International Journal of Endocrinology The latest articles from Hindawi Publishing Corporation © 2016 , Hindawi Publishing Corporation . All rights reserved. Effects of Inositol(s) in Women with PCOS: A Systematic Review of Randomized Controlled Trials Sun, 23 Oct 2016 12:05:49 +0000 Polycystic ovary syndrome (PCOS) is a common endocrine disorder, with complex etiology and pathophysiology, which remains poorly understood. It affects about 5–10% of women of reproductive age who typically suffer from obesity, hyperandrogenism, ovarian dysfunction, and menstrual irregularity. Indeed, PCOS is the most common cause of anovulatory infertility in industrialized nations, and it is associated with insulin resistance, type 2 diabetes mellitus, and increased cardiovascular risk. Although insulin resistance is not included as a criterion for diagnosis, it is a critical pathological condition of PCOS. The purpose of this systematic review is the analysis of recent randomized clinical trials of inositol(s) in PCOS, in particular myo- and D-chiro-inositol, in order to better elucidate their physiological involvement in PCOS and potential therapeutic use, alone and in conjunction with assisted reproductive technologies, in the clinical treatment of women with PCOS. Vittorio Unfer, John E. Nestler, Zdravko A. Kamenov, Nikos Prapas, and Fabio Facchinetti Copyright © 2016 Vittorio Unfer et al. All rights reserved. Challenges in Modelling Hypoglycaemia-Associated Autonomic Failure: A Review of Human and Animal Studies Sun, 23 Oct 2016 11:09:10 +0000 Recurrent insulin-induced hypoglycaemia is a major limitation to insulin treatment in diabetes patients leading to a condition called hypoglycaemia-associated autonomic failure (HAAF). HAAF is characterised by reduced sympathoadrenal response to subsequent hypoglycaemia thereby predisposing the patients to severe hypoglycaemia that can lead to coma or even death. Despite several attempts being made, the mechanism of HAAF is yet to be clearly established. In order for the mechanism of HAAF to be elucidated, establishing a human/animal model of the phenomenon is the foremost requirement. Several research groups have attempted to reproduce the phenomenon in diabetic and nondiabetic humans and rodents and reported variable results. The success of the phenomenon is marked by a significant reduction in plasma adrenaline response to subsequent hypoglycaemic episode relative to that of the antecedent hypoglycaemic episode. A number of factors such as the insulin dosage, route of administration, fasting conditions, blood sampling methods and analyses, depth, duration, and number of antecedent hypoglycaemic episodes can impact the successful reproduction of the phenomenon and thus have to be carefully considered while developing the protocol. In this review, we have outlined the protocols followed by different research groups to reproduce the phenomenon in diabetic and nondiabetic humans and rodents including our own observations in rats and discussed the factors that have to be given careful consideration in reproducing the phenomenon successfully. Manjula Senthilkumaran, Xin-Fu Zhou, and Larisa Bobrovskaya Copyright © 2016 Manjula Senthilkumaran et al. All rights reserved. Rationale and Design of RNAFH Study: Effect of Rosuvastatin (10 mg/d) on Nonalcoholic Fatty Liver in Metabolic Syndrome Patients without Overt Diabetes Evaluated by 1H-Magnetic Resonance Spectroscopy Wed, 19 Oct 2016 12:00:38 +0000 Objective. The RNAFH study (effect of rosuvastatin on nonalcoholic fatty liver disease in metabolic syndrome patients without overt diabetes evaluated by 1H-MRS) is a prospective randomized, single-center, open-label trail designed to assess the effect of rosuvastatin on the intrahepatocellular lipid (IHCL) level of nonalcoholic fatty liver disease (NAFLD). Methods. 40 NAFLD patients meeting inclusion and exclusion criteria with metabolic syndrome (MS) but without overt diabetes mellitus will be included. Patients will be randomized to 52-week treatment with either rosuvastatin (10 mg/d) or blank control. The primary end point is IHCL evaluated by 1H-MRS, which was considered to be the most accurate noninvasive method for the evaluation of NAFLD. Secondary end points include homeostasis model assessment of insulin resistance (HOMA-IR) index on behalf of insulin resistance level and lipid parameters. Safety indicators will be monitored such as liver function, renal function, muscle stability, and glucose metabolism. The aims of the present study are noteworthy in respect that (1) IHCL is a quantitative indicator for evaluating the degree of fatty liver disease and 1H-MRS is a noninvasive technique to provide this specific index precisely, (2) meanwhile the HOMA-IR index and lipid parameters will be monitored, and (3) the safety of rosuvastatin treatment for 52 weeks will be evaluated including glucose metabolism, muscle stability, liver function, and renal function. Fan Ping, Xuan Wang, Jing Yang, Mei-cen Zhou, Wei Li, Ling-ling Xu, and Yu-xiu Li Copyright © 2016 Fan Ping et al. All rights reserved. No Contribution of GAD-65 and IA-2 Autoantibodies around Time of Diagnosis to the Increasing Incidence of Juvenile Type 1 Diabetes: A 9-Year Nationwide Danish Study Thu, 13 Oct 2016 16:26:12 +0000 Aims. A new perspective on autoantibodies as pivotal players in the pathogenesis of type 1 diabetes (T1D) has recently emerged. Our key objective was to examine whether increased levels of autoantibodies against the β-cell autoantigens glutamic acid decarboxylase (isoform 65) (GADA) and insulinoma associated antigen-2A (IA-2A) mirrored the 3.4% annual increase in incidence of T1D. Methods. From the Danish Childhood Diabetes Register, we randomly selected 500 patients and 500 siblings for GADA and IA-2A analysis (1997 through 2005). Blood samples were taken within three months after onset. A robust log-normal regression model was used. Nine hundred children and adolescents had complete records and were included in the analysis. Cochran-Armitage test for trend was used to evaluate changes in prevalence of autoantibody positivity by period. Results. No significant changes in levels of GADA and IA-2A were found over our 9-year study period. No trends in autoantibody positivity—in either patients or siblings—were found. Levels of GADA and IA-2A were significantly associated with HLA risk groups and GADA with age. Conclusion. The prevalence of positivity and the levels of GADA and IA-2A have not changed between 1997 and 2005 in newly diagnosed patients with T1D and their siblings without T1D. Steffen U. Thorsen, Christian B. Pipper, Henrik B. Mortensen, Flemming Pociot, Jesper Johannesen, and Jannet Svensson Copyright © 2016 Steffen U. Thorsen et al. All rights reserved. The Effectiveness of Myo-Inositol and D-Chiro Inositol Treatment in Type 2 Diabetes Tue, 11 Oct 2016 09:41:17 +0000 Inositol has been used as a supplement in treating several pathologies such as PCOS, metabolic syndrome, and gestational diabetes. Both myo-inositol and its isomer d-chiro-inositol showed insulin mimetic effects in conditions of insulin resistance. Type 2 diabetes (T2DM) is a condition typically caused by insulin resistance. There is a lack of evidence of inositol use in T2DM. We evaluated the effectiveness and safety of myo-inositol and d-chiro-inositol treatment in T2DM. This was a pilot study involving a consecutive sample of patients with T2DM with suboptimal glycemic control (HbA1c 7.0–10.0%) already treated with glucose-lowering agents. Patients (23.1% males, mean age of years) took for three months a combination of myo-inositol (550 mg) and d-chiro-inositol (13.8 mg) orally twice a day as add-on supplement to their glucose-lowering drugs. Possible occurrence of side effects was investigated. After three months of treatment fasting blood glucose ( versus ; ) and HbA1c levels ( versus ; ) significantly decreased compared to baseline. There was no significant difference in blood pressure, lipid profile, and BMI levels. None of the participants reported side effects. In conclusion, a supplementation with a combination of myo- and d-chiro-inositol is an effective and safe strategy for improving glycemic control in T2DM. Basilio Pintaudi, Giacoma Di Vieste, and Matteo Bonomo Copyright © 2016 Basilio Pintaudi et al. All rights reserved. Abnormalities of Thyroid Hormone Metabolism during Systemic Illness: The Low T3 Syndrome in Different Clinical Settings Mon, 10 Oct 2016 12:05:30 +0000 Thyroid hormone abnormalities are common in critically ill patients. For over three decades, a mild form of these abnormalities has been described in patients with several diseases under outpatient care. These alterations in thyroid hormone economy are a part of the nonthyroidal illness and keep an important relationship with prognosis in most cases. The main feature of this syndrome is a fall in free triiodothyronine (T3) levels with normal thyrotropin (TSH). Free thyroxin (T4) and reverse T3 levels vary according to the underlying disease. The importance of recognizing this condition in such patients is evident to physicians practicing in a variety of specialties, especially general medicine, to avoid misdiagnosing the much more common primary thyroid dysfunctions and indicating treatments that are often not beneficial. This review focuses on the most common chronic diseases already known to present with alterations in serum thyroid hormone levels. A short review of the common pathophysiology of the nonthyroidal illness is followed by the clinical and laboratorial presentation in each condition. Finally, a clinical case vignette and a brief summary on the evidence about treatment of the nonthyroidal illness and on the future research topics to be addressed are presented. Arnaldo Moura Neto and Denise Engelbrecht Zantut-Wittmann Copyright © 2016 Arnaldo Moura Neto and Denise Engelbrecht Zantut-Wittmann. All rights reserved. Broad Spectrum Anticancer Activity of Myo-Inositol and Inositol Hexakisphosphate Tue, 04 Oct 2016 13:25:51 +0000 Inositols (myo-inositol and inositol hexakisphosphate) exert a wide range of critical activities in both physiological and pathological settings. Deregulated inositol metabolism has been recorded in a number of diseases, including cancer, where inositol modulates different critical pathways. Inositols inhibit pRB phosphorylation, fostering the pRB/E2F complexes formation and blocking progression along the cell cycle. Inositols reduce PI3K levels, thus counteracting the activation of the PKC/RAS/ERK pathway downstream of PI3K activation. Upstream of that pathway, inositols disrupt the ligand interaction between FGF and its receptor as well as with the EGF-transduction processes involving IGF-II receptor and AP-1 complexes. Additionally, Akt activation is severely impaired upon inositol addition. Downregulation of both Akt and ERK leads consequently to NF-kB inhibition and reduced expression of inflammatory markers (COX-2 and PGE2). Remarkably, inositol-induced downregulation of presenilin-1 interferes with the epithelial-mesenchymal transition and reduces Wnt-activation, β-catenin translocation, Notch-1, N-cadherin, and SNAI1 release. Inositols interfere also with the cytoskeleton by upregulating Focal Adhesion Kinase and E-cadherin and decreasing Fascin and Cofilin, two main components of pseudopodia, leading hence to invasiveness impairment. This effect is reinforced by the inositol-induced inhibition on metalloproteinases and ROCK1/2 release. Overall, these effects enable inositols to remodel the cytoskeleton architecture. Mariano Bizzarri, Simona Dinicola, Arturo Bevilacqua, and Alessandra Cucina Copyright © 2016 Mariano Bizzarri et al. All rights reserved. Inositol Treatment and ART Outcomes in Women with PCOS Tue, 04 Oct 2016 07:51:51 +0000 Polycystic ovary syndrome (PCOS) affects 5–10% of women in reproductive age and is characterized by oligo/amenorrhea, androgen excess, insulin resistance, and typical polycystic ovarian morphology. It is the most common cause of infertility secondary to ovulatory dysfunction. The underlying etiology is still unknown but is believed to be multifactorial. Insulin-sensitizing compounds such as inositol, a B-complex vitamin, and its stereoisomers (myo-inositol and D-chiro-inositol) have been studied as an effective treatment of PCOS. Administration of inositol in PCOS has been shown to improve not only the metabolic and hormonal parameters but also ovarian function and the response to assisted-reproductive technology (ART). Accumulating evidence suggests that it is also capable of improving folliculogenesis and embryo quality and increasing the mature oocyte yield following ovarian stimulation for ART in women with PCOS. In the current review, we collate the evidence and summarize our current knowledge on ovarian stimulation and ART outcomes following inositol treatment in women with PCOS undergoing in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI). Deepika Garg and Reshef Tal Copyright © 2016 Deepika Garg and Reshef Tal. All rights reserved. Arterial Calcium Stimulation with Hepatic Venous Sampling in the Localization Diagnosis of Endogenous Hyperinsulinism Mon, 03 Oct 2016 08:56:22 +0000 Objective. The aim of this study was to assess the utility of arterial calcium stimulation with hepatic venous sampling (ASVS) in the localization diagnosis of endogenous hyperinsulinism. Patients and Methods. A retrospective descriptive study was performed including patients with endogenous hyperinsulinism who underwent ASVS. The histopathological diagnosis in patients who underwent a surgical procedure was used as the reference for the statistical study of the accuracy of this technique. Results. 30 patients were included with endogenous hyperinsulinism and nonconclusive imaging diagnosis was included. ASVS was performed in all cases. Surgery was performed in 20 cases. Insulinoma was removed in 19 patients; the location of all cases was detected in the ASVS. All cases of endogenous hyperinsulinism had a positive result for the ASVS, with this association being statistically significant (; ). A good and statistically significant agreement was obtained between histopathologic diagnosis and ASVS results (, ). Conclusions. ASVS is a useful procedure in the localization diagnosis of endogenous hyperinsulinism undetected by other imaging tests. This technique allows the localization of intrapancreatic insulinomas and represents useful tool for the diagnosis and surgical management of these tumors. Paloma Moreno-Moreno, María Rosa Alhambra-Expósito, Aura Dulcinea Herrera-Martínez, Rafel Palomares-Ortega, Luis Zurera-Tendero, Juan José Espejo Herrero, and María Angeles Gálvez-Moreno Copyright © 2016 Paloma Moreno-Moreno et al. All rights reserved. Myoinositol Improves Embryo Development in PCOS Patients Undergoing ICSI Thu, 29 Sep 2016 13:53:29 +0000 The aim of this study was to investigate the activity of myoinositol, in a court of 217 PCOS women undergoing intracytoplasmic sperm injection (ICSI), on pregnancy rate, embryo development, estradiol, and progesterone concentration in blood serum, superoxide dismutase (SOD), and catalase (CAT) in follicular fluid. Concerning the court of patient, 112 (groups I and II) out of 217 were PCOS women, whereas group III consisted of healthy subjects (not PCOS). Group I patients were treated with 400 μg of folic acid per day for 3 months before ICSI, whereas group II patients received 4000 mg of myoinositol and 400 μg of folic acid per day for 3 months before ICSI. Group II revealed a shorter embryo/blastocyst development period between microinjection and 5-cell stage compared to group I. The difference in SOD concentration between groups I and II and between groups II and III was statistically significant. In group II, 34.62% of pregnancies were obtained, whereas in group I this number reached 20% (NS). Myoinositol increased embryo development dynamics and accelerated blastocyst stage reaching time; however, no effect was shown on clinical pregnancy. Furthermore, it restored SOD concentration, lowered in PCOS women, but did not exert any effect on CAT concentration. Artur Wdowiak Copyright © 2016 Artur Wdowiak. All rights reserved. Arterial Stiffness in Nonhypertensive Type 2 Diabetes Patients in Ghana Wed, 28 Sep 2016 13:25:53 +0000 Background. Increased arterial stiffness is an independent cardiovascular risk factor in diabetes patients and general population. However, the contribution of diabetes to arterial stiffness is often masked by coexistent obesity and hypertension. In this study, we assessed arterial stiffness in nonhypertensive, nonobese type 2 diabetes (T2DM) patients in Ghana. Methods. In case-control design, 166 nonhypertensive, nonobese participants, comprising 96 T2DM patients and 70 nondiabetes controls, were recruited. Peripheral and central blood pressure (BP) indices were measured, and arterial stiffness was assessed as aortic pulse wave velocity (PWVao), augmentation index (AIx), cardioankle vascular index (CAVI), and heart-ankle pulse wave velocity (haPWV). Results. With similar peripheral and central BP indices, T2DM patients had higher PWVao ( versus , ) and CAVI ( versus , ) than nondiabetic control. AIx and haPWV were similar between T2DM and nondiabetic controls. Multiple regression models showed that, in the entire study participants, the major determinants of PWVao were diabetes status, age, gender, systolic BP, and previous smoking status (β = 0.22, 0.36, 0.48, 0.21, and 0.25, resp.; all ); the determinants of CAVI were diabetes status, age, BMI, heart rate, HbA1c, total cholesterol, HDL cholesterol, and previous smoking status (β = 0.21, 0.38, 0.2, 0.18, 0.24. 0.2, −0.19, and 0.2, resp.; all ). Conclusion. Our findings suggest that nonhypertensive, nonobese T2DM patients have increased arterial stiffness without appreciable increase in peripheral and central pressure indices. Kwame Yeboah, Daniel A. Antwi, and Ben Gyan Copyright © 2016 Kwame Yeboah et al. All rights reserved. Valproic Acid, a Histone Deacetylase Inhibitor, in Combination with Paclitaxel for Anaplastic Thyroid Cancer: Results of a Multicenter Randomized Controlled Phase II/III Trial Tue, 27 Sep 2016 15:38:23 +0000 Anaplastic thyroid cancer (ATC) has a median survival less than 5 months and, to date, no effective therapy exists. Taxanes have recently been stated as the main drug treatment for ATC, and the histone deacetylase inhibitor valproic acid efficiently potentiates the effects of paclitaxel in vitro. Based on these data, this trial assessed the efficacy and safety of the combination of paclitaxel and valproic acid for the treatment of ATC. This was a randomized, controlled phase II/III trial, performed on 25 ATC patients across 5 centers in northwest Italy. The experimental arm received the combination of paclitaxel (80 mg/m2/weekly) and valproic acid (1,000 mg/day); the control arm received paclitaxel alone. Overall survival and disease progression, evaluated in terms of progression-free survival, were the primary outcomes. The secondary outcome was the pharmacokinetics of paclitaxel. The coadministration of valproic acid did not influence the pharmacokinetics of paclitaxel. Neither median survival nor median time to progression was statistically different in the two arms. Median survival of operated-on patients was significantly better than that of patients who were not operated on. The present trial demonstrates that the addition of valproic acid to paclitaxel has no effect on overall survival and disease progression of ATC patients. This trial is registered with EudraCT 2008-005221-11. Maria Graziella Catalano, Mariateresa Pugliese, Marco Gallo, Enrico Brignardello, Paola Milla, Fabio Orlandi, Paolo Piero Limone, Emanuela Arvat, Giuseppe Boccuzzi, and Alessandro Piovesan Copyright © 2016 Maria Graziella Catalano et al. All rights reserved. Does Tumor Size Influence the Diagnostic Accuracy of Ultrasound-Guided Fine-Needle Aspiration Cytology for Thyroid Nodules? Tue, 27 Sep 2016 14:33:29 +0000 Background. Fine-needle aspiration cytology (FNAC) is diagnostic standard for thyroid nodules. However, the influence of size on FNAC accuracy remains unclear especially in too small or too large thyroid nodules. The objective of this retrospective cohort study was to investigate the effect of nodule size on FNAC accuracy. Methods. All consecutive patients who underwent thyroidectomy for nodules in 2010 were enrolled. FNAC results (according to the Bethesda system) were compared to pathological diagnosis. The nodules were categorized into groups A–E on the basis of maximal diameter on ultrasound (≤0.5, >0.5–1, >1-2, >2–4, and >4 cm, resp.). Results. There were 502 cases with 690 nodules. Overall FNAC sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 95.4%, 98.2%, 99.4%, 86.4%, and 96.0%, respectively. False-negative rates (FNRs) of groups A–E were 3.2%, 5.1%, 1.3%, 13.3%, and 50%, respectively. Accuracy rates of groups A–E were 96.8%, 94.8%, 99%, 94.7%, and 87.5%, respectively. Conclusion. Although accuracy rates of FNAC in thyroid nodules smaller than 0.5 cm are comparable to the other group, thyroid nodules larger than 4 cm with benign cytology carry a higher risk of malignancy, which suggest that those should be considered for intensive follow-up or repeated biopsy. Do Hoon Koo, KwangSeop Song, Hyungju Kwon, Dong Sik Bae, Ji-hoon Kim, Hye Sook Min, Kyu Eun Lee, and Yeo-Kyu Youn Copyright © 2016 Do Hoon Koo et al. All rights reserved. Differential Role of Adipose Tissues in Obesity and Related Metabolic and Vascular Complications Tue, 27 Sep 2016 07:40:06 +0000 This review focuses on the contribution of white, brown, and perivascular adipose tissues to the pathophysiology of obesity and its associated metabolic and vascular complications. Weight gain in obesity generates excess of fat, usually visceral fat, and activates the inflammatory response in the adipocytes and then in other tissues such as liver. Therefore, low systemic inflammation responsible for insulin resistance contributes to atherosclerotic process. Furthermore, an inverse relationship between body mass index and brown adipose tissue activity has been described. For these reasons, in recent years, in order to combat obesity and its related complications, as a complement to conventional treatments, a new insight is focusing on the role of the thermogenic function of brown and perivascular adipose tissues as a promising therapy in humans. These lines of knowledge are focused on the design of new drugs, or other approaches, in order to increase the mass and/or activity of brown adipose tissue or the browning process of beige cells from white adipose tissue. These new treatments may contribute not only to reduce obesity but also to prevent highly prevalent complications such as type 2 diabetes and other vascular alterations, such as hypertension or atherosclerosis. Almudena Gómez-Hernández, Nuria Beneit, Sabela Díaz-Castroverde, and Óscar Escribano Copyright © 2016 Almudena Gómez-Hernández et al. All rights reserved. The Prevalence of Metabolic Syndrome and Cardiovascular Risk Factors in Obese Children and Adolescents in Dalmatia: A Hospital Based Study Mon, 26 Sep 2016 12:53:45 +0000 Obesity and metabolic syndrome (MS) are one of the biggest public health issues in child and adolescent population. To the best of the authors’ knowledge, this hospital based study is the first report on the prevalence of MS in obese children and adolescents in Dalmatia, the Mediterranean part of Croatia. The objectives of this study were to determine the prevalence of individual cardiovascular risk factors and MS. Between January 2009 and June 2014, 201 obese subjects aged 6 to 18 were analyzed retrospectively from our Pediatric Endocrine Unit database. The subjects were then classified in two groups of obesity; subjects with BMI score 2.0–3.0 were classified as moderately obese and subjects with BMI score > 3.0 were classified as severely obese. The overall prevalence of MS using the modified IDF criteria was 30.3%. The most common component of MS in both groups was arterial hypertension, while impaired fasting glucose was the least common component of MS. Our finding of high prevalence of MS underlines the importance of early childhood obesity treatment. Marko Šimunović, Joško Božić, Lukrecija Milić, Ivana Unić, and Veselin Škrabić Copyright © 2016 Marko Šimunović et al. All rights reserved. Effect of Myoinositol and Antioxidants on Sperm Quality in Men with Metabolic Syndrome Mon, 26 Sep 2016 10:58:31 +0000 This prospective longitudinal study investigated the effects of a dietary supplement in patients affected by reduced sperm motility (asthenospermic males) with metabolic syndrome. The product tested was Andrositol®, which contains myoinositol (MI) as principal compound, in association with other molecules, and the parameters evaluated were semen characteristics as well as hormone and metabolic profiles. The inclusion criteria were subjects aged over 18 years, with asthenospermia and metabolic syndrome. The exclusion criteria were presence of cryptorchidism, varicocele, and prostatitis. For this study, 45 males who had such features were enrolled. Their selection was made according to the 2010 World Health Organization (WHO) criteria (5th Edition) for the Evaluation of Human Semen. Hormone and metabolic profiles and semen parameters were assessed at the beginning of the study and after three months of treatment with Andrositol. The differences between the values before and after the supplementation were found statistically significant. Andrositol normalized the metabolic profile of these patients, improving their insulin sensitivity. Moreover, testosterone levels were increased and the semen characteristics, such as sperm concentration, motility, and morphology, highly improved. In conclusion, the association of MI with other molecules (micronutrients and vitamins) could be an effective therapy for metabolic disorders, as well as hormonal and spermatic changes responsible for male infertility. Mario Montanino Oliva, Elisa Minutolo, Assunta Lippa, Paola Iaconianni, and Alberto Vaiarelli Copyright © 2016 Mario Montanino Oliva et al. All rights reserved. Disproportionately Elevated Proinsulin Levels as an Early Indicator of β-Cell Dysfunction in Nondiabetic Offspring of Chinese Diabetic Patients Sun, 25 Sep 2016 07:14:52 +0000 Objective. To study the characteristics of β-cell dysfunction and insulin resistance (IR) in the first-degree relatives (FDRs) of T2DM in Chinese population and to examine the usefulness of proinsulin (PI) for evaluating β-cell dysfunction. Methods. 229 subjects of nondiabetic FDRs, 71 newly diagnosed T2DM, and 114 with normal glucose tolerance (NGT) but not FDRs (NGT-non-FDRs) were verified by a 2-hour oral glucose tolerance test. Specific insulin (SI) and PI were measured by highly sensitive ELISA. Results. Compared to NGT-non-FDRs, NGT-FDRs showed higher levels of fasting and 2-hour PI, fasting PI-to-SI ratio (FPI/SI), and HOMA-IR (). Meanwhile, fasting PI, FPI/SI, and HOMA-IR were increased steadily from NGT-FDRs to prediabetes-FDRs and were highest in T2DM group (), whereas a significant decrease in HOMA-B could be observed only in T2DM group. Moreover, a progressive deterioration of β-cell function in NGT-FDRs, prediabetes-FDRs, and T2DM could be identified by FPI/SI even after adjusting for HOMA-IR: relative to non-FDRs controls, mean FPI/SI levels were increased 1.5, 2.0, and 4.7-fold, respectively (all ). Conclusions.  β-cell dysfunction as assessed by disproportionate secretion of proinsulin and IR by HOMA (using specific insulin assay) already exist in FDRs of T2DM even with normal glucose status. Compared with HOMA-B, FPI/SI could detect β-cell failure in earlier stage of diabetes development. Ming Li, Dan Feng, Kui Zhang, Shan Gao, and Juming Lu Copyright © 2016 Ming Li et al. All rights reserved. Putative Key Role of Inositol Messengers in Endothelial Cells in Preeclampsia Wed, 21 Sep 2016 09:24:45 +0000 Immunological alterations, endothelial dysfunction, and insulin resistance characterize preeclampsia. Endothelial cells hold the key role in the pathogenesis of this disease. The signaling pathways mediating these biological abnormalities converge on PKB/Akt, an intracellular kinase regulating cell survival, proliferation, and metabolism. Inositol second messengers are involved in metabolic and cell signaling pathways and are highly expressed during preeclampsia. Intracellular action of these molecules is deeply affected by zinc, manganese, and calcium. To evaluate the pathophysiological significance, we present the response of the intracellular pathways of inositol phosphoglycans involved in cellular metabolism and propose a link with the disease. Sirilaksana Kunjara, Patricia McLean, Laurens Rademacher, Thomas W. Rademacher, Fabiana Fascilla, Stefano Bettocchi, and Marco Scioscia Copyright © 2016 Sirilaksana Kunjara et al. All rights reserved. Insulin-Sensitizers, Polycystic Ovary Syndrome and Gynaecological Cancer Risk Tue, 20 Sep 2016 10:00:30 +0000 Preclinical, early phase clinical trials and epidemiological evidence support the potential role of insulin-sensitizers in cancer prevention and treatment. Insulin-sensitizers improve the metabolic and hormonal profile in PCOS patients and may also act as anticancer agents, especially in cancers associated with hyperinsulinemia and oestrogen dependent cancers. Several lines of evidence support the protection against cancer exerted by dietary inositol, in particular inositol hexaphosphate. Metformin, thiazolidinediones, and myoinositol postreceptor signaling may exhibit direct inhibitory effects on cancer cell growth. AMPK, the main molecular target of metformin, is emerging as a target for cancer prevention and treatment. PCOS may be correlated to an increased risk for developing ovarian and endometrial cancer (up to threefold). Several studies have demonstrated an increase in mortality rate from ovarian cancer among overweight/obese PCOS women compared with normal weight women. Long-term use of metformin has been associated with lower rates of ovarian cancer. Considering the evidence supporting a higher risk of gynaecological cancer in PCOS women, we discuss the potential use of insulin-sensitizers as a potential tool for chemoprevention, hypothesizing a possible rationale through which insulin-sensitizers may inhibit tumourigenesis. Rosa Lauretta, Giulia Lanzolla, Patrizia Vici, Luciano Mariani, Costanzo Moretti, and Marialuisa Appetecchia Copyright © 2016 Rosa Lauretta et al. All rights reserved. Changes in Testosterone Levels and Sex Hormone-Binding Globulin Levels in Extremely Obese Men after Bariatric Surgery Tue, 20 Sep 2016 08:22:02 +0000 Objective. Obesity is a risk factor for hypogonadotropic hypogonadism in men. Weight loss has been shown to improve hypogonadism in obese men. This study evaluated the early changes in sex hormones profile after bariatric surgery. Methods. This is a prospective study including 29 morbidly obese men. Main outcomes were changes in serum levels of total testosterone (TT), free testosterone (cFT), SHBG, estradiol, adiponectin, and leptin at 1 and 6 months after surgery. Results. The mean age of patients was 31 ± 8 years and the mean BMI was 56.8 ± 11.7 kg/m2. Fifteen patients underwent Roux-en-Y gastric bypass and 14 patients underwent sleeve gastrectomy. At baseline, 22 patients (75.9%) had either low TT levels (<10.4 nmol/L) or low cFT levels (<225 pmol/L). Total testosterone and SHBG levels increased significantly at 1 month after surgery (). At 6 months after surgery, TT and cFT increased significantly () and 22 patients (75.9%) had normalized TT and cFT levels. There were no changes in estradiol levels at either 1 month or 6 months after surgery. Conclusions. Increases in TT and SHBG levels occurred early at 1 month after bariatric surgery while improvements in cFT levels were observed at 6 months after bariatric surgery. Patchaya Boonchaya-anant, Nitchakarn Laichuthai, Preaw Suwannasrisuk, Natnicha Houngngam, Suthep Udomsawaengsup, and Thiti Snabboon Copyright © 2016 Patchaya Boonchaya-anant et al. All rights reserved. Comment on “Bone Regulates Glucose Metabolism as an Endocrine Organ through Osteocalcin” Tue, 20 Sep 2016 06:47:14 +0000 Hitesh Verma and Rajeev Garg Copyright © 2016 Hitesh Verma and Rajeev Garg. All rights reserved. Functional and Structural Consequences of Nine CYP21A2 Mutations Ranging from Very Mild to Severe Effects Mon, 19 Sep 2016 14:24:18 +0000 We present the functional and structural effects of seven novel (p.Leu12Met, p.Arg16Cys, p.Ser101Asn, p.Ser202Gly, p.Pro267Leu, p.Gln389_Ala391del, and p.Thr450Met) and two previously reported but not studied (p.Ser113Phe and p.Thr450Pro) CYP21A2 mutations. Functional analyses were complemented with in silico prediction of mutation pathogenicity based on the recently crystallized human CYP21A2 structure. Mutated proteins were transiently expressed in COS-1 cells and enzyme activities towards 17-hydroxyprogesterone and progesterone were determined. Residual enzyme activities between 43% and 97% were obtained for p.Arg16Cys, p.Ser101Asn, p.Ser202Gly, p.Pro267Leu, and p.Thr450Met, similar to the activities of the well-known nonclassic mutations p.Pro453Ser and p.Pro482Ser, whereas the p.Leu12Met variant showed an activity of 100%. Conversely, the novel p.Ser113Phe, p.Gln389_Ala391del, and p.Thr450Pro mutations drastically reduced the enzyme function below 4%. The values for all novel variants were in the same order of magnitude as for the wild-type protein except for p.The450Met. The maximum velocity was decreased for all mutants except for p.Leu12Met. We conclude that p.Leu12Met is a normal variant; the mutations p.Arg16Cys, p.Ser101Asn, p.Ser202Gly, p.Pro267Leu, and p.Thr450Met could be associated with very mild nonclassic CAH, and the mutations p.Ser113Phe, p.Gln389_Ala391del, and p.Thr450Pro are associated with classic CAH. The obtained residual activities indicated a good genotype-phenotype correlation. Débora de Paula Michelatto, Leif Karlsson, Ana Letícia Gori Lusa, Camila D’Almeida Mgnani Silva, Linus Joakim Östberg, Bengt Persson, Gil Guerra-Júnior, Sofia Helena Valente de Lemos-Marini, Michela Barbaro, Maricilda Palandi de Mello, and Svetlana Lajic Copyright © 2016 Débora de Paula Michelatto et al. All rights reserved. Effect on Insulin-Stimulated Release of D-Chiro-Inositol-Containing Inositolphosphoglycan Mediator during Weight Loss in Obese Women with and without Polycystic Ovary Syndrome Sun, 18 Sep 2016 14:08:54 +0000 Background. A deficiency of D-chiro-inositol-inositolphosphoglycan mediator (DCI-IPG) may contribute to insulin resistance in polycystic ovary syndrome (PCOS). Whether the relationship between impaired DCI-IPG release and insulin resistance is specific to PCOS rather than obesity is unknown. We assessed insulin-released DCI-IPG and its relationship to insulin sensitivity at baseline and after weight loss in obese women with and without PCOS. Methods. Obese PCOS () and normal () women underwent 8 weeks of a hypocaloric diet. The Matsuda index, area under the curve DCI-IPG (), , and were measured during a 2 hr OGTT at baseline and 8 weeks. Results. PCOS women had lower at baseline and a significant relationship between and Matsuda index (), which was not present in controls. Weight loss was similar between PCOS (−4.08 kg) and normal women (−4.29 kg, ). Weight loss in PCOS women did not change the relationship between and Matsuda index (), and this relationship remained absent in control women. Conclusion. The association between and insulin sensitivity was only found in PCOS but not in normal women, and this relationship was unaffected by weight loss. DCI and its messenger may contribute to insulin resistance in PCOS independent of obesity. Kai I. Cheang, Sakita N. Sistrun, Kelley S. Morel, and John E. Nestler Copyright © 2016 Kai I. Cheang et al. All rights reserved. Human Adrenocortical Remodeling Leading to Aldosterone-Producing Cell Cluster Generation Sun, 18 Sep 2016 07:05:30 +0000 Background. The immunohistochemical detection of aldosterone synthase (CYP11B2) and steroid 11β-hydroxylase (CYP11B1) has enabled the identification of aldosterone-producing cell clusters (APCCs) in the subcapsular portion of the human adult adrenal cortex. We hypothesized that adrenals have layered zonation in early postnatal stages and are remodeled to possess APCCs over time. Purposes. To investigate changes in human adrenocortical zonation with age. Methods. We retrospectively analyzed adrenal tissues prepared from 33 autopsied patients aged between 0 and 50 years. They were immunostained for CYP11B2 and CYP11B1. The percentage of APCC areas over the whole adrenal area (AA/WAA, %) and the number of APCCs (NOA, APCCs/mm2) were calculated by four examiners. Average values were used in statistical analyses. Results. Adrenals under 11 years old had layered zona glomerulosa (ZG) and zona fasciculata (ZF) without apparent APCCs. Some adrenals had an unstained (CYP11B2/CYP11B1-negative) layer between ZG and ZF, resembling the rat undifferentiated cell zone. Average AA/WAA and NOA correlated with age, suggesting that APCC development is associated with aging. Possible APCC-to-APA transitional lesions were incidentally identified in two adult adrenals. Conclusions. The adrenal cortex with layered zonation remodels to possess APCCs over time. APCC generation may be associated with hypertension in adults. Koshiro Nishimoto, Tsugio Seki, Yuichiro Hayashi, Shuji Mikami, Ghaith Al-Eyd, Ken Nakagawa, Shinya Morita, Takeo Kosaka, Mototsugu Oya, Fumiko Mitani, Makoto Suematsu, Yasuaki Kabe, and Kuniaki Mukai Copyright © 2016 Koshiro Nishimoto et al. All rights reserved. Early Intervention of Didang Decoction on MLCK Signaling Pathways in Vascular Endothelial Cells of Type 2 Diabetic Rats Thu, 15 Sep 2016 16:08:10 +0000 In the study, type 2 diabetic rat model was established using streptozotocin (STZ) combined with a high-fat diet, and the rats were divided into control and diabetic groups. Diabetic groups were further divided into nonintervening, simvastatin, Didang Decoction (DDD) early-phase intervening, DDD mid-phase intervening, and DDD late-phase intervening groups. The expression level of MLCK was detected using Western Blot analysis, and the levels of cyclic adenosine monophosphate (cAMP), protein kinase C (PKC), and protein kinase A (PKA) were examined using Real Time PCR. Under the electron microscope, the cells in the early-DDD-intervention group and the simvastatin group were significantly more continuous and compact than those in the diabetic group. Compared with the control group, the expression of cAMP-1 and PKA was decreased in all diabetic groups, whereas the expression of MLCK and PKC was increased in early- and mid-phase DDD-intervening groups (); compared with the late-phase DDD-intervening group, the expression of cAMP-1 and PKA was higher, but the level of MLCK and PKC was lower in early-phase DDD-intervening group (). In conclusion, the early use of DDD improves the permeability of vascular endothelial cells by regulating the MLCK signaling pathway. Shoujiao Ye, Zhenqiang Song, Jing Li, Chunshen Li, Juhong Yang, and Bai Chang Copyright © 2016 Shoujiao Ye et al. All rights reserved. Corrigendum to “Ferritin as a Risk Factor for Glucose Intolerance amongst Men and Women Originating from the Indian Subcontinent” Wed, 14 Sep 2016 14:13:03 +0000 Jeetesh V. Patel, Paramjit S. Gill, Julia Chackathayil, Elif S. Agaoglu, Zosia Bredow, Rebecca Mirrielees, Paul Flinders, and Elizabeth A. Hughes Copyright © 2016 Jeetesh V. Patel et al. All rights reserved. Diet-Related Knowledge and Physical Activity in a Large Cohort of Insulin-Treated Type 2 Diabetes Patients: PROGENS ARENA Study Wed, 14 Sep 2016 12:04:40 +0000 There is no doubt that behavioral intervention is crucial for type 2 diabetes mellitus (T2DM) prevention and management. We aimed to estimate dietary habits and diet-oriented knowledge as well as the level of physical activity in 2500 insulin-treated Polish type 2 diabetes mellitus (T2DM) patients (55.4% women). The mean age of the study participants was 64.9 ± 9.3 years, mean BMI was 31.4 kg/m2 ± 4.5, mean diabetes duration was 12.4 ± 6.9 years, and mean baseline HbA1c was 8.5%  ± 1.2. At the study onset, all the patients completed a questionnaire concerning health-oriented behavior. Results showed a significant lack of diet-related knowledge. For example, only 37.5% recognized that buckwheat contains carbohydrates; the percentage of correct answers in questions about fruit drinks and pasta was 56.4% and 61.2%, respectively. As for the physical activity, only 57.4% of examined T2DM patients declared any form of deliberate physical activity. To conclude, the cohort of poorly controlled insulin-treated T2DM patients studied by us is characterized by insufficient diet-related knowledge and by a very low level of physical activity. Further studies on other populations of insulin-treated T2DM patients are required to confirm these findings. Tomasz Klupa, Michał Możdżan, Janina Kokoszka-Paszkot, Magdalena Kubik, Małgorzata Masierek, Margerita Czerwińska, and Maciej T. Małecki Copyright © 2016 Tomasz Klupa et al. All rights reserved. The Relationship between Adiposity and Insulin Sensitivity in African Women Living with the Polycystic Ovarian Syndrome: A Clamp Study Thu, 08 Sep 2016 13:58:36 +0000 Objectives. We aimed to assess the variation of insulin sensitivity in relation to obesity in women living with PCOS in a sub-Sahara African setting. Methods. We studied body composition, insulin sensitivity, and resting energy expenditure in 14 PCOS patients (6 obese and 8 nonobese) compared to 10 matched nonobese non-PCOS subjects. Insulin sensitivity was assessed using the gold standard 80 mU/m2/min euglycemic-hyperinsulinemic clamp and resting energy expenditure was measured by indirect calorimetry. Results. Insulin sensitivity adjusted to lean mass was lowest in obese PCOS subjects and highest in healthy subjects (11.2 10.1–12.4 versus 12.9 12.1–13.8 versus 16.6 13.8–17.9, ); there was a tendency for resting energy expenditure adjusted for total body mass to decrease across the groups highest in obese PCOS subjects (1411 1368–1613 versus 1274 1174–1355 versus 1239 1195–1454, ). Conclusion. In this sub-Saharan population, insulin resistance is associated with PCOS per se but is further aggravated by obesity. Obesity did not seem to be explained by low resting energy expenditure suggesting that dietary intake may be a determinant of the obesity in this context. Emmanuella Doh, Armand Mbanya, Jean Dupont Kemfang-Ngowa, Sama Dohbit, Mycilline Tchana-Sinou, Pascal Foumane, Olivier Trésor Donfack, Anderson S. Doh, Jean Claude Mbanya, and Eugene Sobngwi Copyright © 2016 Emmanuella Doh et al. All rights reserved. In Vitro Antioxidant Treatment of Semen Samples in Assisted Reproductive Technology: Effects of Myo-Inositol on Nemaspermic Parameters Thu, 08 Sep 2016 11:53:27 +0000 Male infertility and the poor quality of sperm seem to be influenced by oxidative stress. In particular, the reactive oxygen species (ROS) mainly produced by morphologically altered spermatozoa affect sperm motility, morphology, and integrity. The aim of this study was to evaluate the efficacy of Myo-Inositol (Myo-Ins) on a number of parameters such as viscosity and total and progressive motility of spermatozoa, in order to better validate its possible practical application in vitro, in order to improve the capacitation protocols commonly used in Assisted Reproductive Technology (ART). A total of 100 fresh and 25 thawed semen samples were analyzed in vitro prior to and after addition of Myo-Ins. Treatment of samples with Myo-Ins showed an increase in the sperm total and progressive motility in both fresh and thawed samples. Furthermore, Myo-Ins proved to be well tolerated by spermatozoa in vitro, demonstrating that it can be efficiently and safely used as antioxidant in the laboratory practice and for preparation of semen samples in ART. Mariangela Palmieri, Palma Papale, Antonietta Della Ragione, Giuseppa Quaranta, Giovanni Russo, and Sabatino Russo Copyright © 2016 Mariangela Palmieri et al. All rights reserved. Myo-Inositol Safety in Pregnancy: From Preimplantation Development to Newborn Animals Tue, 06 Sep 2016 08:52:34 +0000 Myo-inositol (myo-Ins) has a physiological role in mammalian gametogenesis and embryonic development and a positive clinical impact on human medically assisted reproduction. We have previously shown that mouse embryo exposure to myo-Ins through preimplantation development in vitro increases proliferation activity and blastocyst production, representing an improvement in culture conditions. We have herein investigated biochemical mechanisms elicited by myo-Ins in preimplantation embryos and evaluated myo-Ins effects on postimplantation/postnatal development. To this end naturally fertilized embryos were cultured in vitro to blastocyst in the presence or absence of myo-Ins and analyzed for activation of the PKB/Akt pathway, known to modulate proliferation/survival cellular processes. In parallel, blastocyst-stage embryos were transferred into pseudopregnant females and allowed to develop to term and until weaning. Results obtained provide evidence that myo-Ins induces cellular pathways involving Akt and show that (a) exposure of preimplantation embryos to myo-Ins increases the number of blastocysts available for uterine transfer and of delivered animals and (b) the developmental patterns of mice obtained from embryos cultured in the presence or absence of myo-Ins, up to three weeks of age, overlap. These data further identify myo-Ins as a possibly important supplement for human preimplantation embryo culture in assisted reproduction technology. Nilay Kuşcu, Mariano Bizzarri, and Arturo Bevilacqua Copyright © 2016 Nilay Kuşcu et al. All rights reserved.