Assessing and treating insulin resistance in women with polycystic ovarian syndrome

Polycystic ovarian syndrome(PCOS) is a highly prevalent hormonal and metabolic disorder among reproductive aged women worldwide.Women with PCOS have widely varying phenotypes and seek medical care for differing reasons.In addition to concern for menstrual cycle function,ovulation,hirsutism and acne,many PCOS women have abnormal glucose metabolism.While diabetes mellitus and impaired glucose tolerance are easily diagnosed,the diagnosis of and concern for insulin resistance as a precursor disorder is underappreciated.Insulin resistance may be the first important marker of metabolic disease in PCOS women at risk for metabolic syndrome and coronary artery disease.     

Metabolic syndrome:A review of the role of vitamin D in mediating susceptibility and outcome

Despite the well-recognised role of vitamin D in a wide range of physiological processes,hypovitaminosis is common worldwide(prevalence 30%-50%) presumably arising from inadequate exposure to ultraviolet radiation and insufficient consumption.While generally not at the very low levels associated with rickets,hypovitaminosis D has been implicated in various very different,pathophysiological processes.These include putative effects on the pathogenesis of neoplastic change,inflammatory and demyelinating conditions,cardiovascular disease(CVD) and diabetes.This review focuses on the association between hypovitaminosis D and the metabolic syndrome as well as its component characteristics which are central obesity,glucose homeostasis,insulin resistance,hypertension and atherogenic dyslipidaemia.We also consider the effects of hypovitaminosis D on outcomes associated with the metabolic syndrome such as CVD,diabetes and non-alcoholic fatty liver disease.We structure this review into 3 distinct sections; the metabolic syndrome,vitamin D biochemistry and the putative association between hypovitaminosis D,the metabolic syndrome and cardiovascular risk.     

Testosterone in men's health: a new role for an old hormone

Testosterone is an anabolic hormone with a wide range of beneficial effects on men's health. A considerable body of evidence suggests that testosterone (T) deficiency contributes to the onset and/or progression of type 2 diabetes mellitus (T2D), insulin resistance (IR), metabolic syndrome (MetS), cardiovascular disease (CVD), and erectile dysfunction (ED). Low testosterone precedes elevated fasting insulin, glucose, and hemoglobin A1c (HbA1C) values and may even predict the onset of diabetes. Low testosterone also produces adverse effects on cardiovascular health. Androgen deficiency is associated with increased levels of total cholesterol, low density lipoprotein (LDL), increased production of pro-inflammatory factors, increased thickness of the arterial wall, and contributes to endothelial dysfunction. Testosterone therapy of hypogonadal men improves insulin sensitivity, fasting glucose, and hemoglobin A1c levels. Testosterone supplementation restores arterial vaso-reactivity, reduces pro-inflammatory cytokines, total cholesterol, and triglyceride levels and improves endothelial function and high density lipoprotein (HDL) levels. The therapeutic role of testosterone in men's health, however, remains a hotly debated issue for a number of reasons, including the purported risk of prostate cancer. In view of the emerging evidence suggesting that androgen deficiency is a risk factor for MetS, T2D, IR, CVD, and ED, androgen replacement therapy in hypogonadal men may potentially reduce the risk for these pathologies.     

The relationship between hyperinsulinemia, hypertension and progressive renal disease

The incidence of end-stage renal disease (ESRD) has risen dramatically in the past decade, mainly due to the increasing prevalence of diabetes mellitus, and both impaired glucose tolerance and hypertension are important contributors to rising rates of ESRD. Obesity, especially the visceral type, is associated with peripheral resistance to insulin actions and hyperinsulinemia, which predisposes to development of diabetes. A common genetic predisposition to insulin resistance and hypertension and the coexistence of these two disorders predisposes to premature atherosclerosis. A constellation of metabolic and cardiovascular derangements, which also includes dyslipidemia, dysglycemia, endothelial dysfunction, fibrinolytic and inflammatory abnormalities, left ventricular hypertrophy, microalbuminuria, and increased oxidative stress, is referred to as the cardiometabolic syndrome. The components of this syndrome, individually and interdependently, substantially increase the risk of renal disease, cardiovascular disease (CVD) and mortality. Similar findings and cardiorenal risk factors can occur in subjects with android obesity without excess body weight.Recently, microalbuminuria has been gaining momentum as a component and marker for the cardiometabolic syndrome, in addition to being an early marker for progressive renal disease in patients with this syndrome or in those with diabetes. Furthermore, it is now established as an independent predictor of CVD and CVD mortality. This review examines the relationship between insulin resistance/hyperinsulinemia and hypertension in the context of cardiometabolic syndrome, progressive renal disease and accelerated CVD. The importance of microalbuminuria as an early marker for the cardiometabolic syndrome is also discussed in this review.     

Insulin resistance, the metabolic syndrome, and incident cardiovascular events in the Framingham Offspring Study

The metabolic syndrome and insulin resistance have been related to incident cardiovascular disease (CVD), but it is uncertain if metabolic syndrome predicts CVD independent of insulin resistance. Our study sample included 2,898 people without diabetes or CVD at baseline. Metabolic syndrome was defined by the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) criteria. Insulin resistance was defined by the homeostasis model assessment (HOMA-IR) and by Gutt et al.'s insulin sensitivity index (ISI(0,120)). Age- and sex-adjusted proportional hazards regression models assessed the association of baseline metabolic syndrome and insulin resistance to 7-year CVD risk (186 events). Metabolic syndrome and both measures of insulin resistance were individually related to incident CVD (age- and sex-adjusted hazard ratio [HR] for metabolic syndrome [present versus absent]: 2.0 [95% CI 1.5-2.6], P = 0.0001; for HOMA-IR: 1.9 [1.2-2.9], P = 0.003; and for ISI(0,120) [both highest versus lowest quartile]: 0.5 [0.3-0.7], P = 0.001). In models adjusted for age, sex, LDL cholesterol, and smoking status and including metabolic syndrome, ISI(0,120) levels were independently related to incident CVD (0.5 [0.3-0.8], P = 0.004), whereas HOMA-IR levels were not (1.3 [0.8-2.1], P = 0.24); metabolic syndrome was associated with increased CVD risk in both models (HR 1.6, P < or = 0.007 in both). In conclusion, metabolic syndrome and ISI(0,120) but not HOMA-IR independently predicted incident CVD. Metabolic syndrome may not capture all the CVD risk associated with insulin resistance.     

Diabetes and COVID-19: Role of insulin resistance as a risk factor for COVID-19 severity

Patients with diabetes are more susceptible to coronavirus disease 2019 (COVID-19), and as a consequence, develop more severe form of disease. This is partly due to a systemic inflammatory state and pro thrombotic milieu seen in metabolic syndrome. In this review, we attempt to explore the pathogenetic links between insulin resistance and COVID-19 disease severity. Insulin resistance is an underlying condition for metabolic syndromes, including type 2 diabetes, which impairs insulin signaling pathways affecting metabolic and cardiovascular homeostasis. A high concentration of circulating insulin shifts the balance to mitogen activated protein kinase (MAPK)-dependent signaling and causes endothelial cell damage. The phosphatidylinositol 3 kinase and MAPK dependent signaling pathways maintain a balance between nitric oxide-dependent vasodilator and endothelin-1 dependent vasoconstriction actions of insulin. Vascular smooth muscle cell dysfunction is responsible for inflammation and blood coagulation leading to microvascular and macrovascular complications in diabetes. Hyperactivity in renin-angiotensin system is implicated in development of islet oxidative stress and subsequent β-cell dysfunction, as it alters the islet blood flow. These deleterious effects of insulin resistance involving altered blood pressure, vascular dysfunction, and inflammation could be associated with increased severity in COVID-19 patients. We conclude that clinical and/or biochemical markers of insulin resistance should be included as prognostic markers in assessment of acute COVID-19 disease.     

The dark side of testosterone deficiency: II. Type 2 diabetes and insulin resistance

A considerable body of evidence exists suggesting a link among reduced testosterone plasma levels, type 2 diabetes (T2D), and insulin resistance (IR). Hypogonadal men are at higher risk for T2D. Here we evaluate the relationships between testosterone, metabolic syndrome (MetS), T2D, and IR and discuss the relationships among androgen deficiency and these factors, especially as it ultimately relates to the development of cardiovascular disease and erectile dysfunction (ED). Thus, a comprehensive literature search was carried out using PubMed, and relevant articles pertinent to androgen deficiency, T2D, IR, MetS, and ED were reviewed and discussed. Low testosterone precedes elevated fasting insulin, glucose, and hemoglobin A1c (HbA1C) values and may even predict the onset of diabetes. Treatment of prostate cancer patients with surgical or medical castration exacerbates IR and glycemic control, strengthening the link between testosterone deficiency and onset of T2D and IR. Androgen therapy of hypogonadal men improves insulin sensitivity, fasting glucose, and HbA1c levels. We suggest that androgen deficiency is associated with IR, T2D, MetS, and with increased deposition of visceral fat, which serves as an endocrine organ, producing inflammatory cytokines and thus promoting endothelial dysfunction and vascular disease.     

Reduced expression of nuclear-encoded genes involved in mitochondrial oxidative metabolism in skeletal muscle of insulin-resistant women with polycystic ovary syndrome

Insulin resistance in skeletal muscle is a major risk factor for the development of type 2 diabetes in women with polycystic ovary syndrome (PCOS). In patients with type 2 diabetes, insulin resistance in skeletal muscle is associated with abnormalities in insulin signaling, fatty acid metabolism, and mitochondrial oxidative phosphorylation (OXPHOS). In PCOS patients, the molecular mechanisms of insulin resistance are, however, less well characterized. To identify biological pathways of importance for the pathogenesis of insulin resistance in PCOS, we compared gene expression in skeletal muscle of metabolically characterized PCOS patients (n = 16) and healthy control subjects (n = 13) using two different approaches for global pathway analysis: gene set enrichment analysis (GSEA 1.0) and gene map annotator and pathway profiler (GenMAPP 2.0). We demonstrate that impaired insulin-stimulated total, oxidative and nonoxidative glucose disposal in PCOS patients are associated with a consistent downregulation of OXPHOS gene expression using GSEA and GenMAPP analysis. Quantitative real-time PCR analysis validated these findings and showed that reduced levels of peroxisome proliferator-activated receptor gamma coactivator alpha (PGC-1alpha) could play a role in the downregulation of OXPHOS genes in PCOS. In these women with PCOS, the decrease in OXPHOS gene expression in skeletal muscle cannot be ascribed to obesity and diabetes. This supports the hypothesis of an early association between insulin resistance and impaired mitochondrial oxidative metabolism, which is, in part, mediated by reduced PGC-1alpha levels. These abnormalities may contribute to the increased risk of type 2 diabetes observed in women with PCOS.     

Exploring new treatment options for polycystic ovary syndrome: Review of a novel antidiabetic agent SGLT2 inhibitor

Polycystic ovary syndrome(PCOS) is the most common endocrinopathy in women of reproductive age associated with long-term metabolic and cardiovascular consequences. A plethora of symptoms and their severity differentiate on an individual level, giving the syndrome numerous phenotypes. Due to menstrual cycle abnormalities, women suffer from irregular menstrual bleeding, difficulty in conception, and infertility. Furthermore, the risk of pregnancy complications such as gestational diabetes mellitus, hypertensive disorders of pregnancy, and preterm birth are higher in women with PCOS than in the general population. Often, women with PCOS have comorbidities such as dyslipidemia, obesity, glucose intolerance or diabetes type 2, non-alcoholic fatty liver disease, and metabolic syndrome, which all influence the treatment plan. Historic insulinsensitizing agents, although good for some of the metabolic derangements, do not offer long-term cardiovascular benefits; therefore, new treatment options are of paramount importance. Sodium-glucose co-transporter-2(SGLT-2) inhibitors, a new class of antidiabetic agents with beneficial cardiovascular, bodyweight, and antihyperglycemic effects, although not approved for the treatment of PCOS, might be an attractive therapeutic addition in the PCOS armamentarium. Namely, recent studies with SGLT-2 inhibitors showed promising improvements in anthropometric parameters and body composition in patients with PCOS. It is important to further explore the SGLT-2 inhibitors potential as an early therapeutic option because of the PCOS-related risk of metabolic, reproductive, and psychological consequences.     

白脂素的研究进展

白脂素（Asprosin）是一种新的糖原性脂肪因子,主要在空腹时由白色脂肪组织合成并释放。Asprosin在中枢神经系统、外周组织和器官中起着复杂的作用。它与食欲、糖代谢、胰岛素抵抗（IR）、细胞凋亡等有关。最近的研究发现,Asprosin在代谢和代谢性疾病中起着重要而复杂的作用。代谢性疾病,主要包括糖尿病（DM）、非酒精性脂肪肝（NAFLD）、多囊卵巢综合征（PCOS）、心血管疾病,其主要是由于正常代谢过程的破坏。目前,这类疾病对人类健康和生命质量构成巨大威胁。本文就近年来发现的阿司匹林在代谢性疾病中的相关进展作一综述,为今后的临床诊疗提供新思路。     

Treatment of Metformin on women with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) appears to be the most common endocrine disorders of women. It is associated with significant reproductive, endocrine, metabolic, and cardiovascular morbidity. Hyperinsulinemia and insulin resistance, which result in hyperandrogenemia have been documented as a central role in the pathogenesis of PCOS. Treatment with insulin sensitizer, metformin, has been shown to follow by regularization of menstrual cycle, improved response to ovulation induction and reduction of hyperandrogenism. It possibly prevents early trimester pregnancy loss and decrease the risk of developing type Ⅱ diabetes and cardiovascular disease. This article aims to review the current evidence on the use of metformin in women with PCOS.     

Glucose intolerance in a large cohort of mediterranean women with polycystic ovary syndrome: phenotype and associated factors

The aim of this study was to investigate the phenotypic parameters and associated factors characterizing the development of glucose intolerance in polycystic ovary syndrome (PCOS). Among the 121 PCOS female subjects from the Mediterranean region, 15.7 and 2.5% displayed impaired glucose tolerance and type 2 diabetes, respectively. These subjects were included in a single group of overweight or obese subjects presenting with glucose intolerance (GI) states. PCOS women with normal glucose tolerance (81.8%) were subdivided into two groups: those who were overweight or obese and those of normal weight. Metabolic and hormonal characteristics of the GI group included significantly higher fasting and glucose-stimulated insulin levels, more severe insulin resistance, hyperandrogenemia, and significantly higher cortisol and androstenedione responses to 1-24 ACTH stimulation. One important finding was that lower birth weight and earlier age of menarche were associated with GI in PCOS women. Frequency of hirsutism, oligomenorrhea, acne, and acanthosis nigricans did not characterize women with GI. Our findings indicate that PCOS patients with GI represent a subgroup with specific clinical and hormonal characteristics. Our observations may have an important impact in preventative and therapeutic strategies.     

维生素D与多囊卵巢综合征相关性的研究进展

维生素D缺乏在多囊卵巢综合征(PCOS)妇女中常见,它与PCOS妇女的胰岛素抵抗、高雄激素表现、心血管疾病危险及生育功能下降有关。适当补充维生素D可减轻PCOS的危险因素,改善PCOS妇女的健康。     

Hypogonadism, ED, metabolic syndrome and obesity: a pathological link supporting cardiovascular diseases

Hypogonadism, erectile dysfunction (ED), visceral adiposity, insulin resistance and metabolic syndrome (MetS) often coexist in the same subjects. This cluster of abnormalities is associated with an increased risk of diabetes and cardiovascular diseases (CVD), affecting not only quality of life but also life expectancy. Longitudinal studies have also demonstrated that ED and male hypogonadism could be considered surrogate markers of incident CVD and MetS. However, how androgens signal fat depots and lessen them is still a matter of active research and whether or not low testosterone could play a pathogenetic role in CVD is still under debate. Hence, pathogenetic mechanisms linking hypogonadism with obesity and insulin resistance appear to be complex and often multi-directional. Visceral obesity can probably be considered a relevant cause of hypogonadism but at the same time, hypogonadism could be a cause of obesity and insulin resistance, consequently establishing a vicious cycle. To provide a critical analysis of these issues, a comprehensive literary search was carried out to discuss the relationship between insulin resistance ED, visceral adiposity, MetS and hypogonadism focusing on their possible involvement in the development of CVD.     

Polymorphism of insulin gene variable number tandem repeats correlated with polycystic ovary syndrome

Objective: To investigate the correlation between the insulin gene variable number tandem repeats (INS-VN-TR) with polycystic ovary syndrome(PCOS) and metabolic features related to insulin resistance (IR).Methods: One hundred and thirty patients with PCOS (PCOS group) and 130 normal women (control group) were included. Genotyping of INS-VNTR was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).Results: The distribution of genotype of INS-VNTR was similar in PCOS group, but the Ⅲ allele frequency of INS-VNTR was higher in PCOS patients than that in controls, and Logistic regression analysis revealed that the Ⅲ allele was associated with increased risk of PCOS[adjusted odd ratio(OR) = 2.31;95% confidence interval(CD =1.07-4.98), compared with the Ⅰ allele. The distribution of genotype and the Ⅲ allele frequency of INS-VNTR in PCOS insulin resistance (PCOS-IR) group were significantly higher than that in PCOS non-insulin resistance group (PCOS-NIR). Moreover, PCOS women with Ⅲ allele had statistically significantly higher fasting insulin level and HOMA-IR than those of PCOS women with Ⅰ allele.Conclusion: INS-VNTR may not be a susceptibility gene, but INS-VNTR polymorphism may play an important role in the occurrence of insulin resistance in patients with PCOS.     

减重手术在多囊卵巢综合征治疗中的作用

多囊卵巢综合征（polycystic ovarian syndrome,PCOS）是女性常见内分泌紊乱性疾病,其发生率近10%。表现为无排卵、高雄激素血症及超声显示卵巢的多囊改变。多数患者伴有代谢综合征（metabolic syndrome,MS）,表现为高血压、高血脂、肥胖、胰岛素抵抗及糖耐量异常。     

二甲双胍在多囊卵巢综合征的作用

生殖及代谢异常是多囊卵巢综合征(PCOS)的特征性表现。已证实高胰岛素血症及胰岛素抵抗,导致血中雄激素水平过高,是PCOS的重要发病机制。二甲双胍(metformin)称为胰岛素增敏剂,用于治疗PCOS后,可减轻高雄激素血症,使月经周期规律,改善卵巢对诱导排卵的反应,提高妊娠率,降低早孕流产率,且能减低发展为II型糖尿病及心血管疾病的危险性。本文就国外近年有关metformin运用于PCOS的进展作一综述。     

Defining the role of bariatric surgery in polycystic ovarian syndrome patients

Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder in women.To meet PCOS criteria,women must have a combination of hyperandrogenism,anovulation and ultrasound findings.Almost 10% of all reproductive age women worldwide show signs of PCOS.Although women often seek care for gynecological or body image concerns,many PCOS women are at risk for metabolic syndrome (MS).Many of the metabolic consequences are overlooked and un-dertreated by physicians because these patients tend to be young,reproductive age women.MS and obesity coexist commonly with PCOS.These young women are predisposed to glucose abnormalities and ulti-mately diabetes mellitus,dyslipidemia and eventually cardiovascular disease.Bariatric surgery can be an ef-fective means of weight loss in PCOS women.Surgical techniques have become safer and less invasive over time and have been found to be effective in achieving significant weight loss.Surgical options have also in-creased,giving patients more choices.Bariatric surgery may prevent or reverse metabolic syndrome.Bariatric surgery may also have reproductive benefits in PCOS patients.Although bariatric surgery has historically been performed in older,reproductive aged women,it has recently gained favor in adolescents as well.This is of particular importance due to the prevalence of both PCOS and MS in adolescents.Treatment of PCOS and MS certainly requires a combination of medical therapy,psychological support and lifestyle modifications.These treatments are difficult and often frustrating for pa-tients and physicians.Bariatric surgery can be effective in achieving significant weight loss,restoration of the hypothalamic pituitary axis,reduction of cardiovascular risk and even in improving pregnancy outcomes.Ulti-mately,bariatric surgery should be considered part of the treatment in PCOS women,especially in those with MS.     

Metabolic cardiovascular syndrome after renal transplantation.

BACKGROUND: Cardiovascular disease (CVD) is the major cause of death in renal transplant recipients. Traditional risk factors like hypertension, dyslipidaemia and diabetes mellitus are common, but cannot completely account for the high prevalence of CVD in this population. The aim of the present study was to assess whether post-transplant glucose intolerance, defined as post-transplant diabetes mellitus, impaired glucose tolerance, or impaired fasting glucose, is associated with metabolic disturbances known to increase risk of cardiovascular disease, similar to what has been observed in the general population. METHODS: One hundred and seventy-three consecutive patients were prospectively examined 10 weeks after transplantation. An oral glucose tolerance test was completed in 167 patients. Questionnaires, medical records, and the results of various blood tests were used to evaluate a number of known cardiovascular risk factors in all patients. RESULTS: Glucose intolerance was present in about one-half the recipients and was associated with age, a positive family history of ischaemic heart disease, acute rejection, higher levels of serum triglycerides, apolipoprotein B and 2-h insulin, and lower levels of serum HDL cholesterol. After adjustment for age and sex, lower HDL cholesterol (P=0.005), higher serum triglycerides (P<0.001), apolipoprotein B (P=0.039) and 2-h insulin (P<0.001) were still associated with post-transplant glucose intolerance. CONCLUSIONS: Ten weeks after renal transplantation glucose intolerance is associated with a clustering of cardiovascular risk factors and metabolic abnormalities, consistent with a post-transplant metabolic cardiovascular syndrome.     

The dark side of testosterone deficiency: I. Metabolic syndrome and erectile dysfunction

The metabolic syndrome (MetS) is considered the most important public health threat of the 21st century. This syndrome is characterized by a cluster of cardiovascular risk factors including increased central abdominal obesity, elevated triglycerides, reduced high-density lipoprotein, high blood pressure, increased fasting glucose, and hyperinsulinemia. These factors increase the risk of cardiovascular disease (CVD) and/or type 2 diabetes. Although the etiology of this syndrome is thought to stem from obesity and physical inactivity, the extent of interactions of the individual MetS components with one another remains poorly defined. Obesity, diabetes, hypogonadism, and specific hormone and metabolic profiles have been implicated in the pathophysiology of CVD. The evolving role of androgens in MetS and CVD is of paramount importance. Reduced androgen levels associated with hypogonadism or androgen deprivation therapy increase cardiovascular risk factors and produce marked adverse effects on cardiovascular function. MetS has been associated with hypogonadism and erectile dysfunction (ED), and MetS may be considered a risk factor for ED. It is suggested that MetS, diabetes, and CVD will increase in the upcoming decades. Thus, it is critically important to develop a better understanding of how obesity, diabetes and hypogonadism contribute to androgen deficiency and the various pathophysiologic states of vascular disease. In this review we discuss the current literature pertaining to androgen deficiency, MetS, and ED, because the relationship of these factors is of scientific and clinical importance. Specifically, we will focus on exploring the relationships between hypogonadism, obesity, MetS, and ED.