The pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), are the principle endocrine drivers of reproductive processes in the gonads of jawed vertebrates. Canonically, FSH recruits and maintains selected ovarian follicles for maturation and LH induces the stages of germinal vesicle breakdown and ovulation. In mammals, LH and FSH specifically activate cognate G-protein-coupled receptors that affect the proteins involved in steroidogenesis, protein hormone synthesis, and gametogenesis. This dual-gonadotropin model also exists in some fish species, but not in all. In fact, due to their diverse number of species, extended number of ecological niches, and remarkably flexible reproductive strategies, fish are appropriate as models to understand the co-evolution of gonadotropins and their receptors. In this study, we cloned and characterized the expression profile over the final stages of ovarian maturation of carp (Cyprinus carpio) LHCGR and FSHR. Expression of both gonadotropin receptors increased in the later stage of early vitellogenesis, suggesting that both LH and FSH play a role in the development of mature follicles. We additionally tested the activation of cLHCGR and cFSHR using homologous and heterologous recombinant gonadotropins in order to gain insight into an evolutionary model of permissive gonadotropin receptor function. These data suggest that carp (Cyprinus carpio) gonad development and maturation depends on a specific gonadotropin profile that does not reflect the temporally distinct dual-gonadotropin model observed in salmonids or mammals, and that permissive gonadotropin receptor activation is a specific feature of Ostariophysi, not all teleosts.
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Lian Hollander-Cohen, Benjamin Böhm, Krist Hausken and Berta Levavi-Sivan
Xiangyu Gao, Wanwan Sun, Yi Wang, Yawen Zhang, Rumei Li, Jinya Huang and Yehong Yang
Islet autoantibodies occur in type 2 diabetes. Our study aimed to investigate the prevalence of positive islet autoimmunity in community patients with type 2 diabetes.
A total of 495 community patients with type 2 diabetes were recruited using the method of cluster sampling in this cross-sectional study. Three islet autoantibodies including glutamic acid decarboxylase antibody (GADA), insulin autoantibody (IAA) and islet cell antibody (ICA) were measured, and clinical characteristics involved in those individuals were evaluated.
The positive rate of islet autoantibodies was 28.5% in total, while combinations of different autoantibodies were rarely seen. Compared with GADA-negative group, positive counterparts significantly tended to have lower levels of body mass index (BMI), waist-hip ratio (WHR), and urinary microalbumin (mALB) (P < 0.05). Adjusted for confounding factors, WHR, triglycerides (TG), and mALB seemed to be negative independent predictors of GADA (OR < 1, P < 0.05). Patients with positive IAA tended to receive insulin treatment (P < 0.0001). Besides, fasting blood glucose (FBG), serum levels of high-density lipoprotein cholesterol (HDL-CH), aspartate transaminase (AST), and γ-glutamyltransferase (GGT) were more likely to be higher in IAA positive subgroup in comparison with the negative counterparts. While after AST was adjusted by unconditional logistic regression analysis, history of insulin treatment, FBG, HDL-CH, and GGT were confirmed as positive predictors of IAA. Furthermore, in patients who were IAA positive, those treated with exogenous insulin tended to have longer duration of diabetes than non-insulin treatment counterparts (P < 0.0001). With regard to ICA, however, there were no significant differences between the two subgroups, except that serum level of AST/ALT seemed to be slightly different (P = 0.064).
These data suggested that type 2 diabetic community patients with positive GADA tended to be lean and were able to maintain normal lipid metabolism, while patients with positivity of IAA were frequently accompanied with insulin treatment and more closely associated with diabetic liver damage.
Ana Carolina de Jesus Paniza, Thais Biude Mendes, Matheus Duarte Borges Viana, Débora Mota Dias Thomaz, Paula B O Chiappini, Gabriel A Colozza-Gama, Susan Chow Lindsey, Marcos Brasilino de Carvalho, Venâncio Avancini Ferreira Alves, Otavio Curioni, André Uchimura Bastos and Janete Maria Cerutti
The recent reclassification of a follicular variant of papillary thyroid carcinoma (FVPTC), subset as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), aims to avoid overtreatment of patients with an indolent lesion. The diagnosis of NIFTP has recently been revisited using more rigid criteria. This study presents histological and molecular findings and a long clinical follow-up of 94 FVPTC, 40 cases of follicular adenoma (FTA) and 22 cases of follicular carcinoma (FTC) that were classified before the advent of the NIFTP reclassification. All slides were reviewed using these rigid criteria and analysis of numerous sections of paraffin blocks and reclassified as 7 NIFTPs, 2 EFVPTCs, 29 infiltrative FVPTC (IFVPTCs), 57 invasive EFVPTC (I-EFVPTCs), 39 FTAs and 22 FTCs. Remarkably, EFVPTC and NIFTP patients were all free of disease at the end of follow-up and showed no BRAF mutation. Only one NIFTP sample harbored mutations, an NRAS Q61R. PAX8/PPARG fusion was found in I-EFVPTCs and FTC. Although additional studies are needed to identify a specific molecular profile to aid in the diagnosis of lesions with borderline morphological characteristics, we confirmed that the BRAF V600E mutation is an important tool to exclude the diagnosis of NIFTP. We also show that rigorous histopathological criteria should be strongly followed to avoid missing lesions in which more aggressive behavior is present, mainly via the analysis of capsule or vascular invasion and the presence of papillary structures.
Stephen A Martin, Kenneth A Philbrick, Carmen P Wong, Dawn A Olson, Adam J Branscum, Donald B Jump, Charles K Marik, Jonathan M DenHerder, Jennifer L Sargent, Russell T Turner and Urszula T Iwaniec
Mice are a commonly used model to investigate aging-related bone loss but, in contrast to humans, mice exhibit cancellous bone loss prior to skeletal maturity. The mechanisms mediating premature bone loss are not well established. However, our previous work in female mice suggests housing temperature is a critical factor. Premature cancellous bone loss was prevented in female C57BL/6J mice by housing the animals at thermoneutral temperature (where basal rate of energy production is at equilibrium with heat loss). In the present study, we determined if the protective effects of thermoneutral housing extend to males. Male C57BL/6J mice were housed at standard room temperature (22°C) or thermoneutral (32°C) conditions from 5 (rapidly growing) to 16 (slowly growing) weeks of age. Mice housed at room temperature exhibited reductions in cancellous bone volume fraction in distal femur metaphysis and fifth lumbar vertebra; these effects were abolished at thermoneutral conditions. Mice housed at thermoneutral temperature had higher levels of bone formation in distal femur (based on histomorphometry) and globally (serum osteocalcin), and lower global levels of bone resorption (serum C-terminal telopeptide of type I collagen) compared to mice housed at room temperature. Thermoneutral housing had no impact on bone marrow adiposity but resulted in higher abdominal white adipose tissue and serum leptin. The overall magnitude of room temperature housing-induced cancellous bone loss did not differ between male (current study) and female (published data) mice. These findings highlight housing temperature as a critical experimental variable in studies using mice of either sex to investigate aging-related changes in bone metabolism.
Marc Blondon, Emmanuel Biver, Olivia Braillard, Marc Righini, Pierre Fontana and Alessandro Casini
Vitamin D deficiency is associated with increased risks of arterial and venous cardiovascular events. Hypothetically, supplementation with vitamin D may lead to a less prothrombotic phenotype, as measured by global coagulation assays and fibrin clot structure.
In this prospective cohort study, we enrolled adult outpatients attending the Primary Care Division of the Geneva University Hospitals with a severe vitamin D deficiency (25-hydroxyvitamin-D3 (25-OHD) <25 nmol/L), excluding obese patients or with a recent acute medical event. We evaluated changes in coagulation times, thrombin generation assay, clot formation and clot lysis time, 25-OHD and parathormone before and 1–3 months after cholecalciferol oral supplementation with one-time 300,000 IU then 800 IU daily. Paired t-tests with a two-sided alpha of 0.05 compared absolute mean differences.
The 48 participants had a mean age of 43.8 ± 13.8 years. After supplementation, 25-OHD levels increased from 17.9 ± 4.6 nmol/L to 62.5 ± 20.7 nmol/L 6.4 ± 3.0 weeks after inclusion. Endogenous thrombin potential and thrombin generation peak values both decreased significantly (−95.4 nM × min (95%CI −127.9 to −62.8), P < 0.001; −15.1 nM (−23.3 to −6.8), P < 0.001). The maximum absorbance by turbidimetry decreased significantly (P = 0.001) after supplementation. There was no change in clot lysis time, coagulation times or plasminogen activator inhibitor-1 and homocysteine levels.
In severe vitamin D deficiency, a high-dose cholecalciferol supplementation was associated with a reduction in thrombin generation and an average decreased number of fibrin protofibrils per fibers and fibrin fiber size measured by turbidimetry. This suggests that severe vitamin D deficiency may be associated with a potentially reversible prothrombotic profile.
Giorgio Bedogni, Andrea Mari, Alessandra De Col, Sofia Tamini, Amalia Gastaldelli and Alessandro Sartorio
Few data are available on the association between serum lipids and insulin secretion (ISEC) in children. We evaluated the association of triglycerides (TG), HDL cholesterol (HDL-C) and LDL cholesterol (LDL-C) with ISEC in 1150 non-diabetic obese children and adolescents using multivariable robust median regression. The following models were employed: (1) IGI or incAUCR as the ISEC response variable; (2) QUICKI, OGIS, the Stumvoll index or the Matsuda insulin sensitivity index as the insulin sensitivity (ISEN) predictor; (3) TG, HDL-C and LDL-C as the predictors of interest; (4) 120-min glucose, age, sex and body mass index as confounders. LDL-C and TG were not associated with ISEC in any model. In three out of four IGI models, an increase of 1 interquartile range (IQR) of HDL-C was associated with a decrease of median incAUCR ranging from −9 (robust 95% CI −17 to −2) to −8 (−14 to −1) pmol/mmol. In two out of four incAUCR models, an increase of 1 IQR of HDL-C was associated with a decrease of median IGI ranging from −8 (−15 to −1) to −7 (−11 to −2) pmol/mmol. TG and LDL-C are not associated and HDL-C is inversely associated with ISEC in obese children and adolescents.
Amalie R Lanng, Lærke S Gasbjerg, Natasha C Bergmann, Sigrid Bergmann, Mads M Helsted, Matthew P Gillum, Bolette Hartmann, Jens J Holst, Tina Vilsbøll and Filip K Knop
Ingestion of the calorically dense compound alcohol may cause metabolic disturbances including hypoglycaemia, hepatic steatosis and insulin resistance, but the underlying mechanisms are uncertain. The gastrointestinal tract is well recognised as a major influencer on glucose, protein and lipid metabolism, but its role in alcohol metabolism remains unclear.
To examine the effects of oral and intravenous alcohol, respectively, on plasma concentrations of several gluco-regulatory hormones including serum/plasma insulin, C-peptide, glucagon, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1) and fibroblast growth factor 21 (FGF21).
Design and methods
In a double-blinded, randomised, crossover design, we subjected 12 healthy men to intragastric ethanol infusion (IGEI) and an isoethanolaemic intravenous ethanol infusion (IVEI) (0.7 g alcohol per kg body weight), respectively, on two separate experimental days.
Isoethanolaemia during the two alcohol administration forms was obtained (P = 0.38). During both interventions, plasma glucose peaked after ~30 min and thereafter fell below baseline concentrations. GIP and GLP-1 concentrations were unaffected by the two interventions. Insulin concentrations were unaffected by IGEI but decreased during IVEI. C-peptide, insulin secretion rate and glucagon concentrations were lowered similarly during IGEI and IVEI. FGF21 concentrations increased dramatically (nine-fold) and similarly during IGEI and IVEI.
Alcohol does not seem to affect the secretion of incretin hormones but decreased insulin and glucagon secretion independently of gut-derived factors. IGEI as well as IVEI potently stimulate FGF21 secretion indicating a gut-independent effect of alcohol on FGF21 secretion in humans.
Leanne Hodson and Fredrik Karpe
In health, the liver is metabolically flexible over the course of the day, as it undertakes a multitude of physiological processes including the regulation of intrahepatic and systemic glucose and lipid levels. The liver is the first organ to receive insulin and through a cascade of complex metabolic processes, insulin not only plays a key role in the intrahepatic regulation of glucose and lipid metabolism, but also in the regulation of systemic glucose and lipid concentrations. Thus, when intrahepatic insulin signalling becomes aberrant then this may lead to perturbations in intrahepatic metabolic processes that have the potential to impact on metabolic health. For example, obesity is associated with intrahepatic fat accumulation (known as nonalcoholic liver disease (NAFLD)) and hyperinsulinaemia, the latter as a result of insulin hypersecretion or impaired hepatic insulin extraction. Although insulin signalling directly alters intra- and extrahepatic metabolism, the regulation of hepatic glucose and fatty acid metabolism is also indirectly driven by substrate availability. Here we discuss the direct and indirect effects of insulin on intrahepatic processes such as the synthesis of fatty acids and peripherally regulating the flux of fatty acids to the liver; processes that may play a role in the development of insulin resistance and/or intrahepatocellular triacylglycerol (IHTAG) accumulation in humans.
Dorte Glintborg, Katrine Hass Rubin, Mads Nybo, Bo Abrahamsen and Marianne Andersen
To investigate risk of thyroid disease in Danish women with PCOS.
National register-based study on women with PCOS in Denmark. 18,476 women had a diagnosis of PCOS in the Danish National Patient Register. PCOS Odense University Hospital (PCOS OUH, n = 1146) was an embedded cohort of women with PCOS and clinical and biochemical examination. Three age-matched controls were included for each woman with PCOS (n = 54,757). The main outcome measures were thyroid disease (hypothyroidism, Graves’ disease, goiter, thyroiditis) according to hospital diagnosis codes and/or inferred from filled medicine prescriptions. Associations between baseline TSH and development of cardio-metabolic disease was examined in PCOS OUH.
The median (quartiles) age at inclusion was 29 (23–35) years and follow-up duration was 11.1 (6.9–16.0) years. The hazard ratio (95% CI) for thyroid disease development was 2.5 (2.3–2.7) (P < 0.001). The event rate of thyroid disease was 6.0 per 1000 patient-years in PCOS Denmark versus 2.4 per 1000 patient-years in controls (P < 0.001). Women in PCOS OUH with TSH ≥2.5 mIU/L (n = 133) had higher BMI (median 29 vs 27 kg/m2), wider waist, higher triglycerides and free testosterone by the time of PCOS diagnosis compared to women in PCOS OUH with TSH <2.5 mIU/L (n = 588). Baseline TSH did not predict later development of cardio-metabolic diseases in PCOS OUH.
The event rate of thyroid disease was significantly and substantially higher in women with PCOS compared to controls.
Kaisu Luiro, Kristiina Aittomäki, Pekka Jousilahti and Juha S Tapanainen
To study the use of hormone therapy (HT), morbidity and reproductive outcomes of women with primary ovarian insufficiency (POI) due to FSH-resistant ovaries (FSHRO).
A prospective follow-up study in a university-based tertiary clinic setting.
Twenty-six women with an inactivating A189V FSH receptor mutation were investigated by means of a health questionnaire and clinical examination. Twenty-two returned the health questionnaire and 14 were clinically examined. Main outcome measures in the health questionnaire were reported as HT, morbidity, medication and infertility treatment outcomes. In the clinical study, risk factors for cardiovascular disease (CVD) and metabolic syndrome (MetS) were compared to age-matched controls from a national population survey (FINRISK). Average number of controls was 326 per FSHRO subject (range 178–430). Bone mineral density and whole-body composition were analyzed with DXA. Psychological and sexual well-being was assessed with Beck Depression Inventory (BDI21), Generalized Anxiety Disorder 7 (GAD-7) and Female Sexual Function Index (FSFI) questionnaires.
HT was initiated late (median 18 years of age) compared with normal puberty and the median time of use was shorter (20–22 years) than the normal fertile period. Osteopenia was detected in 9/14 of the FSHRO women despite HT. No major risk factors for CVD or diabetes were found.
HT of 20 years seems to be associated with a similar cardiovascular and metabolic risk factor profile as in the population control group. However, optimal bone health may require an early-onset and longer period of HT, which would better correspond to the natural fertile period.