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ABIGAIL L. FOWDEN
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SUMMARY

The effect of l-arginine on fetal insulin release has been investigated in the chronically catheterized sheep fetus and the findings have been compared with the β cell response to glucose. An infusion of arginine for 5 min (200 mg as a solution of 11·5 mmol/l) stimulated a rapid release of insulin in all the fetuses from 119 to 142 days of gestational age. The maximum insulin concentration occurred at the end of infusion; the mean insulin increase between 0 and 5 min was 18·0 ± 2·0 μu./ml (n = 20). The response to infusion of glucose for 5 min (1 g as a solution of 2·8 mol/l) was more variable and slower than that to arginine with the peak concentration of insulin occurring 10 min after the end of infusion. The mean increase in the concentration of insulin between 0 and 15 min in response to glucose was 42·5 ± 10·0 μu./ml (n = 11). The response to arginine but not to glucose was related to the gestational age of the fetus. The increment in insulin in response to glucose was dependent upon the initial concentration of fetal plasma glucose. The observations are discussed in relation to the regulation of insulin release in utero and the mechanisms of insulin secretion.

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ABIGAIL L. FOWDEN
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The effects of adrenaline and amino acids on β-cell function have been investigated in chronically catheterized fetal sheep. Infusion of adrenaline (1 μg/min) abolished the normal β-cell response to both glucose and arginine. The adrenaline infusion also caused hyperglycaemia and a reduction in the basal plasma insulin concentration in the fetus in the period before the infusion of glucose or arginine was given. Infusion of amino acids increased the speed and the magnitude of the β-cell response to glucose. The maximum increment in the fetal insulin level in response to glucose was 68·5 ± 13·5 (s.e.m.) μu./ml (n = 5) during amino acid infusion which was significantly greater than the value of 16·1 ± 3·4 μu./ml observed in the control experiments. The observations are discussed in relation to the regulation of insulin release in utero.

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ABIGAIL L. FOWDEN
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R. J. BARNES
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R. S. COMLINE
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MARIAN SILVER
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Insulin secretion and the factors influencing β-cell function were investigated in the chronically catheterized fetal foal and mare during the second half of gestation. The response of the fetal β cells to exogenous glucose was also examined. The mean concentration of insulin in the fetal foal was 7·5 ± 0·5 (s.e.m.) μu./ml (n = 20) which was significantly less than the corresponding maternal value of 49·0 ± 5·0μu./ml (n = 20, P<0·01). The insulin concentration in non-pregnant horses was 24·5 ± 1·5 μu./ml (n = 5) which was significantly less than the value in the pregnant animals (P<0·01). However, there was no significant difference in the mean glucose concentration between the groups of adult animals.

The insulin concentration was related to the endogenous glucose level in both adult and fetal horses. Wide variation in the maternal insulin concentration was observed above a glucose concentration of about 5·0 mmol/l. The mean concentration of insulin in pregnant mares decreased with increasing gestational age while the mean glucose concentration remained unaltered throughout the second half of gestation. There was no change in the basal concentrations of insulin or glucose in the fetus with gestational age although the fetal β-cell response to exogenous glucose appeared to increase with increasing fetal age after 270 days of gestation (term 330 days). There was a significant arterio-venous difference in the concentration of insulin across the gravid uterus in the mare when the arterial insulin level was greater than 30 μu./ml. Below this value, there was no consistent uptake of insulin by the uterus. The observations are discussed in relation to the regulation of insulin release in utero and the effects of pregnancy on maternal β-cell function.

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Alison J Forhead
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Juanita K Jellyman
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Katherine Gillham
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Janelle W Ward
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Dominique Blache Department of Physiology, Faculty of Natural and Agricultural Sciences, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK

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Abigail L Fowden
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The actions of angiotensin II on type 1 (AT1) and type 2 (AT2) receptor subtypes are important for normal kidney development before birth. This study investigated the effect of AT1 receptor antagonism on renal growth and growth regulators in fetal sheep during late gestation. From 125 days of gestation (term 145±2 days), chronically catheterised sheep fetuses were infused intravenously for 5 days with either an AT1-specific receptor antagonist (GR138950, 2–4 mg/kg per day, n=5) or saline (0.9% NaCl, n=5). Blockade of the AT1 receptor decreased arterial blood oxygenation and pH and increased blood pCO2, haemoglobin and lactate, and plasma cortisol and IGF-II. Blood glucose and plasma thyroid hormones and IGF-I were unchanged between the treatment groups. On the 5th day of infusion, the kidneys of the GR-treated fetuses were lighter than those of the control fetuses, both in absolute and relative terms, and were smaller in transverse cross-sectional width and cortical thickness. In the GR-infused fetuses, renal AT2 receptor protein concentration and glomerular density were significantly greater than in the saline-infused fetuses. Blockade of the AT1 receptor had no effect on relative cortical thickness, fractional or mean glomerular volumes, or renal protein levels of the AT1 receptor, IGF type 1 receptor, insulin receptor or protein kinase C ζ. Therefore, in the ovine fetus, AT1 receptor antagonism causes increased renal protein expression of the AT2 receptor subtype, which, combined with inhibition of AT1 receptor activity, may be partly responsible for growth retardation of the developing kidney.

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Stuart A Lanham Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, School of Medicine, University of Southampton, Southampton, UK

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Dominique Blache School of Agriculture and Environment, University of Western Australia, Crawley, Australia

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Richard O C Oreffo Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, School of Medicine, University of Southampton, Southampton, UK

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Abigail L Fowden Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK

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Alison J Forhead Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, UK

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Hormones have an important role in the regulation of fetal growth and development, especially in response to nutrient availability in utero. Using micro-CT and an electromagnetic three-point bend test, this study examined the effect of pancreas removal at 0.8 fraction of gestation on the developing bone structure and mechanical strength in fetal sheep. When fetuses were studied at 10 and 25 days after surgery, pancreatectomy caused hypoinsulinaemia, hyperglycaemia and growth retardation which was associated with low plasma concentrations of leptin and a marker of osteoclast activity and collagen degradation. In pancreatectomized fetuses compared to control fetuses, limb lengths were shorter, and trabecular (Tb) bone in the metatarsi showed greater bone volume fraction, Tb thickness, degree of anisotropy and porosity, and lower fractional bone surface area and Tb spacing. Mechanical strength testing showed that pancreas deficiency was associated with increased stiffness and a greater maximal weight load at fracture in a subset of fetuses studied near term. Overall, pancreas deficiency in utero slowed the growth of the fetal skeleton and adapted the developing bone to generate a more compact and connected structure. Maintenance of bone strength in growth-retarded limbs is especially important in a precocial species in preparation for skeletal loading and locomotion at birth.

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