. (2023). Status of research on natural protein tyrosine phosphatase 1B inhibitors as potential antidiabetic agents: Update. Biomed. Pharmacother., 157.","DOI":"10.1016\/j.biopha.2022.113990"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/s41467-017-02252-2","article-title":"Harnessing insulin- and leptin-induced oxidation of PTP1B for therapeutic development","volume":"9","author":"Krishnan","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.cmet.2009.08.009","article-title":"Reactive oxygen species enhance insulin sensitivity","volume":"10","author":"Loh","year":"2009","journal-title":"Cell Metab."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"49689","DOI":"10.1074\/jbc.C400261200","article-title":"Protein-tyrosine phosphatase 1B potentiates IRE1 signaling during endoplasmic reticulum stress","volume":"279","author":"Gu","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.vph.2018.05.011","article-title":"Protein tyrosine phosphatase 1B regulates endothelial endoplasmic reticulum stress; role in endothelial dysfunction","volume":"109","author":"Thiebaut","year":"2018","journal-title":"Vasc. Pharmacol."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/j.chembiol.2004.03.025","article-title":"Phosphoinositide signaling; from affinity probes to pharmaceutical targets","volume":"11","author":"Prestwich","year":"2004","journal-title":"Chem. Biol."},{"key":"ref_138","doi-asserted-by":"crossref","unstructured":"Boucher, J., Kleinridders, A., and Kahn, C.R. (2014). Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb. Perspect. Biol., 6.","DOI":"10.1101\/cshperspect.a009191"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/35051094","article-title":"The lipid phosphatase SHIP2 controls insulin sensitivity","volume":"409","author":"Clement","year":"2001","journal-title":"Nature"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1210\/en.2007-0820","article-title":"Impact of transgenic overexpression of SH2-containing inositol 5\u2032-phosphatase 2 on glucose metabolism and insulin signaling in mice","volume":"149","author":"Kagawa","year":"2008","journal-title":"Endocrinology"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"a036137","DOI":"10.1101\/cshperspect.a036137","article-title":"Metabolic Role of PTEN in Insulin Signaling and Resistance","volume":"10","author":"Li","year":"2020","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"2082","DOI":"10.1073\/pnas.0308617100","article-title":"Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity [corrected]","volume":"101","author":"Stiles","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/S0968-0004(99)01375-4","article-title":"Regulation of protein kinase cascades by protein phosphatase 2A","volume":"24","author":"Millward","year":"1999","journal-title":"Trends Biochem. Sci."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"20517","DOI":"10.1073\/pnas.0610290104","article-title":"FoxO transcription factors activate Akt and attenuate insulin signaling in heart by inhibiting protein phosphatases","volume":"104","author":"Ni","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1007\/s11434-016-1058-2","article-title":"Adapter proteins regulate insulin resistance and lipid metabolism in obesity","volume":"61","author":"Chen","year":"2016","journal-title":"Sci. Bull."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.gene.2009.06.001","article-title":"Human TRB3 is upregulated in stressed cells by the induction of translationally efficient mRNA containing a truncated 5\u2032-UTR","volume":"444","author":"Ord","year":"2009","journal-title":"Gene"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1038\/ni0901-870","article-title":"Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells","volume":"2","author":"Fang","year":"2001","journal-title":"Nat. Immunol."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"4798","DOI":"10.1128\/MCB.01347-08","article-title":"Ubiquitin ligase Cbl-b is a negative regulator for insulin-like growth factor 1 signaling during muscle atrophy caused by unloading","volume":"29","author":"Nakao","year":"2009","journal-title":"Mol. Cell Biol."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1002\/oby.22759","article-title":"Absence of MyD88 from Skeletal Muscle Protects Female Mice from Inactivity-Induced Adiposity and Insulin Resistance","volume":"28","author":"Mahmassani","year":"2020","journal-title":"Obesity"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.advnut.2022.10.002","article-title":"Healthy plant-based diets improve dyslipidemias, insulin resistance, and inflammation in metabolic syndrome. A narrative review","volume":"14","author":"Thomas","year":"2023","journal-title":"Adv. Nutr."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"61","DOI":"10.7812\/TPP\/12-085","article-title":"Nutritional update for physicians: Plant-based diets","volume":"17","author":"Tuso","year":"2013","journal-title":"Perm. J."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/1743-7075-7-83","article-title":"Long-term effect of metformin on blood glucose control in non-obese patients with type 2 diabetes mellitus","volume":"7","author":"Ito","year":"2010","journal-title":"Nutr. Metab."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"357","DOI":"10.7326\/0003-4819-147-6-200709180-00005","article-title":"Effects of aerobic training, resistance training, or both on glycemic control in type 2 diabetes: A randomized trial","volume":"147","author":"Sigal","year":"2007","journal-title":"Ann. Intern. Med."},{"key":"ref_154","doi-asserted-by":"crossref","unstructured":"Kumar, A., P, N., Kumar, M., Jose, A., Tomer, V., Oz, E., Proestos, C., Zeng, M., Elobeid, T., and K, S. (2023). Major Phytochemicals: Recent Advances in Health Benefits and Extraction Method. Molecules, 28.","DOI":"10.3390\/molecules28020887"},{"key":"ref_155","doi-asserted-by":"crossref","unstructured":"Yahfoufi, N., Alsadi, N., Jambi, M., and Matar, C. (2018). The Immunomodulatory and Anti-Inflammatory Role of Polyphenols. Nutrients, 10.","DOI":"10.3390\/nu10111618"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"715","DOI":"10.24976\/Discov.Med.202335178.68","article-title":"Phenolic Compounds as Preventive and Therapeutic Agents in Diabetes-Related Oxidative Stress, Inflammation, Advanced Glycation End-Products Production and Insulin Sensitivity","volume":"35","author":"Pannucci","year":"2023","journal-title":"Discov. Med."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1002\/jcsm.12530","article-title":"Astaxanthin stimulates mitochondrial biogenesis in insulin resistant muscle via activation of AMPK pathway","volume":"11","author":"Nishida","year":"2020","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_158","doi-asserted-by":"crossref","unstructured":"Li, J., Zhang, Y., Zeng, X., Cheng, Y., Tang, L., Hong, D., and Yang, X. (2022). Lycopene ameliorates insulin resistance and increases muscle capillary density in aging via activation of SIRT1. J. Nutr. Biochem., 99.","DOI":"10.1016\/j.jnutbio.2021.108862"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1093\/ajcn\/71.4.908","article-title":"Soy sterol esters and beta-sitostanol ester as inhibitors of cholesterol absorption in human small bowel","volume":"71","author":"Normen","year":"2000","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1007\/s11010-017-3235-2","article-title":"1,25(OH)2-vitamin D3 upregulates glucose uptake mediated by SIRT1\/IRS1\/GLUT4 signaling cascade in C2C12 myotubes","volume":"444","author":"Manna","year":"2018","journal-title":"Mol. Cell. Biochem."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.abb.2017.01.002","article-title":"Vitamin D supplementation inhibits oxidative stress and upregulate SIRT1\/AMPK\/GLUT4 cascade in high glucose-treated 3T3L1 adipocytes and in adipose tissue of high fat diet-fed diabetic mice","volume":"615","author":"Manna","year":"2017","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"5677","DOI":"10.1007\/s12011-023-03639-7","article-title":"Association Between Parameters of Cortisol Metabolism, Biomarkers of Minerals (Zinc, Selenium, and Magnesium), and Insulin Resistance and Oxidative Stress in Women with Obesity","volume":"201","author":"Morais","year":"2023","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s40199-015-0127-4","article-title":"Zinc and diabetes mellitus: Understanding molecular mechanisms and clinical implications","volume":"23","author":"Ranasinghe","year":"2015","journal-title":"Daru"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.abb.2006.05.007","article-title":"Magnesium metabolism in type 2 diabetes mellitus, metabolic syndrome and insulin resistance","volume":"458","author":"Barbagallo","year":"2007","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jnutbio.2018.02.012","article-title":"Omega-3 fatty acids in obesity and metabolic syndrome: A mechanistic update","volume":"58","author":"Kalupahana","year":"2018","journal-title":"J. Nutr. Biochem."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"114130","DOI":"10.1016\/j.phytochem.2024.114130","article-title":"Natural products with potential hypoglycemic activity in T2DM: 2019\u20132023","volume":"223","author":"Fei","year":"2024","journal-title":"Phytochemistry"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1016\/j.jacl.2016.07.001","article-title":"Low advanced glycation end product diet improves the lipid and inflammatory profiles of prediabetic subjects","volume":"10","author":"Currenti","year":"2016","journal-title":"J. Clin. Lipidol."},{"key":"ref_168","doi-asserted-by":"crossref","unstructured":"Nishida, Y., Nawaz, A., Hecht, K., and Tobe, K. (2021). Astaxanthin as a Novel Mitochondrial Regulator: A New Aspect of Carotenoids, beyond Antioxidants. Nutrients, 14.","DOI":"10.3390\/nu14010107"},{"key":"ref_169","doi-asserted-by":"crossref","unstructured":"Prasad, M., Jayaraman, S., Eladl, M.A., El-Sherbiny, M., Abdelrahman, M.A.E., Veeraraghavan, V.P., Vengadassalapathy, S., Umapathy, V.R., Jaffer Hussain, S.F., and Krishnamoorthy, K. (2022). A Comprehensive Review on Therapeutic Perspectives of Phytosterols in Insulin Resistance: A Mechanistic Approach. Molecules, 27.","DOI":"10.3390\/molecules27051595"},{"key":"ref_170","first-page":"819","article-title":"Plant Sterols: Diversity, Biosynthesis, and Physiological Functions","volume":"81","author":"Valitova","year":"2016","journal-title":"Biochemistry"},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"I","DOI":"10.1016\/j.orcp.2008.06.002","article-title":"Administration of phytosterols isolated from Aloe vera gel reduce visceral fat mass and improve hyperglycemia in Zucker diabetic fatty (ZDF) rats","volume":"2","author":"Misawa","year":"2008","journal-title":"Obes. Res. Clin. Pract."},{"key":"ref_172","first-page":"37","article-title":"[Advances in the knowledge of the use of micronutrients in artificial nutrition]","volume":"26","year":"2011","journal-title":"Nutr. Hosp."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1016\/j.clnu.2022.02.015","article-title":"ESPEN micronutrient guideline","volume":"41","author":"Berger","year":"2022","journal-title":"Clin. Nutr."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1152\/physrev.00010.2017","article-title":"Dietary Modulation of the Epigenome","volume":"98","author":"Ideraabdullah","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref_175","doi-asserted-by":"crossref","unstructured":"Charoenngam, N., and Holick, M.F. (2020). Immunologic Effects of Vitamin D on Human Health and Disease. Nutrients, 12.","DOI":"10.3390\/nu12072097"},{"key":"ref_176","doi-asserted-by":"crossref","unstructured":"Chang, E., and Kim, Y. (2017). Vitamin D Insufficiency Exacerbates Adipose Tissue Macrophage Infiltration and Decreases AMPK\/SIRT1 Activity in Obese Rats. Nutrients, 9.","DOI":"10.3390\/nu9040338"},{"key":"ref_177","first-page":"68","article-title":"Magnesium and Vitamin D Deficiency as a Potential Cause of Immune Dysfunction, Cytokine Storm and Disseminated Intravascular Coagulation in covid-19 patients","volume":"118","author":"DiNicolantonio","year":"2021","journal-title":"Mo. Med."},{"key":"ref_178","doi-asserted-by":"crossref","unstructured":"Steinbrenner, H., Duntas, L.H., and Rayman, M.P. (2022). The role of selenium in type-2 diabetes mellitus and its metabolic comorbidities. Redox Biol., 50.","DOI":"10.1016\/j.redox.2022.102236"},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.ceca.2017.05.001","article-title":"Endoplasmic reticulum-resident selenoproteins as regulators of calcium signaling and homeostasis","volume":"70","author":"Pitts","year":"2018","journal-title":"Cell Calcium"},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"4220","DOI":"10.1172\/JCI43653","article-title":"Mutations in the selenocysteine insertion sequence-binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans","volume":"120","author":"Schoenmakers","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.nutres.2021.06.008","article-title":"Dietary copper and selenium are associated with insulin resistance in overweight and obese Malaysian adults","volume":"93","author":"Tan","year":"2021","journal-title":"Nutr. Res."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"1499S","DOI":"10.1093\/ajcn\/83.6.1499S","article-title":"n-3 fatty acids and the metabolic syndrome","volume":"83","author":"Carpentier","year":"2006","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1111\/eci.12781","article-title":"Anti-inflammatory effects of exercise: Role in diabetes and cardiovascular disease","volume":"47","author":"Pedersen","year":"2017","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1152\/japplphysiol.00164.2004","article-title":"The anti-inflammatory effect of exercise","volume":"98","author":"Petersen","year":"2005","journal-title":"J. Appl. Physiol."},{"key":"ref_185","doi-asserted-by":"crossref","unstructured":"Civitarese, A.E., Carling, S., Heilbronn, L.K., Hulver, M.H., Ukropcova, B., Deutsch, W.A., Smith, S.R., Ravussin, E., and Team, C.P. (2007). Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med., 4.","DOI":"10.1371\/journal.pmed.0040076"},{"key":"ref_186","doi-asserted-by":"crossref","unstructured":"Malkowska, P., and Sawczuk, M. (2023). Cytokines as Biomarkers for Evaluating Physical Exercise in Trained and Non-Trained Individuals: A Narrative Review. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241311156"},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1038\/ni.3153","article-title":"IL-6 as a keystone cytokine in health and disease","volume":"16","author":"Hunter","year":"2015","journal-title":"Nat. Immunol."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1152\/physrev.90100.2007","article-title":"Muscle as an endocrine organ: Focus on muscle-derived interleukin-6","volume":"88","author":"Pedersen","year":"2008","journal-title":"Physiol. Rev."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1038\/s41577-023-00856-y","article-title":"Targeting IL-6 trans-signalling: Past, present and future prospects","volume":"23","author":"Jenkins","year":"2023","journal-title":"Nat. Rev. Immunol."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"2688","DOI":"10.2337\/db05-1404","article-title":"Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase","volume":"55","author":"Carey","year":"2006","journal-title":"Diabetes"},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1038\/nm.2513","article-title":"Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells","volume":"17","author":"Ellingsgaard","year":"2011","journal-title":"Nat. Med."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1038\/nrc.2017.78","article-title":"Exercise-dependent regulation of the tumour microenvironment","volume":"17","author":"Koelwyn","year":"2017","journal-title":"Nat. Rev. Cancer"},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1007\/s40279-021-01612-9","article-title":"Effects of Exercise Training on Anabolic and Catabolic Hormones with Advanced Age: A Systematic Review","volume":"52","author":"Zouhal","year":"2022","journal-title":"Sports Med."},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/S0896-6273(01)80035-0","article-title":"Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area","volume":"23","author":"Elias","year":"1999","journal-title":"Neuron"},{"key":"ref_195","first-page":"73","article-title":"Exercise and the stress system","volume":"4","author":"Mastorakos","year":"2005","journal-title":"Hormones"},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.mce.2009.08.017","article-title":"Obesity, growth hormone and weight loss","volume":"316","author":"Rasmussen","year":"2010","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.2337\/db16-1138","article-title":"Rac1 and AMPK Account for the Majority of Muscle Glucose Uptake Stimulated by Ex Vivo Contraction but Not In Vivo Exercise","volume":"66","author":"Sylow","year":"2017","journal-title":"Diabetes"},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1097\/WNR.0000000000002048","article-title":"The activation of AMPK\/PGC-1alpha\/GLUT4 signaling pathway through early exercise improves mitochondrial function and mitigates ischemic brain damage","volume":"35","author":"Wu","year":"2024","journal-title":"Neuroreport"},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1007\/s11064-014-1377-0","article-title":"PPARgamma and PGC-1alpha as therapeutic targets in Parkinson\u2019s","volume":"40","author":"Corona","year":"2015","journal-title":"Neurochem. Res."},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.2337\/diabetes.48.5.1192","article-title":"Acute exercise induces GLUT4 translocation in skeletal muscle of normal human subjects and subjects with type 2 diabetes","volume":"48","author":"Kennedy","year":"1999","journal-title":"Diabetes"},{"key":"ref_201","first-page":"E197","article-title":"Exercise-induced increase in glucose transport, GLUT-4, and VAMP-2 in plasma membrane from human muscle","volume":"270","author":"Kristiansen","year":"1996","journal-title":"Am. J. Physiol."},{"key":"ref_202","doi-asserted-by":"crossref","first-page":"13427","DOI":"10.1016\/S0021-9258(18)77362-6","article-title":"Exercise induces recruitment of the \u201cinsulin-responsive glucose transporter\u201d. Evidence for distinct intracellular insulin- and exercise-recruitable transporter pools in skeletal muscle","volume":"265","author":"Douen","year":"1990","journal-title":"J. Biol. Chem."},{"key":"ref_203","first-page":"E270","article-title":"Glucose transport and transporters in muscle giant vesicles: Differential effects of insulin and contractions","volume":"264","author":"Ploug","year":"1993","journal-title":"Am. J. Physiol."},{"key":"ref_204","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1152\/physrev.00038.2012","article-title":"Exercise, GLUT4, and skeletal muscle glucose uptake","volume":"93","author":"Richter","year":"2013","journal-title":"Physiol. Rev."},{"key":"ref_205","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.tem.2013.12.001","article-title":"SIRT1 and other sirtuins in metabolism","volume":"25","author":"Chang","year":"2014","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_206","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/nm1557","article-title":"Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions","volume":"13","author":"Yamauchi","year":"2007","journal-title":"Nat. Med."},{"key":"ref_207","doi-asserted-by":"crossref","unstructured":"Anirudhan, A., Ahmad, S.F., Emran, T.B., Angulo-Bejarano, P.I., Sharma, A., and Ahmed, S. (2023). Comparative Efficacy of Metformin and Glimepiride in Modulating Pharmacological Network to Increase BDNF Levels and Benefit Type 2 Diabetes-Related Cognitive Impairment. Biomedicines, 11.","DOI":"10.3390\/biomedicines11112939"},{"key":"ref_208","doi-asserted-by":"crossref","unstructured":"Haddad, F., Dokmak, G., Bader, M., and Karaman, R. (2023). A Comprehensive Review on Weight Loss Associated with Anti-Diabetic Medications. Life, 13.","DOI":"10.3390\/life13041012"},{"key":"ref_209","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1038\/s41574-023-00833-4","article-title":"Metformin: Update on mechanisms of action and repurposing potential","volume":"19","author":"Foretz","year":"2023","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_210","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.4239\/wjd.v15.i5.1011","article-title":"Dipeptidyl peptidase-4 inhibitors and the risk of infection: A systematic review and meta-analysis of cardiovascular outcome trials","volume":"15","author":"Yang","year":"2024","journal-title":"World J. Diabetes"},{"key":"ref_211","doi-asserted-by":"crossref","unstructured":"Haddad, D., Dsouza, V.S., Al-Mulla, F., and Al Madhoun, A. (2024). New-Generation Glucokinase Activators: Potential Game-Changers in Type 2 Diabetes Treatment. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25010571"},{"key":"ref_212","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s11892-023-01531-1","article-title":"Imeglimin: The New Kid on the Block","volume":"24","author":"Shrestha","year":"2024","journal-title":"Curr. Diab Rep."},{"key":"ref_213","doi-asserted-by":"crossref","first-page":"116991","DOI":"10.1016\/j.taap.2024.116991","article-title":"Dapagliflozin dampens liver fibrosis induced by common bile duct ligation in rats associated with the augmentation of the hepatic Sirt1\/AMPK\/PGC1alpha\/FoxO1 axis","volume":"489","author":"Hassan","year":"2024","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_214","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1039\/D3MD00647F","article-title":"Glucosamine substituted sulfonylureas: IRS-PI3K-PKC-AKT-GLUT4 insulin signalling pathway intriguing agent","volume":"15","author":"Suaifan","year":"2024","journal-title":"RSC Med. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/16\/9113\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:41:21Z","timestamp":1760110881000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/16\/9113"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,22]]},"references-count":214,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["ijms25169113"],"URL":"https:\/\/doi.org\/10.3390\/ijms25169113","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,22]]}}}