{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T04:04:03Z","timestamp":1792641843479,"version":"4.5.0"},"reference-count":94,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,5]],"date-time":"2023-02-05T00:00:00Z","timestamp":1675555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004329","name":"Slovenian Research Agency (ARRS)","doi-asserted-by":"publisher","award":["P1-0170"],"award-info":[{"award-number":["P1-0170"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004329","name":"Slovenian Research Agency (ARRS)","doi-asserted-by":"publisher","award":["P3-0298"],"award-info":[{"award-number":["P3-0298"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in women of reproductive age. Its heterogeneous clinical presentation is characterized by hyperandrogenemia, reproductive changes, polycystic ovary morphology, and insulin resistance (IR). The primary pathophysiological process in its multifactorial etiology has not yet been identified. However, the two most proposed core etiologies are the disruption of insulin metabolism and hyperandrogenemia, both of which begin to intertwine and propagate each other in the later stages of the disease. Insulin metabolism can be viewed as the interconnectedness of beta cell function, IR or insulin sensitivity, and insulin clearance. Previous studies of insulin metabolism in PCOS patients have yielded conflicting results, and literature reviews have focused mainly on the molecular mechanisms and clinical implications of IR. In this narrative review, we comprehensively explored the role of insulin secretion, clearance, and decreased sensitivity in target cells as a potential primary insult in PCOS pathogenesis, along with the molecular mechanism behind IR in PCOS.<\/jats:p>","DOI":"10.3390\/ijms24043140","type":"journal-article","created":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T03:34:30Z","timestamp":1675654470000},"page":"3140","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":70,"title":["Insulin Metabolism in Polycystic Ovary Syndrome: Secretion, Signaling, and Clearance"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6053-5686","authenticated-orcid":false,"given":"Rok","family":"Herman","sequence":"first","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia"},{"name":"Department of Internal Medicine, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7843-8107","authenticated-orcid":false,"given":"Jaka","family":"Sikonja","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia"},{"name":"Department of Internal Medicine, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8861-8803","authenticated-orcid":false,"given":"Mojca","family":"Jensterle","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia"},{"name":"Department of Internal Medicine, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6594-5254","authenticated-orcid":false,"given":"Andrej","family":"Janez","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia"},{"name":"Department of Internal Medicine, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6707-6649","authenticated-orcid":false,"given":"Vita","family":"Dolzan","sequence":"additional","affiliation":[{"name":"Pharmacogenetics Laboratory, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"261","DOI":"10.4103\/jhrs.JHRS_95_18","article-title":"The Prevalence of Polycystic Ovary Syndrome: A Brief Systematic Review","volume":"13","author":"Deswal","year":"2020","journal-title":"J. Hum. Reprod. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Jensterle, M., Herman, R., and Jane\u017e, A. (2022). Therapeutic Potential of Glucagon-like Peptide-1 Agonists in Polycystic Ovary Syndrome: From Current Clinical Evidence to Future Perspectives. Biomedicines, 10.","DOI":"10.3390\/biomedicines10081989"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.coemr.2020.03.004","article-title":"Polycystic Ovary Syndrome Phenotypes and Prevalence: Differential Impact of Diagnostic Criteria and Clinical versus Unselected Population","volume":"12","author":"Mumusoglu","year":"2020","journal-title":"Curr. Opin. Endocr. Metab. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"116940","DOI":"10.1016\/j.lfs.2019.116940","article-title":"Hyperandrogenemia and Insulin Resistance: The Chief Culprit of Polycystic Ovary Syndrome","volume":"236","author":"Wang","year":"2019","journal-title":"Life Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e9240569","DOI":"10.1155\/2022\/9240569","article-title":"Association of Insulin Resistance and Elevated Androgen Levels with Polycystic Ovarian Syndrome (PCOS): A Review of Literature","volume":"2022","author":"Xu","year":"2022","journal-title":"J. Healthc. Eng."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Giampaolino, P., Foreste, V., Di Filippo, C., Gallo, A., Mercorio, A., Serafino, P., Improda, F.P., Verrazzo, P., Zara, G., and Buonfantino, C. (2021). Microbiome and PCOS: State-of-Art and Future Aspects. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22042048"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1210\/jcem-50-1-113","article-title":"Correlation of Hyperandrogenism with Hyperinsulinism in Polycystic Ovarian Disease","volume":"50","author":"Burghen","year":"1980","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1210\/jcem-64-5-1066","article-title":"Evidence for Insulin Resistance in Nonobese Patients with Polycystic Ovarian Disease","volume":"64","author":"Jialal","year":"1987","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"s72","DOI":"10.7861\/clinmedicine.15-6-s72","article-title":"Polycystic Ovary Syndrome: Insight into Pathogenesis and a Common Association with Insulin Resistance","volume":"15","author":"Barber","year":"2015","journal-title":"Clin. Med. Lond. Engl."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"16057","DOI":"10.1038\/nrdp.2016.57","article-title":"Polycystic Ovary Syndrome","volume":"2","author":"Azziz","year":"2016","journal-title":"Nat. Rev. Dis. Primer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1007\/s12020-019-01899-9","article-title":"Relationship among Obesity, Insulin Resistance, and Hyperinsulinemia in the Polycystic Ovary Syndrome","volume":"64","author":"Dahan","year":"2019","journal-title":"Endocrine"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.2337\/diab.38.9.1165","article-title":"Profound Peripheral Insulin Resistance, Independent of Obesity, in Polycystic Ovary Syndrome","volume":"38","author":"Dunaif","year":"1989","journal-title":"Diabetes"},{"key":"ref_13","first-page":"65","article-title":"Insulin Resistance in Nonobese Patients with Polycystic Ovary Syndrome","volume":"55","author":"Toprak","year":"2001","journal-title":"Horm. Res."},{"key":"ref_14","first-page":"1636","article-title":"Normal Basal and Insulin-Stimulated Fuel Metabolism in Lean Women with the Polycystic Ovary Syndrome","volume":"77","author":"Ovesen","year":"1993","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_15","first-page":"1052","article-title":"Enhanced Early Insulin Response to Glucose in Relation to Insulin Resistance in Women with Polycystic Ovary Syndrome and Normal Glucose Tolerance","volume":"78","author":"Holte","year":"1994","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2942","DOI":"10.1210\/jc.2003-031378","article-title":"Insulin Sensitivity in Women with Polycystic Ovary Syndrome","volume":"89","author":"Cibula","year":"2004","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1093\/humrep\/15.6.1266","article-title":"Insulin Sensitivity, Insulin Secretion, and Metabolic and Hormonal Parameters in Healthy Women and Women with Polycystic Ovarian Syndrome","volume":"15","author":"Vauhkonen","year":"2000","journal-title":"Hum. Reprod."},{"key":"ref_18","first-page":"3984","article-title":"Premature Response to Luteinizing Hormone of Granulosa Cells from Anovulatory Women with Polycystic Ovary Syndrome: Relevance to Mechanism of Anovulation","volume":"83","author":"Willis","year":"1998","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_19","first-page":"774","article-title":"Insulin Resistance and the Polycystic Ovary Syndrome: Mechanism and Implications for Pathogenesis","volume":"18","author":"Dunaif","year":"1997","journal-title":"Endocr. Rev."},{"key":"ref_20","first-page":"3227","article-title":"Portal Insulin Concentrations Rather than Insulin Sensitivity Regulate Serum Sex Hormone-Binding Globulin and Insulin-like Growth Factor Binding Protein 1 in Vivo","volume":"80","author":"Utriainen","year":"1995","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1007\/s40618-020-01351-0","article-title":"Insulin Resistance and PCOS: Chicken or Egg?","volume":"44","author":"Moghetti","year":"2021","journal-title":"J. Endocrinol. Investig."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"657889","DOI":"10.3389\/fendo.2021.657889","article-title":"Improvement of Insulin Sensitivity Increases Pregnancy Rate in Infertile PCOS Women: A Systemic Review","volume":"12","author":"Liu","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.fertnstert.2011.11.036","article-title":"All Women With PCOS Should Be Treated For Insulin Resistance","volume":"97","author":"Marshall","year":"2012","journal-title":"Fertil. Steril."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/s40200-018-0371-5","article-title":"Lean Polycystic Ovary Syndrome (PCOS): An Evidence-Based Practical Approach","volume":"17","author":"Toosy","year":"2018","journal-title":"J. Diabetes Metab. Disord."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"673","DOI":"10.2337\/db14-0694","article-title":"Insulin Resistance as a Physiological Defense against Metabolic Stress: Implications for the Management of Subsets of Type 2 Diabetes","volume":"64","author":"Nolan","year":"2015","journal-title":"Diabetes"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"H1693","DOI":"10.1152\/ajpheart.00854.2012","article-title":"Insulin Resistance Protects the Heart from Fuel Overload in Dysregulated Metabolic States","volume":"305","author":"Taegtmeyer","year":"2013","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1111\/1440-1681.12315","article-title":"Metabolic Remodelling in Obesity and Type 2 Diabetes: Pathological or Protective Mechanisms in Response to Nutrient Excess?","volume":"42","author":"Connor","year":"2015","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/S2213-8587(13)70027-5","article-title":"Intensive Insulin for Type 2 Diabetes: The Risk of Causing Harm","volume":"1","author":"Nolan","year":"2013","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1177\/1479164119827611","article-title":"Insulin Resistance and Insulin Hypersecretion in the Metabolic Syndrome and Type 2 Diabetes: Time for a Conceptual Framework Shift","volume":"16","author":"Nolan","year":"2019","journal-title":"Diabetes Vasc. Dis. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1007\/s11684-021-0862-5","article-title":"Mechanism of Insulin Resistance in Obesity: A Role of ATP","volume":"15","author":"Ye","year":"2021","journal-title":"Front. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1007\/s40618-015-0372-x","article-title":"Hyperinsulinism and Polycystic Ovary Syndrome (PCOS): Role of Insulin Clearance","volume":"38","author":"Amato","year":"2015","journal-title":"J. Endocrinol. Investig."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.2337\/diacare.25.7.1217","article-title":"Insulin Sensitivity and Beta-Cell Function in Women with Polycystic Ovary Syndrome","volume":"25","author":"Hill","year":"2002","journal-title":"Diabetes Care"},{"key":"ref_33","first-page":"1241","article-title":"Defects in Beta-Cell Function in Functional Ovarian Hyperandrogenism","volume":"76","author":"Blackman","year":"1993","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Manco, M., Castagneto-Gissey, L., Arrighi, E., Carnicelli, A., Brufani, C., Luciano, R., and Mingrone, G. (2014). Insulin Dynamics in Young Women with Polycystic Ovary Syndrome and Normal Glucose Tolerance across Categories of Body Mass Index. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0092995"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1210\/jc.2013-2669","article-title":"No Phenotypic Differences for Polycystic Ovary Syndrome (PCOS) between Women with and without Type 1 Diabetes Mellitus","volume":"99","author":"Amato","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1111\/cen.14281","article-title":"Obesity, Menstrual Irregularity and Polycystic Ovary Syndrome in Young Women with Type 1 Diabetes: A Population-Based Study","volume":"93","author":"Thong","year":"2020","journal-title":"Clin. Endocrinol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"639","DOI":"10.2337\/dc15-2577","article-title":"Type 1 Diabetes and Polycystic Ovary Syndrome: Systematic Review and Meta-Analysis","volume":"39","year":"2016","journal-title":"Diabetes Care"},{"key":"ref_38","first-page":"265","article-title":"Induction of Insulin Resistance by Androgens and Estrogens","volume":"79","author":"Polderman","year":"1994","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_39","first-page":"4420","article-title":"Effects of Methyltestosterone on Insulin Secretion and Sensitivity in Women","volume":"83","author":"Diamond","year":"1998","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_40","first-page":"952","article-title":"The Insulin Resistance in Women with Hyperandrogenism Is Partially Reversed by Antiandrogen Treatment: Evidence That Androgens Impair Insulin Action in Women","volume":"81","author":"Moghetti","year":"1996","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1016\/S0015-0282(16)56213-X","article-title":"Insulin Resistance Improves in Hyperandrogenic Women Treated with Lupron","volume":"60","author":"Valdes","year":"1993","journal-title":"Fertil. Steril."},{"key":"ref_42","first-page":"324","article-title":"Dysbiosis of Gut Microbiota Associated with Clinical Parameters in Polycystic Ovary Syndrome","volume":"8","author":"Liu","year":"2017","journal-title":"Front. Microbiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1210\/jc.2017-02153","article-title":"Gut Microbial Diversity in Women With Polycystic Ovary Syndrome Correlates With Hyperandrogenism","volume":"103","author":"Torres","year":"2018","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2552","DOI":"10.1210\/jc.2017-02799","article-title":"Gut Microbiota and the Polycystic Ovary Syndrome: Influence of Sex, Sex Hormones, and Obesity","volume":"103","author":"Insenser","year":"2018","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1042\/BCJ20160510","article-title":"Introduction to the Human Gut Microbiota","volume":"474","author":"Thursby","year":"2017","journal-title":"Biochem. J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1186\/s13048-020-00670-3","article-title":"Role of Gut Microbiota in the Development of Insulin Resistance and the Mechanism Underlying Polycystic Ovary Syndrome: A Review","volume":"13","author":"He","year":"2020","journal-title":"J. Ovarian Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1080\/09513590.2017.1342165","article-title":"\u03b2 Cell Function and Insulin Resistance in Lean Cases with Polycystic Ovary Syndrome","volume":"33","author":"Pande","year":"2017","journal-title":"Gynecol. Endocrinol. Off. J. Int. Soc. Gynecol. Endocrinol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Song, D.K., Hong, Y.S., Sung, Y.-A., and Lee, H. (2017). Insulin Resistance According to \u03b2-Cell Function in Women with Polycystic Ovary Syndrome and Normal Glucose Tolerance. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0178120"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3381","DOI":"10.1210\/jc.2004-1973","article-title":"Preserved Insulin Sensitivity and \u03b2-Cell Activity, but Decreased Glucose Effectiveness in Normal-Weight Women with the Polycystic Ovary Syndrome","volume":"90","author":"Gennarelli","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Chang, R.J. (1996). Polycystic Ovary Syndrome, Springer. Serono Symposia USA.","DOI":"10.1007\/978-1-4613-8483-0"},{"key":"ref_51","first-page":"777","article-title":"Early Impaired \u03b2-Cell Function in Chinese Women with Polycystic Ovary Syndrome","volume":"5","author":"Tao","year":"2012","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_52","first-page":"2027","article-title":"Heritability of Insulin Secretion and Insulin Action in Women with Polycystic Ovary Syndrome and Their First Degree Relatives","volume":"86","author":"Colilla","year":"2001","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.metabol.2007.08.010","article-title":"Evidence for Pancreatic Beta-Cell Dysfunction in Brothers of Women with Polycystic Ovary Syndrome","volume":"57","author":"Sam","year":"2008","journal-title":"Metabolism"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1210\/jc.2004-1006","article-title":"Beta-Cell Function: A Key Pathological Determinant in Polycystic Ovary Syndrome","volume":"90","author":"Goodarzi","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"27408","DOI":"10.1038\/srep27408","article-title":"Developmental Programming of Polycystic Ovary Syndrome (PCOS): Prenatal Androgens Establish Pancreatic Islet \u03b1\/\u03b2 Cell Ratio and Subsequent Insulin Secretion","volume":"6","author":"Ramaswamy","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Rae, M., Grace, C., Hogg, K., Wilson, L.M., McHaffie, S.L., Ramaswamy, S., MacCallum, J., Connolly, F., McNeilly, A.S., and Duncan, C. (2013). The Pancreas Is Altered by in Utero Androgen Exposure: Implications for Clinical Conditions Such as Polycystic Ovary Syndrome (PCOS). PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0056263"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Nicol, L.E., O\u2019Brien, T.D., Dumesic, D.A., Grogan, T., Tarantal, A.F., and Abbott, D.H. (2014). Abnormal Infant Islet Morphology Precedes Insulin Resistance in PCOS-like Monkeys. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0106527"},{"key":"ref_58","first-page":"B4890","article-title":"Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance","volume":"61","year":"2014","journal-title":"Dan. Med. J."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1038\/s41580-021-00390-6","article-title":"The Aetiology and Molecular Landscape of Insulin Resistance","volume":"22","author":"James","year":"2021","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1172\/JCI118126","article-title":"Excessive Insulin Receptor Serine Phosphorylation in Cultured Fibroblasts and in Skeletal Muscle. A Potential Mechanism for Insulin Resistance in the Polycystic Ovary Syndrome","volume":"96","author":"Dunaif","year":"1995","journal-title":"J. Clin. Investig."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1152\/physrev.00063.2017","article-title":"Mechanisms of Insulin Action and Insulin Resistance","volume":"98","author":"Petersen","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"751","DOI":"10.2337\/diabetes.55.03.06.db05-0453","article-title":"Enhanced Mitogenic Signaling in Skeletal Muscle of Women With Polycystic Ovary Syndrome","volume":"55","author":"Corbould","year":"2006","journal-title":"Diabetes"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1042\/BJ20082176","article-title":"Insulin Resistance in Polycystic Ovary Syndrome Is Associated with Defective Regulation of ERK1\/2 by Insulin in Skeletal Muscle in Vivo","volume":"418","author":"Rajkhowa","year":"2009","journal-title":"Biochem. J."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1210\/er.2011-1034","article-title":"Insulin Resistance and the Polycystic Ovary Syndrome Revisited: An Update on Mechanisms and Implications","volume":"33","author":"Dunaif","year":"2012","journal-title":"Endocr. Rev."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.diabres.2017.06.011","article-title":"Insulin and the Polycystic Ovary Syndrome","volume":"130","author":"Macut","year":"2017","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.2337\/diab.41.10.1257","article-title":"Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome","volume":"41","author":"Dunaif","year":"1992","journal-title":"Diabetes"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"E1047","DOI":"10.1152\/ajpendo.00361.2004","article-title":"Insulin Resistance in the Skeletal Muscle of Women with PCOS Involves Intrinsic and Acquired Defects in Insulin Signaling","volume":"288","author":"Corbould","year":"2005","journal-title":"Am. J. Physiol.-Endocrinol. Metab."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3440","DOI":"10.1016\/S0021-9258(18)69090-8","article-title":"Phorbol Ester-Induced Serine Phosphorylation of the Insulin Receptor Decreases Its Tyrosine Kinase Activity","volume":"263","author":"Takayama","year":"1988","journal-title":"J. Biol. Chem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4088","DOI":"10.1210\/jc.2002-020363","article-title":"Decreased Insulin Receptor (IR) Autophosphorylation in Fibroblasts from Patients with PCOS: Effects of Serine Kinase Inhibitors and IR Activators","volume":"87","author":"Li","year":"2002","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"E392","DOI":"10.1152\/ajpendo.2001.281.2.E392","article-title":"Defects in Insulin Receptor Signaling in Vivo in the Polycystic Ovary Syndrome (PCOS)","volume":"281","author":"Dunaif","year":"2001","journal-title":"Am. J. Physiol.-Endocrinol. Metab."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Wang, Z. (2020). Polycystic Ovarian Syndrome, IntechOpen.","DOI":"10.5772\/intechopen.83161"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/s12958-019-0509-4","article-title":"Polycystic Ovary Syndrome and Mitochondrial Dysfunction","volume":"17","author":"Zhang","year":"2019","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2349","DOI":"10.2337\/db07-0275","article-title":"Reduced Expression of Nuclear-Encoded Genes Involved in Mitochondrial Oxidative Metabolism in Skeletal Muscle of Insulin-Resistant Women With Polycystic Ovary Syndrome","volume":"56","author":"Skov","year":"2007","journal-title":"Diabetes"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Skov, V., Glintborg, D., Knudsen, S., Tan, Q., Jensen, T., Kruse, T.A., Beck-Nielsen, H., and H\u00f8jlund, K. (2008). Pioglitazone Enhances Mitochondrial Biogenesis and Ribosomal Protein Biosynthesis in Skeletal Muscle in Polycystic Ovary Syndrome. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0002466"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1089\/ars.2005.7.1040","article-title":"The Molecular Basis for Oxidative Stress-Induced Insulin Resistance","volume":"7","author":"Evans","year":"2005","journal-title":"Antioxid. Redox Signal."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1677\/jme.0.0330059","article-title":"The Molecular Characteristics of Polycystic Ovary Syndrome (PCOS) Ovary Defined by Human Ovary CDNA Microarray","volume":"33","author":"Diao","year":"2004","journal-title":"J. Mol. Endocrinol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1093\/humrep\/deu352","article-title":"Genome-Wide Association Study Identified New Susceptibility Loci for Polycystic Ovary Syndrome","volume":"30","author":"Lee","year":"2015","journal-title":"Hum. Reprod."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/ng.732","article-title":"Genome-Wide Association Study Identifies Susceptibility Loci for Polycystic Ovary Syndrome on Chromosome 2p16.3, 2p21 and 9q33.3","volume":"43","author":"Chen","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1038\/ng.2384","article-title":"Genome-Wide Association Study Identifies Eight New Risk Loci for Polycystic Ovary Syndrome","volume":"44","author":"Shi","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1136\/jmedgenet-2011-100427","article-title":"Replication of Association of DENND1A and THADA Variants with Polycystic Ovary Syndrome in European Cohorts","volume":"49","author":"Goodarzi","year":"2012","journal-title":"J. Med. Genet."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"7502","DOI":"10.1038\/ncomms8502","article-title":"Genome-Wide Association of Polycystic Ovary Syndrome Implicates Alterations in Gonadotropin Secretion in European Ancestry Populations","volume":"6","author":"Hayes","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"E2006","DOI":"10.1210\/jc.2013-2495","article-title":"Cross-Ethnic Meta-Analysis of Genetic Variants for Polycystic Ovary Syndrome","volume":"98","author":"Louwers","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Day, F., Karaderi, T., Jones, M.R., Meun, C., He, C., Drong, A., Kraft, P., Lin, N., Huang, H., and Broer, L. (2018). Large-Scale Genome-Wide Meta-Analysis of Polycystic Ovary Syndrome Suggests Shared Genetic Architecture for Different Diagnosis Criteria. PLoS Genet., 14.","DOI":"10.1371\/journal.pgen.1007813"},{"key":"ref_84","first-page":"608","article-title":"Insulin Degradation: Progress and Potential","volume":"19","author":"Duckworth","year":"1998","journal-title":"Endocr. Rev."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"dgaa095","DOI":"10.1210\/clinem\/dgaa095","article-title":"Serum Androgens Are Independent Predictors of Insulin Clearance but Not of Insulin Secretion in Women With PCOS","volume":"105","author":"Tosi","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1111\/j.1365-2362.1972.tb00669.x","article-title":"Release of Immunoreactive Insulin from the Human Heart","volume":"2","author":"Wahlqvist","year":"1972","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"57","DOI":"10.2337\/diab.46.1.57","article-title":"Effects of Free Fatty Acids and Glucose on Splanchnic Insulin Dynamics","volume":"46","author":"Hennes","year":"1997","journal-title":"Diabetes"},{"key":"ref_88","first-page":"R682","article-title":"Effect of Lactate on Hepatic Insulin Clearance in Perfused Rat Liver","volume":"270","author":"Pagano","year":"1996","journal-title":"Am. J. Physiol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"570","DOI":"10.2337\/diab.39.5.570","article-title":"Free-Fatty Acid Inhibition of Insulin Binding, Degradation, and Action in Isolated Rat Hepatocytes","volume":"39","author":"Svedberg","year":"1990","journal-title":"Diabetes"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"17519","DOI":"10.1016\/S0021-9258(19)85364-4","article-title":"Receptor Accessory Factor Enhances Specific DNA Binding of Androgen and Glucocorticoid Receptors","volume":"268","author":"Kupfer","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"20622","DOI":"10.1016\/S0021-9258(17)32038-0","article-title":"Androgen and Glucocorticoid Receptors Interact with Insulin Degrading Enzyme","volume":"269","author":"Kupfer","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1016\/0026-0495(94)90029-9","article-title":"Evidence for a Defect in Insulin Metabolism in Hyperandrogenic Women with Polycystic Ovarian Syndrome","volume":"43","author":"Buffington","year":"1994","journal-title":"Metabolism"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1093\/humrep\/12.9.1897","article-title":"Heterogeneity in Beta Cell Activity, Hepatic Insulin Clearance and Peripheral Insulin Sensitivity in Women with Polycystic Ovary Syndrome","volume":"12","author":"Ciampelli","year":"1997","journal-title":"Hum. Reprod."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1055\/s-0042-119199","article-title":"C-Peptide, Baseline and Postprandial Insulin Resistance after a Carbohydrate-Rich Test Meal\u2014Evidence for an Increased Insulin Clearance in PCOS Patients?","volume":"77","author":"Stassek","year":"2017","journal-title":"Geburtshilfe Frauenheilkd."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3140\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:24:46Z","timestamp":1760120686000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3140"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,5]]},"references-count":94,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24043140"],"URL":"https:\/\/doi.org\/10.3390\/ijms24043140","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,5]]}}}