http://informahealthcare.com/gye ISSN: 0951-3590 (print), 1473-0766 (electronic) Gynecol Endocrinol, 2016; 32(6): 431–438 ! 2016 Informa UK Limited, trading as Taylor & Francis Group. DOI: 10.3109/09513590.2016.1144741 INOSITOLS AND PCO Inositol’s and other nutraceuticals’ synergistic actions counteract insulin resistance in polycystic ovarian syndrome and metabolic syndrome: state-of-the-art and future perspectives Cristiana Paul 1 , Antonio Simone Lagana ` 2 , Paolo Maniglio 3 , Onofrio Triolo 2 , and David M. Brady 4 1 Independent Nutrition Research Consultant, Los Angeles, CA, USA, 2 Unit of Gynecology and Obstetrics, Department of Human Pathology in Adulthood and Childhood ‘‘G. Barresi’’, University of Messina, Messina, Italy, 3 Department of Obstetrics, Gynecology and Urology, Sant’Andrea Hospital, Sapienza University of Rome, Rome, Italy, and 4 Human Nutrition Institute, University of Bridgeport, Bridgeport, CT, USA Abstract The incidence of metabolic syndrome (MetS), type II diabetes (T2D) and polycystic ovarian syndrome (PCOS) has been progressively increasing. Insulin resistance (InsR) seems to play a key role in a majority of phenotypes of these conditions, altering metabolic homeostasis, within muscle, liver, adipose and other tissues. Hyperinsulinemia is often associated with InsR and causes hormonal imbalances especially within ovaries and adrenals. Inositol is a polyalcohol, naturally occurring as nine stereoisomers, including D-chiro-inositol (DCI) and myo-inositol (MI), which have prominent roles in the metabolism of glucose and free fatty acids. MI and DCI have been classified as insulin-sensitizers and seem to adequately counteract several InsR-related metabolic alterations with a safe nutraceutical profile. Based on our analysis of selected studies that investigated MI and/or DCI, we conclude that supplementation with MI and/or DCI complement each other in their metabolic actions and act in synergy with other insulin sensitizing drugs and/or nutraceuticals. Nevertheless, considering the possible severe bias due to different methodologies across published studies, we conclude that there is a need for further studies on larger cohorts and with greater statistical power. These should further clarify outcomes and suitable therapeutic dosages of MI and DCI, possibly based on each patient’s clinical status. Keywords Diabetes, insulin, insulin resistance, insulin sensitizer, polycystic ovary syndrome History Received 6 October 2015 Revised 14 January 2016 Accepted 18 January 2016 Published online 26 February 2016 Insulin resistance, polycystic ovarian syndrome, meta- bolic syndrome, and type II diabetes: master and minions To date, the incidence of metabolic syndrome (MetS), type II diabetes (T2D), and polycystic ovarian syndrome (PCOS) is progressively increasing [1–3]. Insulin resistance (InsR) can be defined as a deregulation of glucose and insulin metabolism, and may display various degrees of elevated fasting and/or postpran- dial glucose and/or elevated insulin levels [4–6]. In particular, InsR plays a key role in the pathophysiology of MetS, T2D, gestational diabetes mellitus (GDM) and many PCOS phenotypes [1–13]. According to Reaven [9], values of insulin-mediated glucose disposal vary by a difference of  600% between the most insulin-sensitive and the most insulin-resistant individuals. This variability has been attributed to differences in adiposity (25%), fitness (25%), and genetics (50%), although the dietary aspect may play an important role. Furthermore, the more insulin- resistant a person is, the more insulin must be secreted to support glucose disposal [10]. InsR seems to alter several cellular events within liver, muscle, and adipose tissue [11,12] as follows: 1) impaired glucose transported type 4 (GLUT4) receptor translocation to the cell membranes, where GLUT4 is responsible for intracellular glucose transport; 2) reduced activity of pyruvate dehydrogenase (PDH), where PDH enables glucose entry in the Krebs’ cycle for conversion to ATP; 3) reduced activity of glycogen synthase (GS), where GS catalyzes glucose conversion to glycogen; 4) impaired insulin inhibition of adenylate cyclase enzyme (ADC), which controls free fatty acid (FFA) release from fat stores [4,11,12]. This results in elevated plasma FFAs, which are further increased by excess body fat and/or excess intake of fat. InsR-related cellular events affect metabolic homeostasis, causing several detrimental effects [13]: 1) less glucose is taken up and used inside muscle cells, leading to hyperglycemia; 2) more glucose is directed to the liver, which converts it into excess triglycerides in addition to those synthesized from elevated plasma FFAs; 3) hyperglycemia stimulates excess insulin pro- duction, which in turn causes excessive triglyceride and choles- terol synthesis; 4) subsequently, blood triglycerides are elevated leading to fat storage, especially in the liver and adipose tissue. To date, several insulin sensitizing drugs have been used to alleviate InsR and many symptoms of InsR-related conditions. Inositol is a polyalcohol classified as an insulin sensitizer and it is naturally occurring as nine stereoisomers, two of which, D-chiro- inositol (DCI) and myo-inositol (MI) showed a safe nutraceutical profile and seem to significantly alleviate InsR and several InsR- related metabolic alterations [14]. Inositol is synthesized by both prokaryotic and eukaryotic cells, while in mammals, it is obtained Address for correspondence: Dr. Antonio Simone Lagana `, Department of Pediatric, Gynecological, Microbiological and Biomedical Sciences, University of Messina, Via C. Valeria 1, 98125, Messina - Italy. Tel: +39 0902212183. Fax: +39 0902937083. E-mail: antlagana@unime.it