Diamanti-Kandarakis E, Dunaif A (2012) Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev 33:981–1030. https://doi.org/10.1210/er.2011-1034

Article  PubMed  PubMed Central  Google Scholar 

Tosi F, Lando MG et al (2025) Alterations of insulin sensitivity, clearance, and secretion, either alone or in combination, in women with PCOS: impact on metabolic profile and androgenemia. Hum Reprod 40:1550–1561. https://doi.org/10.1093/humrep/deaf114

Article  PubMed  Google Scholar 

Houston EJ, Templeman NM (2025) Reappraising the relationship between hyperinsulinemia and insulin resistance in PCOS. J Endocrinol 265(2):e240269. https://doi.org/10.1530/JOE-24-0269

Article  PubMed  PubMed Central  Google Scholar 

Nestler JE, Jakubowicz DJ, de Vergas AF, Brik C, Quintero N, Medina F (1998) Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. J Clin Endocrinol Metab 83:2001–2005. https://doi.org/10.1210/jcem.83.6.4886

Article  PubMed  Google Scholar 

Tosi F, Negri C, Perrone F, Dorizzi R, Castello R, Bonora E, Moghetti P (2012) Hyperinsulinemia amplifies GnRH agonist stimulated ovarian steroid secretion in women with polycystic ovary syndrome. J Clin Endocrinol Metab 97:1712–1719. https://doi.org/10.1210/jc.2011-2939

Article  PubMed  Google Scholar 

Tosi F, Negri C et al (2011) Insulin enhances ACTH-stimulated androgen and glucocorticoid metabolism in hyperandrogenic women. Eur J Endocrinol 164:197–203. https://doi.org/10.1530/EJE-10-0782

Article  PubMed  Google Scholar 

Nestler JE, Powers LP et al (1991) A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab 72:83–89. https://doi.org/10.1210/jcem-72-1-83

Article  PubMed  Google Scholar 

Duckworth WC, Bennett RG, Hamel FG (1998) Insulin degradation: progress and potential. Endocr Rev 19:608–624. https://doi.org/10.1210/edrv.19.5.0349

Article  PubMed  Google Scholar 

Ferrannini E, Balkau B (2002) Insulin: in search of a syndrome. Diabet Med 19:724–729. https://doi.org/10.1046/j.1464-5491.2002.00794.x

Article  PubMed  Google Scholar 

Amato MC, Vesco R, Vigneri E, Ciresi A, Giordano C (2015) Hyperinsulinism and polycystic ovary syndrome (PCOS): role of insulin clearance. J Endocrinol Invest 38:1319–1326. https://doi.org/10.1007/s40618-015-0372-x

Article  PubMed  Google Scholar 

Ciampelli M, Fulghesu AM et al (1997) Heterogeneity in b cell activity, hepatic insulin clearance and peripheral insulin sensitivity in women with polycystic ovary syndrome. Hum Reprod 12:1897–1901. https://doi.org/10.1093/humrep/12.9.1897

Article  PubMed  Google Scholar 

Buffington CK, Kitabchi AE (1994) Evidence for a defect in insulin metabolism in hyperandrogenic women with polycystic ovarian syndrome. Metabolism 43:1367–1372. https://doi.org/10.1016/0026-0495(94)90029-9

Article  PubMed  Google Scholar 

Tosi F, Dal Molin F et al (2020) Serum androgens are independent predictors of insulin clearance but not of insulin secretion in women with PCOS. J Clin Endocrinol Metab 105:e1981-1989. https://doi.org/10.1210/clinem/dgaa095

Article  Google Scholar 

Morin-Papunen LC, Vauhkonen I, Koivunen RM, Ruokonen A, Martikainen HK, Tapanainen JS (2000) Endocrine and metabolic effects of metformin versus ethinyl estradiol-cyproterone acetate in obese women with polycystic ovary syndrome: a randomized study. J Clin Endocrinol Metab 85:3161–3168. https://doi.org/10.1210/jcem.85.9.6792

Article  PubMed  Google Scholar 

Morin-Papunen L, Vauhkonen I, Koivunen R, Ruokonen A, Martikainen H, Tapanainen JS (2003) Metformin versus ethinyl estradiol-cyproterone acetate in the treatment of nonobese women with polycystic ovary syndrome: a randomized study. J Clin Endocrinol Metab 88:148–156. https://doi.org/10.1210/jc.2002-020997

Article  PubMed  Google Scholar 

Cagnacci A, Paoletti AM, Renzi A, Orrù M, Pilloni M, Melis GB, Volpe A (2003) Glucose metabolism and insulin resistance in women with polycystic ovary syndrome during therapy with oral contraceptives containing cyproterone acetate or desogestrel. J Clin Endocrinol Metab 88:3621–3625. https://doi.org/10.1210/jc.2003-030328

Article  PubMed  Google Scholar 

Romualdi D, Guido M, Ciampelli M, Giuliani M, Leoni F, Perri C, Lanzone A (2003) Selective effects of pioglitazone on insulin and androgen abnormalities in normo- and hyperinsulinaemic obese patients with polycystic ovary syndrome. Hum Reprod 18(1210):1218. https://doi.org/10.1093/humrep/deg264

Article  Google Scholar 

Polonsky KS, Rubenstein AH (1984) C-peptide as a measure of the secretion and hepatic extraction of insulin. Pitfalls and limitations. Diabetes 33:486–494. https://doi.org/10.2337/diab.33.5.486

Article  PubMed  Google Scholar 

Moghetti P, Tosi F et al (1996) The insulin resistance in women with hyperandrogenism is partially reversed by antiandrogen treatment: evidence that androgens impair insulin action in women. J Clin Endocrinol Metab 81:952–960. https://doi.org/10.1210/jcem.81.3.8772557

Article  PubMed  Google Scholar 

Moghetti P, Castello R et al (2000) Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metab 85:139–146. https://doi.org/10.1210/jcem.85.1.6293

Article  PubMed  Google Scholar 

Zawadzki JK, Dunaif A (1992) Diagnostic criteria for Polycystic Ovary Syndrome: towards a rational approach. In: Dunaif A, Givens JR, Haseltine FP, Merriam GR (eds) Polycystic Ovary Syndrome. Blackwell Scientific Publications, Cambridge MA p, pp 377–384

Google Scholar 

Escobar-Morreale HF, Carmina E et al (2012) Epidemiology, diagnosis and management of hirsutism: a consensus statement by the androgen excess and polycystic ovary syndrome society. Hum Reprod Update 18:146–170. https://doi.org/10.1093/humupd/dmr042

Article  PubMed  Google Scholar 

Gray DS, Bray GA, Gemayel N, Kaplan K (1989) Effect of obesity on bioelectrical impedance. Am J Clin Nutr 50:255–260. https://doi.org/10.1093/ajcn/50.2.255

Article  PubMed  Google Scholar 

World Health Organization Study Group (1985) Diabetes mellitus. World Health Organization Technical Report Series 727:1–113

Google Scholar 

DeFronzo RA, Tobin JD, Andres R (1979) Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237:E214-223. https://doi.org/10.1152/ajpendo.1979.237.3.E214

Article  Google Scholar 

DeFronzo RA (1988) The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 37:667–687. https://doi.org/10.2337/diab.37.6.667

Article  PubMed  Google Scholar 

Ferrannini E, Mari A (1988) How to measure insulin sensitivity. J Hypertens 16:895–906. https://doi.org/10.1097/00004872-199816070-00001

Article  Google Scholar 

Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419. https://doi.org/10.1007/BF00280883

Article  PubMed  Google Scholar 

Moghetti P, Tosi F (2021) Insulin resistance and PCOS: chicken or egg? J Endocrinol Invest 44:233–244. https://doi.org/10.1007/s40618-020-01351-0

Article  PubMed  Google Scholar 

van Vliet S, Koh HE et al (2020) Obesity is associated with increased basal and postprandial β-cell insulin secretion even in the absence of insulin resistance. Diabetes 69:2112–2119. https://doi.org/10.2337/db20-0377

Article  PubMed  PubMed Central  Google Scholar 

Mittendorfer B, Patterson BW, Smith GI, Yoshino M, Klein S (2022) β cell function and plasma insulin clearance in people with obesity and different glycemic status. J Clin Invest 132(3):e154068. https://doi.org/10.1172/JCI154068

Article  PubMed  PubMed Central  Google Scholar 

Svedberg J, Bjorntorp P, Smith U, Lonnroth P (1990) Free-fatty acid inhibition of insulin binding, degradation, and action in isolated rat hepatocytes. Diabetes 39:570–574. https://doi.org/10.2337/diab.39.5.570

Article  PubMed  Google Scholar 

London A, Lundsgaard A-M, Kiens B, Nyvold Bojsen-Møller K (2021) The role of hepatic fat accumulation in glucose and insulin homeostasis-dysregulation by the liver. J Clin Med 10:390. https://doi.org/10.3390/jcm10030390

Article