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The role of brown adipose tissue in total energy balance and cold-induced thermogenesis was studied. Mice expressing mitochondrial uncoupling protein 1 (UCP-1) from the fat-specific aP2 gene promoter (heterozygous and homozygous aP2 -Ucp transgenic mice) and their nontransgenic C57BL6/J littermates were used. The transgenic animals are resistant to obesity induced by a high-fat diet, presumably due to ectopic synthesis of UCP-1 in white fat. These animals exhibited atrophy of brown adipose tissue, as indicated by smaller size of brown fat and reduction of its total UCP-1 and DNA contents. Norepinephrine-induced respiration (measured in pentobarbital sodium-anesthetized animals) was decreased proportionally to the dosage of the transgene, and the homozygous (but not heterozygous) transgenic mice exhibited a reduction in their capacity to maintain body temperature in the cold. Our results indicate that the role of brown fat in cold-induced thermogenesis cannot be substituted by increased energy expenditure in other tissues.

Objective: Polycystic ovary syndrome (PCOS) has been linked to a high risk of type 2 diabetes mellitus. Disturbances in the secretion of the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) have been observed in states with impaired glucose regulation. This paper considers the secretion of GIP and GLP-1 after oral glucose load in a group of lean, glucose-tolerant PCOS women in comparison with age-and body mass index (BMI)-matched healthy women. Design: Case control. Methods: PCOS (nZ21, 25.8G4.1 years, BMI 21.6G1.7 kg/m 2 ) and control healthy women (CT, nZ13, 28.5G7.2 years, BMI 20.3G2.5 kg/m 2 ) underwent oral glucose tolerance test (OGTT) with blood sampling for glucose, insulin, C-peptide, total GIP, and active GLP-1. Insulin sensitivity was determined both at fasting and during the test. Statistics: Repeated measures ANOVA. Results: Glucose levels and insulin sensitivity did not differ between PCOS and CT. PCOS had significantly higher levels of C-peptide (P!0.05) and tended to have higher insulin levels. The levels of total GIP were significantly higher in PCOS than in CT (P!0.001). Active GLP-1 levels exhibited a significantly different time-dependent pattern in PCOS (P!0.002 for PCOS versus time interaction). GLP-1 concentrations were similar in PCOS and CT in the early phase of OGTT and then reached significantly lower levels in PCOS than in CT at 180 min (P!0.05). Conclusions: Increased total GIP and lower late phase active GLP-1 concentrations during OGTT characterize PCOS women with higher C-peptide secretion in comparison with healthy controls, and may be the early markers of a pre-diabetic state.

The impact of sex and age on glucose metabolism in the development of overweight/obesity is a matter of debate. We hypothesized that insulin sensitivity (IS) and beta-cell function (BF) in a normal white population will differ between males and females and aimed to evaluate the possible effects of BMI and age on metabolic parameters of both sexes. This study is a cross-sectional analysis of the general community. IS was measured with quantitative insulin sensitivity check index (QUICKI) and oral glucose insulin sensitivity (OGIS) and BF with the insulinogenic index during 75-g 2-h oral glucose-tolerance tests (OGTTs). We studied 611 females and 361 males with normal glycemia according to both fasting and 2-h glucose (85 ± 0.3 mg/dl (means ± SE) in females and 89 ± 0.4 in males (P < 0.0001), and 93 ± 1 in females and 89 ± 1 in males (P = 0.005), respectively). Females were younger (37 ± 1 years) than males (40 ± 1, P < 0.0001), but no difference was found in mean BMI (BMI = 25.8 ± 0.2 kg/m2 in both). Student’s two-sample t-test was used for simple comparison between and within genders, multiple linear regressions to account for covariates. During the OGTT, females had lower glucose (area under the curve (AUC) 133 ± 1 mg/ml 2 h vs. 148 ± 2; P < 0.00001), while insulinemia was comparable (AUC 5.3 ± 0.1 mU/ml 2 h vs. 5.7 ± 0.2, P = 0.15). IS remained higher in females (473 ± 3 ml/min/m2 vs. 454 ± 3, P < 0.0001) also after having accounted for age and BMI (P = 0.015). No difference was observed in fasting insulin or BF. However, BF increased by 46% with BMI and when accounting for age and BMI, BF of females was significantly higher (P < 0.0001). Because IS and BF are higher in females than in males, sex should be considered in metabolic studies and overweight/obese populations

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Introduction: Conservative active surveillance has been proposed for low-risk papillary thyroid microcarcinoma (PTMC), defined as 1.0 cm and lacking clinical aggressive features, but controversy exists with accepting it as not all such PTMCs are uniformly destined for benign prognosis. This study investigated whether BRAF V600E status could further risk stratify PTMC, particularly low-risk PTMC, and can thus help with more accurate case selection for conservative management. Methods: This international multicenter study included 743 patients treated with total thyroidectomy for PTMC (584 women and 159 men), with a median age of 49 years (interquartile range [IQR], 39e59 years) and a median follow-up time of 53 months (IQR, 25e93 months). Results: On overall analyses of all PTMCs, tumour recurrences were 6.4% (32/502) versus 10.8% (26/241) in BRAF mutation-negative versus BRAF mutation-positive patients (P Z 0.041), with a hazard ratio (HR) of 2.44 (95% CI (confidence interval), 1.15e5.20) after multivariate adjustment for confounding clinical factors. On the analyses of low-risk PTMC, recurrences were 1.3% (5/383) versus 4.3% (6/139) in BRAF mutation-negative versus BRAF mutation-positive patients, with an HR of 6.65 (95% CI, 1.80e24.65) after adjustment for confounding clinical factors. BRAF mutation was associated with a significant decline in the KaplaneMeier recurrence-free survival curve in low-risk PTMC. Conclusions: BRAF V600E differentiates the recurrence risk of PTMC, particularly low-risk PTMC. Given the robust negative predictive value, conservative active surveillance of BRAF mutation-negative low-risk PTMC is reasonable whereas the increased recurrence risk and other well-known adverse effects of BRAF V600E make the feasibility of long-term conservative surveillance uncertain for BRAF mutation-positive PTMC.

Objective: To evaluate adrenal and ovarian steroidogenesis before and after long-term treatment with metformin in women with polycystic ovary syndrome (PCOS). Design and Methods: Twenty-four women with PCOS were evaluated before and after treatment (27^4 weeks) with metformin (1000 mg/day) using adrenocorticotrophin (ACTH), GnRH analogue and oral glucose tolerance (oGTT) tests. For statistical evaluation, ANOVA and Wilcoxon's test were used. Results: In 58% of the women a significant improvement in menstrual cyclicity was observed. No significant change in basal steroid levels was found. After ACTH stimulation, a significant decrease in the activity of 3b-hydroxysteroid dehydrogenase in C 21 steroids P , 0X05 and in 17b-hydroxysteroid dehydrogenase P , 0X01 was observed, as was an increase in the activity of C17,20-lyase in the D 4 pathway P , 0X01X A significant growth in the dehydroepiandrosterone (DHEA)/DHEA-sulfate ratio P , 0X05 was detected. With regard to ovarian steroidogenesis, a significant decrease in the stimulated levels of testosterone P , 0X05Y index of free testosterone P , 0X01Y LH P , 0X05 and oestradiol P , 0X01Y and an increase in the levels of 17-hydroxypregnenolone P , 0X05 were detected. In the indices of ovarian enzyme activities, we observed a significant decrease in 3b-hydroxysteroid dehydrogenase in C 21 steroids P , 0X01Y in C17,20-lyase in the D5 pathway P , 0X01Y in 17b-hydroxysteroid dehydrogenase P , 0X05 and in aromatase. In glucose metabolism, a tendency towards reduction in the homeostasis model assessment (HOMA)-R (for insulin resistance) and HOMA-F (for b cell function) was detected. In addition, an increase in the levels of C peptide during oGTT was observed P , 0X01X Conclusions: Long-term metformin treatment reduced various steroid enzymatic activities both in the ovary and the adrenal glands, without apparent changes in basal steroid levels and in insulin sensitivity.