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Eliana H Akamine Departments of, Physiology and Biophysics, Pharmacology, Cell and Development of Biology, Department of Biological Sciences, Institute of Biomedical Sciences
Departments of, Physiology and Biophysics, Pharmacology, Cell and Development of Biology, Department of Biological Sciences, Institute of Biomedical Sciences

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Anderson C Marçal Departments of, Physiology and Biophysics, Pharmacology, Cell and Development of Biology, Department of Biological Sciences, Institute of Biomedical Sciences

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João Paulo Camporez Departments of, Physiology and Biophysics, Pharmacology, Cell and Development of Biology, Department of Biological Sciences, Institute of Biomedical Sciences

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Mara S Hoshida Departments of, Physiology and Biophysics, Pharmacology, Cell and Development of Biology, Department of Biological Sciences, Institute of Biomedical Sciences

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Luciana C Caperuto Departments of, Physiology and Biophysics, Pharmacology, Cell and Development of Biology, Department of Biological Sciences, Institute of Biomedical Sciences

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Estela Bevilacqua Departments of, Physiology and Biophysics, Pharmacology, Cell and Development of Biology, Department of Biological Sciences, Institute of Biomedical Sciences

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Carla R O Carvalho Departments of, Physiology and Biophysics, Pharmacology, Cell and Development of Biology, Department of Biological Sciences, Institute of Biomedical Sciences

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Besides the effects on peripheral energy homeostasis, insulin also has an important role in ovarian function. Obesity has a negative effect on fertility, and may play a role in the development of the polycystic ovary syndrome in susceptible women. Since insulin resistance in the ovary could contribute to the impairment of reproductive function in obese women, we evaluated insulin signaling in the ovary of high-fat diet-induced obese rats. Female Wistar rats were submitted to a high-fat diet for 120 or 180 days, and the insulin signaling pathway in the ovary was evaluated by immunoprecipitation and immunoblotting. At the end of the diet period, we observed insulin resistance, hyperinsulinemia, an increase in progesterone serum levels, an extended estrus cycle, and altered ovarian morphology in obese female rats. Moreover, in female obese rats treated for 120 days with the high-fat diet, the increase in progesterone levels occurred together with enhancement of LH levels. The ovary from high-fat-fed female rats showed a reduction in the insulin receptor substrate/phosphatidylinositol 3-kinase/AKT intracellular pathway, associated with an increase in FOXO3a, IL1B, and TNFα protein expression. These changes in the insulin signaling pathway may have a role in the infertile state associated with obesity.

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Alice S Green Departments of, Animal Sciences, Pharmacology and Physiology, University of Arizona, 1650 East Limberlost Drive, Tucson, Arizona 85719, USA

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Xiaochuan Chen Departments of, Animal Sciences, Pharmacology and Physiology, University of Arizona, 1650 East Limberlost Drive, Tucson, Arizona 85719, USA

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Antoni R Macko Departments of, Animal Sciences, Pharmacology and Physiology, University of Arizona, 1650 East Limberlost Drive, Tucson, Arizona 85719, USA

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Miranda J Anderson Departments of, Animal Sciences, Pharmacology and Physiology, University of Arizona, 1650 East Limberlost Drive, Tucson, Arizona 85719, USA

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Amy C Kelly Departments of, Animal Sciences, Pharmacology and Physiology, University of Arizona, 1650 East Limberlost Drive, Tucson, Arizona 85719, USA

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Nathaniel J Hart Departments of, Animal Sciences, Pharmacology and Physiology, University of Arizona, 1650 East Limberlost Drive, Tucson, Arizona 85719, USA

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Ronald M Lynch Departments of, Animal Sciences, Pharmacology and Physiology, University of Arizona, 1650 East Limberlost Drive, Tucson, Arizona 85719, USA

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Sean W Limesand Departments of, Animal Sciences, Pharmacology and Physiology, University of Arizona, 1650 East Limberlost Drive, Tucson, Arizona 85719, USA

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Children from diabetic pregnancies have a greater incidence of type 2 diabetes. Our objective was to determine if exposure to mild–moderate hyperglycemia, by modeling managed diabetic pregnancies, affects fetal β-cell function. In sheep fetuses, β-cell responsiveness was examined after 2 weeks of sustained hyperglycemia with 3 pulses/day, mimicking postprandial excursions, and compared to saline-infused controls (n=10). Two pulsatile hyperglycemia (PHG) treatments were studied: mild (mPHG, n=5) with +15% sustained and +55% pulse; and moderate (PHG, n=10) with +20% sustained and +100% pulse. Fetal glucose-stimulated insulin secretion and glucose-potentiated arginine insulin secretion were lower (P<0.05) in PHG (0.86±0.13 and 2.91±0.39 ng/ml plasma insulin) but not in mPHG fetuses (1.21±0.08 and 4.25±0.56 ng/ml) compared to controls (1.58±0.25 and 4.51±0.56 ng/ml). Islet insulin content was 35% lower in PHG and 35% higher in mPHG vs controls (P<0.01). Insulin secretion and maximally stimulated insulin release were also reduced (P<0.05) in PHG islets due to lower islet insulin content. Isolated PHG islets also had 63% greater (P<0.01) reactive oxygen species (ROS) accumulation at 11.1 mmol/l glucose than controls (P<0.01), but oxidative damage was not detected in islet proteins. PHG fetuses showed evidence of oxidative damage to skeletal muscle proteins (P<0.05) but not insulin resistance. Our findings show that PHG induced dysregulation of islet ROS handling and decreased islet insulin content, but these outcomes are independent. The β-cell outcomes were dependent on the severity of hyperglycemia because mPHG fetuses had no distinguishable impairments in ROS handling or insulin secretion but greater insulin content.

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Lesley A Hill Departments of Cellular and Physiological Sciences and Obstetrics and Gynaecology, The University of British Columbia, Vancouver, British Columbia, Canada

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Dimitra A Vassiliadi Endocrine Unit, Second Department of Internal Medicine-Research Institute and Diabetes Center, Attiko University Hospital, Athens, Greece

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Ioanna Dimopoulou Endocrine Unit, Second Department of Internal Medicine-Research Institute and Diabetes Center, Attiko University Hospital, Athens, Greece

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Anna J Anderson BHF Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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Luke D Boyle BHF Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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Alixe H M Kilgour BHF Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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Roland H Stimson BHF Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

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Yoan Machado Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, British Columbia, Canada

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Christopher M Overall Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, British Columbia, Canada

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Brian R Walker BHF Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom

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John G Lewis Canterbury Health Laboratories, Christchurch, New Zealand

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Geoffrey L Hammond Departments of Cellular and Physiological Sciences and Obstetrics and Gynaecology, The University of British Columbia, Vancouver, British Columbia, Canada

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Corticosteroid-binding globulin (CBG) transports glucocorticoids in blood and is a serine protease inhibitor family member. Human CBG has a reactive center loop (RCL) which, when cleaved by neutrophil elastase (NE), disrupts its steroid-binding activity. Measurements of CBG levels are typically based on steroid-binding capacity or immunoassays. Discrepancies in ELISAs using monoclonal antibodies that discriminate between intact vs RCL-cleaved CBG have been interpreted as evidence that CBG with a cleaved RCL and low affinity for cortisol exists in the circulation. We examined the biochemical properties of plasma CBG in samples with discordant ELISA measurements and sought to identify RCL-cleaved CBG in human blood samples. Plasma CBG-binding capacity and ELISA values were consistent in arterial and venous blood draining skeletal muscle, liver and brain, as well as from a tissue (adipose) expected to contain activated neutrophils in obese individuals. Moreover, RCL-cleaved CBG was undetectable in plasma from critically ill patients, irrespective of whether their ELISA measurements were concordant or discordant. We found no evidence of RCL-cleaved CBG in plasma using a heat-dependent polymerization assay, and CBG that resists immunoprecipitation with a monoclonal antibody designed to specifically recognize an intact RCL, bound steroids with a high affinity. In addition, mass spectrometry confirmed the absence of NE-cleaved CBG in plasma in which ELISA values were highly discordant. Human CBG with a NE-cleaved RCL and low affinity for steroids is absent in blood samples, and CBG ELISA discrepancies likely reflect structural differences that alter epitopes recognized by specific monoclonal antibodies.

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