We tested the hypothesis of a lower respiratory capacity per mitochondrion in skeletal muscle of type 2 diabetic patients compared with obese subjects. Muscle biopsies obtained from 10 obese type 2 diabetic and 8 obese nondiabetic male subjects were used for assessment of 3-hydroxy-Acyl-CoA-dehydrogenase (HAD) and citrate synthase activity, uncoupling protein (UCP)3 content, oxidative stress measured as 4-hydroxy-2-nonenal (HNE), fiber type distribution, and respiration in isolated mitochondria. Respiration was normalized to citrate synthase activity (mitochondrial content) in isolated mitochondria. Maximal ADP-stimulated respiration (state 3) with pyruvate plus malate and respiration through the electron transport chain (ETC) were reduced in type 2 diabetic patients, and the proportion of type 2X fibers were higher in type 2 diabetic patients compared with obese subjects (all P < 0.05). There were no differences in respiration with palmitoyl-l-carnitine plus malate, citrate synthase activity, HAD activity, UCP3 content, or oxidative stress measured as HNE between the groups. In the whole group, state 3 respiration with pyruvate plus malate and respiration through ETC were negatively associated with A1C, and the proportion of type 2X fibers correlated with markers of insulin resistance (P < 0.05). In conclusion, we provide evidence for a functional impairment in mitochondrial respiration and increased amount of type 2X fibers in muscle of type 2 diabetic patients. These alterations may contribute to the development of type 2 diabetes in humans with obesity.

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 γ coactivator α (PGC-1α) 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-1α levels. These abnormalities may contribute to the increased risk of type 2 diabetes observed in women with PCOS.

Objective Polycystic ovary syndrome (PCOS) is associated with insulin resistance and obesity. Prospective population-based data regarding development and possible predictors of type 2 diabetes (T2D) in PCOS are limited. Design National Patient Register–based study. Methods Patients with PCOS [PCOS Denmark and embedded cohort, PCOS Odense University Hospital (OUH)] and a control population with no previous diagnosis of T2D. PCOS OUH (N = 1,162) included premenopausal women with PCOS and standardized clinical and biochemical examination. PCOS Denmark (N = 18,477) included women with PCOS in the Danish National Patient Register. Three age-matched controls were included per patient (N = 54,680). Main outcome T2D events according to diagnosis codes and filled medicine prescriptions. Results The median (quartiles) follow-up was 11.1 (6.9 to 16.0) years. The hazard ratio (HR) with 95% confidence interval (CI) for development of T2D in PCOS Denmark was HR = 4.0 (95% CI, 3.7 to 4.3; P < 0.001), and the total event rate of T2D was 8.0 per 1000 person years in PCOS Denmark vs 2.0 per 1000 person years in controls (P < 0.001). The median age at diagnosis of T2D was 31 (26 to 37) years in PCOS Denmark vs 35 (27 to 44) years in controls (P < 0.001). In multiple regression analyses, body mass index, glycated hemoglobin, fasting blood glucose, 2-hour blood glucose, homeostasis model assessment of insulin resistance, and triglycerides were positively associated with development of T2D, whereas higher number of births was negatively associated with development of T2D. Conclusion The event rate of T2D was higher in PCOS compared with controls, and T2D was diagnosed at a younger age.

Polycystic ovary syndrome (PCOS) is associated with obesity and low grade inflammation and the risk for cardiovascular disease (CVD) could be increased in PCOS. National register-based study including women with PCOS and no previous diagnosis of CVD, hypertension, or dyslipidemia. PCOS Denmark (N = 18,112) included women with PCOS in the Danish National Patient Register. PCOS Odense University Hospital (OUH, N = 1165) was an embedded cohort including premenopausal women with PCOS and clinical and biochemical examination. Three age-matched controls were included per patient in PCOS Denmark (N = 52,769). The main study outcome was CVD events including hypertension and dyslipidemia defined according to nationwide in- and outpatient hospital contact diagnosis codes and/or inferred from filled medicine prescriptions. The age at inclusion was median (quartiles) 29 (23–35) years and follow up was 11.1 (6.9–16.0) years. The Hazard ratio (95% CI) for development of CVD in PCOS Denmark was 1.7 (1.7; 1.8) (P < 0.001) and the total event rate of CVD was 22.6 per 1000 patient years in PCOS Denmark vs. 13.2 per 1000 patient years in controls (P < 0.001). The median age at diagnosis of CVD was 35 (28–42) years in PCOS Denmark vs. 36 (30–43) years in controls (P < 0.001). Obesity, diabetes, and infertility, and previous use of oral contraceptives were associated with increased risk of development of CVD in PCOS Denmark (P < 0.001). Women in PCOS OUH resembled women in PCOS Denmark regarding risk of CVD. Age, BMI, blood pressure, lipid status, and glycemic status predicted development of CVD in PCOS OUH. The event rate of CVD including hypertension and dyslipidemia was higher in PCOS compared to controls. The risk of developing CVD must be considered even in young women with PCOS.

Hirsutism is a common endocrine disorder, defined as increased growth of terminal hairs in a male pattern. Hirsutism is most often caused by polycystic ovary syndrome (PCOS), whereas only 5% patients are diagnosed with rare endocrine diseases. PCOS may be considered a multiorgan disease causing not only increased adrenal and ovarian sex hormone secretion but also changed secretion of gonadotrophins, growth hormone, and adrenocorticotrophic hormone (ACTH) from the pituitary. The majority of patients with PCOS are insulin resistant and PCOS is characterized by an increased inflammatory state with abdominal obesity and increased secretion of interleukins, chemokines, and adipokines. PCOS is therefore associated with an increased risk of the metabolic syndrome and type 2 diabetes (T2D). Patients with hirsutism present with increased bone mineral density despite decreased D-vitamin levels. The etiology to hirsutism and PCOS is most likely multifactorial including both genetic and environmental factors such as increased fetal stress and intrauterine growth retardation. In the present review, we give a comprehensive overview of the pathophysiology and multiple endocrine disturbances of hirsutism and PCOS.

Objective: The prevalence of type 2 diabetes is increased in polycystic ovary syndrome (PCOS), but the prevalence of other diseases is not clarified. We aimed to investigate morbidity and medicine prescriptions in PCOS.Design: A National Register-based study.Methods: Patients with PCOS (PCOS Denmark and an embedded cohort; PCOS Odense University Hospital (OUH)) and one control population. Premenopausal women with PCOS underwent clinical and biochemical examination (PCOS OUH,n=1217). PCOS Denmark (n=19 199) included women with PCOS in the Danish National Patient Register. Three age-matched controls were included per patient (n=57 483).Main outcome measures: Diagnosis codes and filled prescriptions.Results: The mean (range) age of the PCOS Denmark group and controls was 30.6 (12–60) years. Patients in PCOS Denmark had higher Charlson index, higher prevalence of diabetes, dyslipidemia, and hypertension than controls. PCOS was associated with a two times increased risk of stroke and thrombosis, whereas the risk of other cardiovascular diseases was not increased. Thyroid disease, asthma, migraine, and depression were more prevalent in PCOS Denmark vs controls, whereas fractures were rarer. Infertility was increased in patients compared with controls, but the mean number of births was higher in PCOS. Medicine prescriptions within all diagnosis areas were significantly higher in PCOS patients than in controls.In PCOS OUH, polycystic ovaries (PCO) and irregular menses were associated with a more adverse metabolic risk profile, but individual Rotterdam criteria were not associated with cardiometabolic diagnoses.Conclusion: Cardiometabolic and psychiatric morbidity were significantly increased in a Danish population with PCOS. Medical diseases are frequent also in young patients with PCOS.