Dorte Glintborg

Mitochondrial Respiration Is Decreased in Skeletal Muscle of Patients With Type 2 Diabetes

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.

Association of Pioglitazone Treatment with Decreased Bone Mineral Density in Obese Premenopausal Patients with Polycystic Ovary Syndrome: A Randomized, Placebo-Controlled Trial

OBJECTIVE Our objective was to investigate the effect of pioglitazone on bone mineral density (BMD) and bone turnover markers in polycystic ovary syndrome (PCOS). DESIGN AND SETTING We conducted a randomized, placebo-controlled study at an outpatient clinic at a university hospital. PATIENTS Thirty premenopausal patients with PCOS and 14 age- and weight-matched healthy females participated. INTERVENTIONS Pioglitazone (30 mg/d) or placebo was given for 16 wk. MAIN OUTCOME MEASURES Measurements of BMD [hip (neck and total) and lumbar spine (L2-L4)], bone metabolic parameters [alkaline phosphatase (ALP), 25-hydroxyvitamin D, C-telopeptide of type I collagen (ICTP), osteocalcin, and PTH], endocrine profiles (testosterone, estradiol, and insulin), and body composition (waist to hip ratio, body mass index, and whole-body dual-energy x-ray absorptiometry scans) were performed. RESULTS Patients with PCOS had significantly higher levels of ICTP, fasting insulin, and testosterone than controls, whereas no differences were measured in ALP, PTH, body composition, or BMD. Pioglitazone treatment was followed by reduced BMD [geometric means (-2 to +2 sd)]: lumbar spine 1.140 (0.964-1.348) vs. 1.127 (0.948-1.341) g/cm(2) (average decline 1.1%) and femoral neck 0.966 (0.767-1.217) vs. 0.952 (0.760-1.192) g/cm(2) (average decline 1.4%), both P < 0.05. Both ALP and PTH decreased significantly during pioglitazone treatment, whereas no significant changes were measured in 25-hydroxyvitamin D, ICTP, osteocalcin, sex hormones, and body composition. CONCLUSION Pioglitazone treatment was followed by decreased lumbar and hip BMD and decreased measures of bone turnover in a premenopausal study population relatively protected from bone mineral loss.

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 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.

Impaired Insulin-Stimulated Phosphorylation of Akt and AS160 in Skeletal Muscle of Women With Polycystic Ovary Syndrome Is Reversed by Pioglitazone Treatment

OBJECTIVE— Insulin resistance in skeletal muscle is a major risk factor for type 2 diabetes in women with polycystic ovary syndrome (PCOS). However, the molecular mechanisms underlying skeletal muscle insulin resistance and the insulin-sensitizing effect of thiazolidinediones in PCOS in vivo are less well characterized. RESEARCH DESIGN AND METHODS— We determined molecular mediators of insulin signaling to glucose transport in skeletal muscle biopsies of 24 PCOS patients and 14 matched control subjects metabolically characterized by euglycemic-hyperinsulinemic clamps and indirect calorimetry, and we examined the effect of 16 weeks of treatment with pioglitazone in PCOS patients. RESULTS— Impaired insulin-mediated total (Rd) oxidative and nonoxidative glucose disposal (NOGD) was paralleled by reduced insulin-stimulated Akt phosphorylation at Ser473 and Thr308 and AS160 phosphorylation in muscle of PCOS patients. Akt phosphorylation at Ser473 and Thr308 correlated positively with Rd and NOGD in the insulin-stimulated state. Serum free testosterone was inversely related to insulin-stimulated Rd and NOGD in PCOS. Importantly, the pioglitazone-mediated improvement in insulin-stimulated glucose metabolism, which did not fully reach normal levels, was accompanied by normalization of insulin-mediated Akt phosphorylation at Ser473 and Thr308 and AS160 phosphorylation. AMPK activity and phosphorylation were similar in the two groups and did not respond to pioglitazone in PCOS patients. CONCLUSIONS— Impaired insulin signaling through Akt and AS160 in part explains insulin resistance at the molecular level in skeletal muscle in PCOS, and the ability of pioglitazone to enhance insulin sensitivity involves improved signaling through Akt and AS160. Moreover, our data provide correlative evidence that hyperandrogenism in PCOS may contribute to insulin resistance.

An update on the pathogenesis, inflammation, and metabolism in hirsutism and polycystic ovary syndrome

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.

The use of medication against attention deficit hyperactivity disorder in Denmark: a drug use study from a national perspective

PurposeThe purpose of the study was to characterize the utilization of medication against attention deficit hyperactivity disorder (ADHD) in Denmark between 1995 and 2011 from a national perspective, by using population-based prescription data.MethodsNational data on drug use in Denmark between 1 January 1995 and 30 September 2011 were extracted from the Registry of Medicinal Product Statistics (RMPS). Drug utilization was characterized using descriptive statistics.ResultsA total of 1,085,090 prescriptions issued to 54,020 persons were identified. The incidence rate was stable in the last 3 years of the study period, and a slightly decreasing incidence rate and a stabilizing prevalence were observed towards the end of this period. The therapeutic intensity was 6.7 defined daily dose/person/day, with large regional differences that ranged from 64 to 145 % of the national average. Methylphenidate accounted for 92.6 % of DDDs used. The general practitioner (GP) rarely initiated treatment, although treatment initiation based on the GP’s advice increased with older age of the patient. Maintenance treatment was found to be distributed roughly equally between prescriber types. For methylphenidate, 1 % of users accounted for 6.1 % of the drug volume and 50 % of users accounted for 84.4 %. The data therefore do not suggest a high proportion of heavy users.ConclusionThe findings of this analysis are mostly reassuring, with the data indicating a seemingly stagnant incidence and prevalence rate and lacking evidence of heavy users. However, the prescriber profile for incident users and the large regional variances raise concerns. It is therefore vital that the use of ADHD drugs is closely monitored.

A 12-month randomized crossover study on the effects of lanreotide Autogel and octreotide long-acting repeatable on GH and IGF-l in patients with acromegaly.

Background  Somatostatin analogues have been used successfully for the treatment of acromegaly but no randomized studies have compared the effects of lanreotide Autogel (LAN) and octreotide acetate long‐acting repeatable (OCT).

Total and high molecular weight (HMW) adiponectin levels and measures of glucose and lipid metabolism following pioglitazone treatment in a randomized placebo-controlled study in polycystic ovary syndrome.

Objective  Recent studies suggested that the effect of adiponectin on insulin‐stimulated glucose metabolism is mediated primarily by the high molecular weight (HMW) form of adiponectin. In the present study we evaluated total and HMW adiponectin in polycystic ovary syndrome (PCOS) patients and controls and examined possible mechanisms for increased insulin sensitivity during pioglitazone treatment.

Pioglitazone Enhances Mitochondrial Biogenesis and Ribosomal Protein Biosynthesis in Skeletal Muscle in Polycystic Ovary Syndrome

Insulin resistance is a common metabolic abnormality in women with PCOS and leads to an elevated risk of type 2 diabetes. Studies have shown that thiazolidinediones (TZDs) improve metabolic disturbances in PCOS patients. We hypothesized that the effect of TZDs in PCOS is, in part, mediated by changes in the transcriptional profile of muscle favoring insulin sensitivity. Using Affymetrix microarrays, we examined the effect of pioglitazone (30 mg/day for 16 weeks) on gene expression in skeletal muscle of 10 obese women with PCOS metabolically characterized by a euglycemic-hyperinsulinemic clamp. Moreover, we explored gene expression changes between these PCOS patients before treatment and 13 healthy women. Treatment with pioglitazone improved insulin-stimulated glucose metabolism and plasma adiponectin, and reduced fasting serum insulin (all P<0.05). Global pathway analysis using Gene Map Annotator and Pathway Profiler (GenMAPP 2.1) and Gene Set Enrichment Analysis (GSEA 2.0.1) revealed a significant upregulation of genes representing mitochondrial oxidative phosphorylation (OXPHOS), ribosomal proteins, mRNA processing reactome, translation factors, and proteasome degradation in PCOS after pioglitazone therapy. Quantitative real-time PCR suggested that upregulation of OXPHOS genes was mediated by an increase in PGC-1α expression (P<0.05). Pretreatment expression of genes representing OXPHOS and ribosomal proteins was down-regulated in PCOS patients compared to healthy women. These data indicate that pioglitazone therapy restores insulin sensitivity, in part, by a coordinated upregulation of genes involved in mitochondrial OXPHOS and ribosomal protein biosynthesis in muscle in PCOS. These transcriptional effects of pioglitazone may contribute to prevent the onset of type 2 diabetes in these women.

Ethnic differences in Rotterdam criteria and metabolic risk factors in a multiethnic group of women with PCOS studied in Denmark

Objective  Clinical manifestations and metabolic risk factors may differ in ethnic subgroups of patients with polycystic ovary syndrome (PCOS).