ORCID Profile
0000-0002-2823-3004
Current Organisation
University of Adelaide
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Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.BRACHY.2018.03.004
Abstract: In nasopharyngeal cancer, brachytherapy is given as boost in primary treatment or as salvage for recurrent or persistent disease. The Rotterdam nasopharyngeal applicator (RNA) allows for suboptimal reduction of soft palate radiation dose, based on image-guided brachytherapy plans. Building on the RNA, we propose a novel design, the Benavides nasopharyngeal applicator (BNA). The virtual BNA was reconstructed on two cases (one T1, one T2) previously treated with intracavitary brachytherapy using the RNA. Dose was prescribed to the high-risk clinical target volumes (CTVs) and optimization was such that high-risk CTV D90 ≥ 100% of prescribed dose (PD), intermediate-risk-CTV D90 ≥ 75% PD, and soft palate D2cc ≤ 120% PD. The optimized RNA and BNA image-guided brachytherapy plans were compared in terms of CTV coverage and organs-at-risk sparing. Optimization objectives were more easily met with the BNA. For the T1 case, all three planning objectives were easily achieved in both the RNA and BNA, but with 18-19% lower soft palate doses with the BNA. For the T2 case, the CTV planning objectives were achieved in both the RNA and BNA, but the soft palate constraint was only achieved with the BNA, with 38-41% lower soft palate doses. Compared to the RNA, the BNA permits easier optimization and improves therapeutic ratio by a significant reduction of soft palate doses, based on simulation using a proposed system for CTV/organs-at-risk delineation, prescription, and optimization for image-guided adaptive brachytherapy. Clinical piloting using a prototype is necessary to evaluate its feasibility and utility.
Publisher: Wiley
Date: 25-07-2014
DOI: 10.1113/EXPPHYSIOL.2014.080630
Abstract: Disrupting circadian rhythms in rodents perturbs glucose metabolism and increases adiposity. To determine whether these effects occur in a large diurnal animal, we assessed the impact of circadian rhythm disruption upon metabolic function in sheep. Adult ewes (n = 7) underwent 3 weeks of a control 12 h light-12 h dark photoperiod, followed by 4 weeks of rapidly alternating photoperiods (RAPs) whereby the time of light exposure was reversed twice each week. Measures of central (melatonin secretion and core body temperature) and peripheral rhythmicity (clock and metabolic gene expression in skeletal muscle) were obtained over 24 h in both conditions. Metabolic homeostasis was assessed by glucose tolerance tests and 24 h glucose and insulin profiles. Melatonin and core body temperature rhythms resynchronized within 2 days of the last photoperiod shift. High- litude Bmal1, Clock, Nr1d1, Cry2 and Per3 mRNA rhythms were apparent in skeletal muscle, which were phase advanced by up to 3.5 h at 2 days after the last phase shift, whereas Per1 expression was downregulated at this time. Pparα, Pgc1α and N t mRNA were constitutively expressed in both conditions. Nocturnal glucose concentrations were reduced following chronic phase shifts (zeitgeber time 0, -5.5% zeitgeber time 12, -2.9% and zeitgeber time 16, -5.7%), whereas plasma insulin, glucose tolerance and glucose-stimulated insulin secretion were not altered. These results demonstrate that clock gene expression within ovine skeletal muscle oscillates over 24 h and responds to changing photoperiods. However, metabolic genes which link circadian and metabolic clocks in rodents were arrhythmic in sheep. Differences may be due to the ruminant versus monogastric digestive organization in each species. Together, these results demonstrate that despite disruptions to central and peripheral rhythmicity following exposure to rapidly alternating photoperiods, there was minimal impact on glucose homeostasis in the sheep.
Publisher: Wiley
Date: 30-05-2018
DOI: 10.1113/JP274948
Publisher: Springer Science and Business Media LLC
Date: 29-07-2020
Publisher: Portland Press Ltd.
Date: 05-2000
DOI: 10.1042/CS19990229
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.PLACENTA.2019.01.014
Abstract: Proper placental function is essential for optimal fetal growth in utero. Placental transfer of nutrients to the fetus can be measured using radiolabelled tracers, but non-radioactive methods have potential advantages. This study aimed to develop a fluorescence-based method to measure placental glucose transport in mice. Time course and localisation of the IRDye 800CW 2-deoxyglucose were recorded (Lumina IVIS Live Imaging System) following tail vein injection into anaesthetised late pregnant mice. Fluorescent signals in placental and fetal tissues were assessed after injecting conscious dams with 10 nmol IRDye 800CW 2-deoxyglucose (3, 30, 60, 120 min) or vehicle. Specificity of dye uptake was determined by comparing uptake of IRDye 800CW conjugated to 2-deoxyglucose or carboxylate, at 2 and 24 h. Finally, we assessed relationships of fetal size and umbilical blood flow velocities with relative dye uptake. In late pregnant mice, uterine fluorescent signal localised rapidly over placentas and remained consistent for >1 h. Signal intensity in whole and homogenised tissues increased in fetuses and decreased in placentas after 3 min and stabilised by 30 min post-injection. Relative fetal dye uptake at 2 and 24 h was greater in littermates with the highest compared to lowest placental efficiency signals were similar for 2-deoxyglucose- or carboxylate-conjugated dyes. Relative fetal dye uptake correlated positively with fetal weight and placental efficiency and negatively with umbilical artery resistance indices. Fetal uptake of IRDye 800CW correlates with markers of placental blood flow and fetal growth, but does not specifically measure placental glucose transport.
Publisher: American Diabetes Association
Date: 13-02-2013
DOI: 10.2337/DC12-1097
Abstract: This study was designed to compare glucose, lipids, and C-reactive protein (CRP) in women with gestational diabetes mellitus treated with metformin or insulin and in cord plasma of their offspring and to examine how these markers relate to infant size at birth. Women with gestational diabetes mellitus were randomly assigned to metformin or insulin in the Metformin in Gestational Diabetes trial. Fasting maternal plasma glucose, lipids, and CRP were measured at randomization, 36 weeks’ gestation, and 6–8 weeks postpartum as well as in cord plasma. Women with available cord blood s les (metformin n = 236, insulin n = 242) were included. Maternal plasma triglycerides increased more from randomization to 36 weeks’ gestation in women treated with metformin (21.93%) versus insulin (9.69%, P & 0.001). Maternal and cord plasma lipids, CRP, and neonatal anthropometry did not differ between treatments. In logistic regression analyses adjusted for confounders, the strongest associations with birth weight & th centile were maternal triglycerides and measures of glucose control at 36 weeks. There were few differences in circulating maternal and neonatal markers of metabolic status and no differences in measures of anthropometry between the offspring of women treated with metformin and the offspring of women treated with insulin. There may be subtle effects of metformin on maternal lipid function, but the findings suggest that treating gestational diabetes mellitus with metformin does not adversely affect lipids or CRP in cord plasma or neonatal anthropometric measures.
Publisher: American Physiological Society
Date: 10-2006
DOI: 10.1152/AJPREGU.00103.2006
Abstract: Intrauterine growth restriction (IUGR) is associated with accelerated growth and increased adiposity in early life due to unknown mechanisms, which could include increased thyroid hormone (TH) action. We hypothesized that placental restriction (PR) of fetal growth would increase circulating TH concentrations and alter their response to fasting, and that these would relate to growth and body composition in the young lamb. PR reduced size at birth, increased fractional growth rates (FGRs) of soft and skeletal tissues up to 30 days of age, and slowed the ontogenic decrease in plasma total T 3 and plasma total T 3 /T 4 . PR did not alter the abundance of plasma THs after short-term fasting. In general, plasma total T 3 and total T 3 /T 4 ratio correlated negatively, whereas plasma total T 4 correlated positively with size at birth. Absolute growth rates of weight and crown-rump length correlated positively with plasma total T 3 and total T 4 between days 15 and 35. Current FGRs for weight and metatarsal length correlated positively with plasma total T 3 between days 20 and 35. In conclusion, PR and small size at birth reduce plasma total T 4 and increase plasma total T 3 postnatally, whereas catch-up growth relates to increased abundance of the more bioactive forms of TH. Finally, greater soft tissue growth occurs in PR compared with control lambs at the same circulating TH concentrations. This suggests that PR and small size at birth may increase activation of T 4 to T 3 and sensitivity of soft tissues to TH, which may contribute to catch-up growth following IUGR.
Publisher: American Physiological Society
Date: 2018
DOI: 10.1152/AJPREGU.00549.2016
Abstract: Perinatal exposures are associated with altered risks of childhood allergy. Human studies and our previous work suggest that restricted growth in utero (IUGR) is protective against allergic disease. The mechanisms are not clearly defined, but reduced fetal abundance and altered metabolism of methyl donors are hypothesized as possible underlying mechanisms. Therefore, we examined whether late-gestation maternal dietary methyl donor and cofactor supplementation of the placentally restricted (PR) sheep pregnancy would reverse allergic protection in progeny. Allergic outcomes were compared between progeny from control pregnancies (CON n = 49), from PR pregnancies without intervention (PR n = 28), and from PR pregnancies where the dam was fed a methyl donor plus cofactor supplement from day 120 of pregnancy until delivery (PR + Methyl n = 25). Both PR and PR + Methyl progeny were smaller than CON supplementation did not alter birth size. PR was protective against cutaneous hypersensitivity responses to ovalbumin (OVA P 0.01 in singletons). Cutaneous hypersensitivity responses to OVA in PR + Methyl progeny were intermediate to and not different from the responses of CON and PR sheep. Cutaneous hypersensitivity responses to house dust mites did not differ between treatments. In singleton progeny, upper dermal mast cell density was greater in PR + Methyl than in PR or CON (each P 0.05). The differences in the cutaneous allergic response were not explained by treatment effects on circulating immune cells or antibodies. Our results suggest that mechanisms underlying in utero programming of allergic susceptibility by IUGR and methyl donor availability may differ and imply that late-gestation methyl donor supplementation may increase allergy risk.
Publisher: Oxford University Press (OUP)
Date: 18-06-2015
Abstract: Being born small for gestational age (SGA) increases the risk for adverse perinatal outcomes and later life vascular and metabolic disorders. The insulin family plays a vital role in intrauterine growth. We investigated the association of functional SNPs in insulin (INS), insulin receptor (INSR) and insulin receptor substrate 2 (IRS2) with small for gestational age (SGA) pregnancies, uterine and umbilical artery Doppler and plasma insulin level. We conducted a nested case-control study of 1401 nulliparous Caucasian women, their partners and babies (216 SGA and 1185 uncomplicated). SGA was defined as a birthweight less than the 10th customized birthweight percentile adjusted for maternal height, weight, parity, ethnicity, gestational age at delivery and infant sex. Uterine and umbilical artery Doppler was performed at 20 ± 1 week gestation. The SNPs in the parent infant trios were genotyped using Sequenom MassARRAY. Plasma insulin was measured by double antibody RIA in 188 healthy non-pregnant adults to assess correlations between SNP genotypes and circulating insulin. Paternal [odds ratio (OR) (95% CI) = 2.2 (1.3-3.9), P = 0.005] and infant [OR (95% CI) = 3.3 (1.7-6.2), P = 0.0001] INSR rs2059806 AA genotype was associated with SGA. Infant INSR rs2059806 A allele was associated with abnormal umbilical artery Doppler [OR (95% CI) = 1.3(1.0-1.7), P = 0.04]. INSR rs2059806 AA homozygous in iduals had lower plasma insulin compared with heterozygotes (P = 0.03) and GG homozygotes (P = 0.03). The INSR rs2059806 SNP previously associated with adult vascular and metabolic diseases is also associated with SGA pregnancies. This polymorphism may associate with the risk of vascular and metabolic disorders across the life course.
Publisher: Springer US
Date: 2006
Publisher: Springer Science and Business Media LLC
Date: 03-10-2023
Publisher: S. Karger AG
Date: 2002
DOI: 10.1159/000048224
Abstract: Somatostatin (SRIH) release into hypophyseal portal blood varies reciprocally with growth hormone (GH) pulse generation in the male rat. However, few studies have directly evaluated this relationship in the female of any species. To address this issue, we carried out intensive (5 min) and extended (240 min) simultaneous monitoring of hypophyseal portal SRIH and internal jugular GH secretion in 7 unanesthetized ewes. Bihormonal synchrony was assessed by three statistically independent but complementary analyses: (i) cross-approximate entropy (X-ApEn) analysis to appraise the conditional regularity of SRIH/GH release patterns (ii) cross-correlation analysis of paired s le SRIH and GH release rates, and (iii) probability analysis of random versus nonrandom SRIH and GH discrete pulse concordance. From a one-variable perspective, ApEn analysis documented consistently more irregular patterns of SRIH than GH release (94 ± 4.3 and 72 ± 8.1%, respectively, of the mean irregularity of 1,000 in idual random-shuffled cognate series, p = 0.034). From a two-variable perspective, X-ApEn analysis revealed a nearly mean random relationship between SRIH and GH release patterns (group mean ± SEM, 94 ± 4.5% of the mean asynchrony of 1,000 randomly shuffled SRIH/GH pairs). Cross-correlation analysis disclosed highly variable linkages between SRIH and GH secretion viz, negative cross-correlations in 5 sheep, positive relationships in 4, and both positive and negative SRIH/GH associations in 2 animals, wherein changes in SRIH secretion either preceded or followed those of GH. Peak detection by model-free cluster analysis quantified a total of 28 SRIH and 31 GH release episodes. Corresponding interpulse intervals (min) were comparable (37 ± 4 (SRIH) and 43 ± 12 (GH)), but the mean fractional (%) litude of SRIH peaks was 3.5-fold lower (60 ± 10%) than that for GH (225 ± 50%) (p = 0.024). Pulse-concordance probability testing showed that discrete peaks of SRIH and GH secretion coincided only 33% of the time, although this value exceeded chance expectation (p 10 sup –4 /sup ). In summary, the present analysis applies intensive (5 min) and extended (240 min) simultaneous s ling of hypophyseal-portal and jugular venous blood to quantitate the degree of coordinate SRIH and GH secretion in the unanesthetized ovariectomized ewe. Thereby, we unmask highly irregular SRIH release patterns, and nearly random SRIH and GH associations. We conclude that, to the extent that in vivo s ling reflects physiological SRIH/somatotrope activity, the female sheep maintains complex time-varying interactions between SRIH and GH release.
Publisher: Bioscientifica
Date: 09-2014
DOI: 10.1530/EC-14-0068
Abstract: Circulating IGFs are important regulators of prenatal and postnatal growth, and of metabolism and pregnancy, and change with sex, age and pregnancy. Single-nucleotide polymorphisms (SNPs) in genes coding for these hormones associate with circulating abundance of IGF1 and IGF2 in non-pregnant adults and children, but whether this occurs in pregnancy is unknown. We therefore investigated associations of plasma IGF1 and IGF2 with age and genotype at candidate SNPs previously associated with circulating IGF1, IGF2 or methylation of the INS – IGF2 – H19 locus in men ( n =134), non-pregnant women ( n =74) and women at 15 weeks of gestation ( n =98). Plasma IGF1 concentrations decreased with age ( P .001) and plasma IGF1 and IGF2 concentrations were lower in pregnant women than in non-pregnant women or men (each P .001). SNP genotypes in the INS – IGF2 – H19 locus were associated with plasma IGF1 ( IGF2 rs680, IGF2 rs1004446 and IGF2 rs3741204) and IGF2 ( IGF2 rs1004446, IGF2 rs3741204 and H19 rs217727). In single SNP models, effects of IGF2 rs680 were similar between groups, with higher plasma IGF1 concentrations in in iduals with the GG genotype when compared with GA ( P =0.016), or combined GA and AA genotypes ( P =0.003). SNPs in the IGF2 gene associated with IGF1 or IGF2 were in linkage disequilibrium, hence these associations could reflect other genotype variations within this region or be due to changes in INS – IGF2 – H19 methylation previously associated with some of these variants. As IGF1 in early pregnancy promotes placental differentiation and function, lower IGF1 concentrations in pregnant women carrying IGF2 rs680 A alleles may affect placental development and/or risk of pregnancy complications.
Publisher: American Physiological Society
Date: 12-2018
DOI: 10.1152/AJPREGU.00391.2017
Abstract: Experimental studies that are relevant to human pregnancy rely on the selection of appropriate animal models as an important element in experimental design. Consideration of the strengths and weaknesses of any animal model of human disease is fundamental to effective and meaningful translation of preclinical research. Studies in sheep have made significant contributions to our understanding of the normal and abnormal development of the fetus. As a model of human pregnancy, studies in sheep have enabled scientists and clinicians to answer questions about the etiology and treatment of poor maternal, placental, and fetal health and to provide an evidence base for translation of interventions to the clinic. The aim of this review is to highlight the advances in perinatal human medicine that have been achieved following translation of research using the pregnant sheep and fetus.
Publisher: SAGE Publications
Date: 14-09-2020
Abstract: Kidney transplantation is a lifechanging event for patients with end-stage kidney disease (ESKD) because it improves the quality of life and survival of these patients. However, it is not a cure and is not without complications. Transplant recipients have an excess risk of premature death (largely from cancer and cardiovascular disease (CVD)) by at least 10-times compared to the general population. Published work has identified cancer as one of the most important and feared outcomes in transplant recipients and is a key research priority recognised by both patients and health professionals. There is also convincing epidemiological evidence, suggesting the overall risk of developing cancer in the transplant population is approximately 2 to 3-fold higher compared to the age-matched general population. Unlike CVD, where the death rates have fallen considerably over the past decade in this population in response to better screening, preventative and intervention approaches, the excess risk of cancer-related deaths in transplant recipients remains at least 10-fold higher compared to cancer patients in the general population. The causes of the increased risk of death are unknown but may be a consequence of possible differences in tumour biology under the influence of immunosuppression. In this review, we will discuss the epidemiology of overall and site-specific cancer risk and death across different countries. We will also focus on the current evidence on the prevention and screening in our at-risk transplant candidates. Finally, management strategies of common cancers such as skin, post-transplant lymphoproliferative disease and solid organ cancers such as colorectal, breast and lung cancer will be evaluated.
Publisher: American Physiological Society
Date: 02-2021
Abstract: This study provides first evidence that gastric vagal afferent signaling is attenuated during pregnancy and inversely associated with meal size. Growth hormone attenuated mechanosensitivity of gastric vagal afferents, adding support that increases in maternal growth hormone may mediate adaptations in gastric vagal afferent signaling during pregnancy. These findings have important implications for the peripheral control of food intake during pregnancy.
Publisher: American Physiological Society
Date: 15-03-2015
DOI: 10.1152/AJPREGU.00466.2014
Abstract: In healthy humans and rodents, chronic and acute exercise improves subsequent insulin sensitivity of skeletal muscle. A large animal species with similar metabolic responses to exercise would permit longitudinal studies, including repeated biopsies of muscle and other tissues not possible in rodents, and enable study of interactions with insulin-resistant physiological states not feasible in humans. Therefore, we examined whether acute exercise increases insulin sensitivity in adult sheep. Insulin sensitivity was measured by hyperinsulinemic euglycemic cl (HEC) in mature female sheep ( n = 7). Sheep were familiarized to treadmill walking and then performed an acute exercise bout (30 min, 8% slope, up to 4.4 km/h). A second HEC was conducted ∼18 h after the acute exercise. Musculus semimembranosus biopsies were obtained before and after each HEC. Glucose infusion rate during the HEC increased 40% ( P = 0.003) and insulin sensitivity (glucose infusion rate lasma insulin concentration) increased 32% ( P = 0.028) after acute exercise. Activation of proximal insulin signaling in skeletal muscle after the HEC, measured as Ser 473 phosphorylation of Akt, increased approximately five-fold in response to insulin ( P 0.001) and was unaltered by acute exercise performed 18 h earlier. PGC 1α and GLUT4 protein, glycogen content and citrate synthase activity in skeletal muscle did not change in response to insulin or exercise. In conclusion, improved insulin sensitivity and unchanged proximal insulin signaling on the day after acute exercise in sheep are consistent with responses in humans and rodents, suggesting that the sheep is an appropriate large-animal model in which to study responses to exercise.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2013
Publisher: Wiley
Date: 28-09-2020
DOI: 10.1113/JP280341
Abstract: Maternal shift work increases the risk of pregnancy complications, although its effects on progeny health after birth are not clear. We evaluated the impact of a simulated shift work protocol for one‐third, two‐thirds or all of pregnancy on the metabolic health of sheep progeny. Simulated shift work had no effect on growth, body size, body composition or glucose tolerance in pre‐pubertal or young adult progeny. Glucose‐stimulated insulin secretion was reduced in adult female progeny and insulin sensitivity was increased in adult female singleton progeny. The results of the present study do not support the hypothesis that maternal shift work exposure impairs metabolic health of progeny in altricial species. Disrupted maternal circadian rhythms, such as those experienced during shift work, are associated with impaired progeny metabolism in rodents. The effects of disrupted maternal circadian rhythms on progeny metabolism have not been assessed in altricial, non‐litter bearing species. We therefore assessed postnatal growth from birth to adulthood, as well as body composition, glucose tolerance, insulin secretion and insulin sensitivity, in pre‐pubertal and young adult progeny of sheep exposed to control conditions (CON: 10 males, 10 females) or to a simulated shift work (SSW) protocol for the first one‐third (SSW0‐7: 11 males, 9 females), the first two‐thirds (SSW0‐14: 8 males, 11 females) or all (SSW0‐21: 8 males, 13 females) of pregnancy. Progeny growth did not differ between maternal treatments. In pre‐pubertal progeny (12–14 weeks of age), adiposity, glucose tolerance and insulin secretion during an i.v. glucose tolerance test and insulin sensitivity did not differ between maternal treatments. Similarly, in young adult progeny (12–14 months of age), food intake, adiposity and glucose tolerance did not differ between maternal treatments. At this age, however, insulin secretion in response to a glucose bolus was 30% lower in female progeny in the combined SSW groups compared to control females ( P = 0.031), and insulin sensitivity of SSW0‐21 singleton females was 236% compared to that of CON singleton female progeny ( P = 0.025). At least in this model, maternal SSW does not impair progeny metabolic health, with some evidence of greater insulin action in female young adult progeny.
Publisher: Cambridge University Press (CUP)
Date: 19-02-2020
DOI: 10.1017/S2040174420000094
Abstract: Preecl sia (PE) is now recognised as a cardiovascular risk factor for women. Emerging evidence suggests that children exposed to PE in utero may also be at increased risk of cardiovascular disease (CVD) in later life. In iduals exposed to PE in utero have higher systolic and diastolic blood pressure and higher body mass index (BMI) compared to those not exposed to PE in utero . The aim of this review is to discuss the potential mechanisms driving the relationship between PE and offspring CVD. Exposure to an adverse intrauterine environment as a consequence of the pathophysiological changes that occur during a pregnancy complicated by PE is proposed as one mechanism that programs the fetus for future CVD risk. Consistent with this hypothesis, animal models of PE where progeny have been studied demonstrate causality for programming of offspring cardiovascular health by the preecl tic environment. Shared alleles between mother and offspring, and shared lifestyle factors between mother and offspring provide alternate pathways explaining associations between PE and offspring CVD risk. In addition, adverse lifestyle habits can also act as second hits for those programmed for increased CVD risk. PE and CVD are both multifactorial diseases and, hence, identifying the relative contribution of PE to offspring risk for CVD is a very complex task. However, considering the emerging strong association between PE and CVD, those exposed to PE in utero may benefit from targeted primary CVD preventive strategies.
Publisher: Cambridge University Press (CUP)
Date: 23-06-2016
DOI: 10.1017/S2040174416000283
Abstract: Intrauterine growth restriction (IUGR) has adverse effects on metabolic health and early life, whereas physical activity is protective against later development of metabolic disease. Relationships between birth weight and physical activity in humans, and effects of IUGR on voluntary activity in rodents, are mixed and few studies have measured physical activity in a free-ranging environment. We hypothesized that induced restriction of placental growth and function (PR) in sheep would decrease spontaneous ambulatory activity (SAA) in free-ranging adolescent and young adult progeny from multi-fetal pregnancies. To test this hypothesis, we used Global Positioning System watches to continuously record SAA between 1800 and 1200 h the following day, twice during a 16-day recording period, in progeny of control (CON, n =5 males, 9 females) and PR pregnancies ( n =9 males, 10 females) as adolescents (30 weeks) and as young adults (43 weeks). PR reduced size at birth overall, but not in survivors included in SAA studies. In adolescents, SAA did not differ between treatments and females were more active than males overall and during the day (each P .001). In adults, daytime SAA was greater in PR than CON females ( P =0.020), with a similar trend in males ( P =0.053) and was greater in females than males ( P =0.016). Adult SAA was negatively correlated with birth weight in females only. Contrary to our hypothesis, restricted placental function and small size at birth did not reduce progeny SAA. The mechanisms for increased daytime SAA in adult female PR and low birth weight sheep require further investigation.
Publisher: Wiley
Date: 15-06-2021
DOI: 10.1113/JP281791
Publisher: Elsevier BV
Date: 09-2015
Publisher: Bioscientifica
Date: 07-2000
Abstract: Circulating growth hormone (GH) concentrations increase in pregnancy and administration of GH during early-mid pregnancy increases fetal growth in well-fed pigs. To determine whether increased maternal GH could promote fetal growth when feed availability is restricted, fifteen cross-bred primiparous sows (gilts) were fed at approximately 30% of ad libitum intake, from mating onwards and were injected daily i.m. with recombinant porcine GH (pGH) at doses of 0, 13.4+/-0.3 and 25.6+/-0.5 microg/kg live weight from day 25 to day 51 of pregnancy (term approximately 115 days). Treatment with pGH increased maternal backfat loss between day 25 and day 51 of pregnancy, and increased maternal plasma IGF-I concentrations measured at day 51 of pregnancy. Fetal body weight, length and skull width at day 51 of pregnancy were increased by maternal treatment with pGH. Fetal plasma glucose concentrations were increased and maternal/fetal plasma glucose concentration gradients were decreased by maternal pGH treatment at 13.4, but not 25.6 microg/kg.day. Fetal plasma concentrations of urea were decreased by both levels of pGH treatment. Overall, fetal weight was negatively correlated with fetal plasma concentrations of urea, positively correlated with maternal plasma alpha-amino nitrogen concentrations and unrelated to glucose concentrations in either maternal or fetal plasma. This suggests that the availability of amino acids, not glucose, limits fetal growth in the first half of pregnancy in underfed gilts, and that maternal GH treatment may improve amino acid delivery to the fetus.
Publisher: CSIRO Publishing
Date: 2017
Publisher: S. Karger AG
Date: 2016
DOI: 10.1159/000443961
Abstract: b i Background: /i /b Around 30-40% of the world's population will experience allergy, the most common and earliest-onset noncommunicable disease. With a steady rise in the incidence of allergic disease over recent decades, up to 18% of children will suffer a respiratory, food or skin allergy before their 18th birthday. There is compelling evidence that the risk of developing allergy is influenced by early life events and particularly in utero exposures. b i Methods: /i /b A comprehensive literature review was undertaken which outlines prenatal risk factors and potential mechanisms underlying the development of allergy in childhood. b i Results: /i /b Exposures including maternal cigarette smoking, preterm birth and Caesarean delivery are implicated in predisposing infants to the later development of allergy. In contrast, restricted growth in utero, a healthy maternal diet and a larger family size are protective, but the mechanisms here are unclear and require further investigation. b i Conclusion: /i /b To ameliorate the allergy pandemic in young children, we must define prenatal mechanisms that alter the programming of the fetal immune system and also identify specific targets for antenatal interventions.
Publisher: Informa UK Limited
Date: 19-10-2016
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.PHYSBEH.2015.08.042
Abstract: Intrauterine growth restriction and slow neonatal growth in humans are each associated with poorer learning, memory and cognitive flexibility in childhood and adulthood. The relative contributions of pre- and post-natal growth to cognitive outcomes are unclear, however. We therefore compared performance in learning, memory and reversal tasks using a modified Y-maze at 18 and 40 weeks of age in offspring of placentally-restricted (PR: 10 M, 13 F) and control (23 M, 17 F) ovine pregnancies. We also investigated relationships between size at birth, neonatal growth rates and cognitive outcomes. PR had limited effects on cognitive outcomes, with PR males requiring more trials to solve the initial learning task than controls (P=0.037) but faster completion of reversal tasks in both sexes at 18 weeks of age. In males, neonatal growth rate correlated inversely with numbers of trials and total time required to solve memory tasks at 40 weeks of age. In females, bleat frequency in the first reversal task at 18 weeks of age correlated positively with birth weight (r=0.734, P<0.05) and neonatal growth rate (r=0.563, P<0.05). We conclude that PR induces limited effects on cognitive outcomes in sheep, with some evidence of impaired learning in males, but little effect on memory or cognitive flexibility in either sex. Rapid neonatal growth predicted improved memory task performance in males, suggesting that strategies to optimize neonatal growth may have long-term cognitive benefits but that these may be sex-specific.
Publisher: Oxford University Press (OUP)
Date: 1996
Abstract: The effects of sex and age on patterns of circulating somatotropin (ST) concentration and plasma IGF-I, IGF-II, insulin, and IGF binding protein-3 (IGFBP-3) were studied in ram, wether, and ewe lambs (n = 7 or 8) s led at mean ages of 81 (I1) and 158 d (I2). Between 81 and 158 d of age, rams grew more rapidly than wethers (P < .01), and wethers grew more rapidly than ewes (P wethers > ewes (P < .05). Mean plasma ST concentrations, ST pulse litude, and integrated plasma ST concentrations were greater (P < .05) in rams than in ewes at I1 and I2. Characteristics of the ST plasma profile in wethers were generally intermediate between those of rams and ewes. The interpulse interval was greater in ewes than in wethers at I2. The IGF-I and IGFBP-3 concentrations were greater in rams than in ewes at both s ling times. Plasma IGF-II was greater in ewes than in rams at I2. Mean plasma ST was approximately two thirds less at I2 than at I1 regardless of sex. Mean plasma ST and IGF-I at both ages were positively correlated with growth. Mean plasma ST at I2 was negatively correlated with fatness at slaughter. Sex and age significantly affected patterns of circulating ST and concentrations of IGF-I and IGFBP-3 in prepubertal growing lambs, under conditions for which growth rates and composition were also sexually dimorphic.
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.JRI.2017.07.002
Abstract: Allergy is a chronic disease that can develop as early as infancy, suggesting that early life factors are important in its aetiology. Variable associations between size at birth, a crude marker of the fetal environment, and allergy have been reported in humans and require comprehensive review. Associations between birth weight and allergy are however confounded in humans, and we and others have therefore begun exploring the effects of early life events on allergy in experimental models. In particular, we are using ovine models to investigate whether and how a restricted environment before birth protects against allergy, whether methyl donor availability contributes to allergic protection in IUGR, and why maternal asthma during pregnancy is associated with increased risks of allergic disease in children. We found that experimental intrauterine growth restriction (IUGR) in sheep reduced cutaneous responses to antigens in progeny, despite normal or elevated IgE responses. Furthermore, maternal methyl donor supplementation in late pregnancy partially reversed effects of experimental IUGR, consistent with the proposal that epigenetic pathways underlie some but not all effects of IUGR on allergic susceptibility. Ovine experimental allergic asthma with exacerbations reduces relative fetal size in late gestation, with some changes in immune populations in fetal thymus suggestive of increased activation. Maternal allergic asthma in mice also predisposes progeny to allergy development. In conclusion, these findings in experimental models provide direct evidence that a perturbed environment before birth alters immune system development and postnatal function, and provide opportunities to investigate underlying mechanisms and develop and evaluate interventions.
Publisher: Bioscientifica
Date: 12-2021
DOI: 10.1530/JOE-21-0087
Abstract: The growth hormone (GH)–insulin-like growth factor (IGF) axis is one of the main drivers of mammalian growth and development. Pituitary secretion of GH is pulsatile and under positive and negative hypothalamic control, as well as stimulation from gastric-secreted acyl-ghrelin. GH acts both directly via the GH-receptor (GHR) and indirectly via stimulation of IGF1 production to induce anabolic and metabolic responses at multiple target tissues. In this review, we describe the major changes to this axis during pregnancy, with increasing GH abundance in the maternal circulation across multiple species. This stimulates the secretion of IGFs, whose bioavailability is also increased by proteolytic cleavage of their circulating binding proteins during pregnancy. These changes in turn induce maternal metabolic adaptations to pregnancy and promote placental function and fetal growth, as does exogenous GH or IGF treatment in animal models of normal and compromised pregnancy. Finally, we explore alternative approaches to enhance maternal GH abundance during pregnancy to promote maternal adaptations, placental function and hence fetal growth.
Publisher: Wiley
Date: 21-03-2012
DOI: 10.1113/EXPPHYSIOL.2011.063560
Abstract: Plasticity of insulin secretion is essential to maintain the action of insulin during insulin resistance and to prevent diabetes. Investigation of the plasticity of insulin secretion and its regulation is challenging, and the objective of this study was to develop a novel large-animal-based model. The effect of chronic moderate hyperglycaemia on the plasticity of insulin secretion, β-cell mass and function was determined in sheep. Adolescent sheep (120 days old) were infused with 25% glucose for 16 days to increase blood glucose by 50% (n = 10), and control animals (n = 9) were infused with saline. Glucose- and arginine-stimulated insulin secretion, insulin sensitivity and glucose effectiveness were measured in vivo before and during treatment (days 10-14), and β-cell mass was measured at the end of treatment. Hyperglycaemia increased blood glucose (+53%) and plasma insulin (+403% each P < 0.003) and did not alter whole-body insulin sensitivity. Hyperglycaemia increased glucose-stimulated insulin secretion (particularly second phase five-fold) and arginine-stimulated insulin secretion (particularly first phase four-fold). Hyperglycaemia reduced β-cell mass (∼50%, P = 0.038) and increased glucose- and arginine-stimulated insulin secretion relative to β-cell mass five-fold (P = 0.060) and 20-fold (P = 0.007), respectively. Chronic hyperglycaemia therefore induces marked adaptation and upregulation of glucose- and arginine-stimulated insulin secretion by enhancing β-cell function rather than increasing β-cell mass in the sheep, consistent with long-term adaptations seen in humans. This marked plasticity of insulin secretion in response to moderate hyperglycaemia provides a novel model for the investigation of factors affecting its capacity and underlying determinants.
Publisher: Bioscientifica
Date: 06-1998
Abstract: Cucumber green mottle mosaic virus (CGMMV) infection causes acidification and rot of watermelon flesh, resulting in serious economic losses. It is widely reported the interaction relationship between boron and reactive oxygen species (ROS) in regulating normal growth and disease resistance in plants. Our previous results demonstrated that exogenous boron could improve watermelon resistance to CGMMV infection. However, the roles of ROS-related genes regulated by boron in resistance to CGMMV infection are unclear. Here, we demonstrated that CGMMV symptoms were alleviated, and viral accumulations were decreased by boron application in
Publisher: American Physiological Society
Date: 03-2009
DOI: 10.1152/AJPENDO.90497.2008
Abstract: Intrafetal insulin-like growth factor (IGF)-I promotes cardiac hypertrophy in the late-gestation fetal sheep whether these effects are sustained is unknown. IGF-I was infused for 4 days at 80 μg/h from 121 to 125 days of gestation, and its effects at 128 days, 3 days after the infusion stopped, were determined by comparison with untreated fetal sheep. After IGF-I treatment, fetal weights were similar to those in control fetuses but kidney weights were bigger ( P 0.05), as were spleen weights of male fetuses ( P 0.05). Cardiac myocytes were larger in female than male fetal sheep ( P 0.001). IGF-I increased male ( P 0.001) but not female myocyte volumes. IGF-I did not alter the proportions of uni- or binucleated right or left ventricular myocytes. Female fetal sheep had a greater proportion of binucleated cardiac myocytes than males ( P 0.05). IGF-I-treated fetuses had a slightly greater proportion of right ventricular nuclei in cell cycle phase G 2 /M and a reduced proportion of G 0 /G 1 phase nuclei ( P 0.1). Therefore, evidence for IGF-I-stimulated cardiac cell hyperplasia in fetal sheep in late gestation was limited. In conclusion, the greater sizes and larger proportion of binucleated cardiac myocytes in female fetal sheep suggest that myocyte maturation may occur earlier in females than in males. This may explain in part the male sex-specific responsiveness of cardiac hypertrophy to IGF-I in late gestation. If IGF-I-stimulated cardiomyocyte growth is accompanied by maturation of contractile function, IGF-I may be a potential therapeutic agent for maintaining cardiac output in preterm males.
Publisher: Public Library of Science (PLoS)
Date: 12-02-2013
Publisher: Cambridge University Press (CUP)
Date: 15-05-2017
DOI: 10.1017/S2040174417000381
Abstract: Low birth weight is associated with increased risk of cardiovascular disease in adulthood. Intrauterine growth restriction (IUGR) hearts have fewer CMs in early postnatal life, which may impair postnatal cardiovascular function and hence, explain increased disease risk, but whether the cardiomyocyte deficit persists to adult life is unknown. We therefore studied the effects of experimentally induced placental restriction (PR) on cardiac outcomes in young adult sheep. Heart size, cardiomyocyte number, nuclearity and size were measured in control ( n =5) and PR ( n =5) male sheep at 1 year of age. PR lambs were 36% lighter at birth ( P =0.007), had 38% faster neonatal relative growth rates ( P =0.001) and had 21% lighter heart weights relative to body weight as adults ( P =0.024) than control lambs. Cardiomyocyte number, nuclearity and size in the left ventricle did not differ between control and PR adults hearts of both groups contained cardiomyocytes (CM) with between one and four nuclei. Overall, cardiomyocyte number in the adult left ventricle correlated positively with birth weight but not with adult weight. This study is the first to demonstrate that intrauterine growth directly influences the complement of CM in the adult heart. Cardiomyocyte size was not correlated with cardiomyocyte number or birth weight. Our results suggest that body weight at birth affects lifelong cardiac functional reserve. We hypothesise that decreased cardiomyocyte number of low birth weight in iduals may impair their capacity to adapt to additional challenges such as obesity and ageing.
Publisher: The Endocrine Society
Date: 03-2007
DOI: 10.1210/EN.2006-0653
Abstract: Most children who are short or light at birth due to intrauterine growth restriction (IUGR) exhibit accelerated growth in infancy, termed “catch-up” growth, which together with IUGR, predicts increased risk of type 2 diabetes and obesity later in life. Placental restriction (PR) in sheep reduces size at birth, and also causes catch-up growth and increased adiposity at 6 wk of age. The physiological mechanisms responsible for catch-up growth after IUGR and its links to these adverse sequelae are unknown. Because insulin is a major anabolic hormone of infancy and its actions are commonly perturbed in these related disorders, we hypothesized that restriction of fetal growth would alter insulin secretion and sensitivity in the juvenile sheep at 1 month, which would be related to their altered growth and adiposity. We show that PR impairs glucose-stimulated insulin production, but not fasting insulin abundance or production in the young sheep. However, PR increases insulin sensitivity of circulating free fatty acids (FFAs), and insulin disposition indices for glucose and FFAs. Catch-up growth is predicted by the insulin disposition indices for amino acids and FFAs, and adiposity by that for FFAs. This suggests that catch-up growth and early-onset visceral obesity after IUGR may have a common underlying cause, that of increased insulin action due primarily to enhanced insulin sensitivity, which could account in part for their links to adverse metabolic and related outcomes in later life.
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.PLACENTA.2019.06.380
Abstract: Maternal asthma increases the risk of adverse pregnancy outcomes and may affect fetal growth and placental function by differential effects on the expression of glucocorticoid receptor (GR) isoforms, leading to altered glucocorticoid signalling. Our aim was to examine the effect of maternal asthma on placental GR profiles using a pregnant sheep model of asthma. Nine known GR isoforms were detected. There was a significant increase in the expression of placental GR isoforms that are known to have low trans-activational activity in other species including GR A, GR P and GRγ which may result in a pro-inflammatory environment in the presence of allergic asthma.
Publisher: American Physiological Society
Date: 05-2014
DOI: 10.1152/AJPENDO.00456.2013
Abstract: In iduals born after intrauterine growth restriction (IUGR) are at an increased risk of developing diabetes in their adult life. IUGR impairs β-cell function and reduces β-cell mass, thereby diminishing insulin secretion. IUGR also induces insulin resistance, with impaired insulin signaling in muscle in adult humans who were small for gestational age (SGA) and in rodent models of IUGR. There is epidemiological evidence in humans that exercise in adults can reduce the risk of metabolic disease following IUGR. However, it is not clear whether adult IUGR in iduals benefit to the same extent from exercise as do normal-birth-weight in iduals, as our rat studies suggest less of a benefit in those born IUGR. Importantly, however, there is some evidence from studies in rats that exercise in early life might be able to reverse or reprogram the long-term metabolic effects of IUGR. Studies are needed to address gaps in current knowledge, including determining the mechanisms involved in the reprogramming effects of early exercise in rats, whether exercise early in life or in adulthood has similar beneficial metabolic effects in larger animal models in which insulin resistance develops after IUGR. Human studies are also needed to determine whether exercise training improves insulin secretion and insulin sensitivity to the same extent in IUGR adults as in control populations. Such investigations will have implications for customizing the recommended level and timing of exercise to improve metabolic health after IUGR.
Publisher: Springer Science and Business Media LLC
Date: 25-05-2018
DOI: 10.1038/S41581-018-0022-6
Abstract: Cancer is the second most common cause of mortality and morbidity in kidney transplant recipients after cardiovascular disease. Kidney transplant recipients have at least a twofold higher risk of developing or dying from cancer than the general population. The increased risk of de novo and recurrent cancer in transplant recipients is multifactorial and attributed to oncogenic viruses, immunosuppression and altered T cell immunity. Transplant candidates and potential donors should be screened for cancer as part of the assessment process. For potential recipients with a prior history of cancer, waiting periods of 2-5 years after remission - largely depending on the cancer type and stage of initial cancer diagnosis - are recommended. Post-transplantation cancer screening needs to be tailored to the in idual patient, considering the cancer risk of the in idual, comorbidities, overall prognosis and the screening preferences of the patient. In kidney transplant recipients diagnosed with cancer, treatment includes conventional approaches, such as radiotherapy and chemotherapy, together with consideration of altering immunosuppression. As the benefits of transplantation compared with dialysis in potential transplant candidates with a history of cancer have not been assessed, current clinical practice relies on evidence from observational studies and registry analyses.
Publisher: The Endocrine Society
Date: 20-03-2012
DOI: 10.1210/EN.2011-1955
Abstract: Poor growth before birth is associated with impaired insulin sensitivity later in life, increasing the risk of type 2 diabetes. The tissue sites at which insulin resistance first develops after intrauterine growth restriction (IUGR), and its molecular basis, are unclear. We have therefore characterized the effects of placental restriction (PR), a major cause of IUGR, on whole-body insulin sensitivity and expression of molecular determinants of insulin signaling and glucose uptake in skeletal muscle and liver of young lambs. Whole-body insulin sensitivity was measured at 30 d by hyperinsulinaemic euglycaemic cl and expression of insulin signaling genes (receptors, pathways, and targets) at 43 d in muscle and liver of control (n = 15) and PR (n = 13) lambs. PR reduced size at birth and increased postnatal growth, fasting plasma glucose (+15%, P = 0.004), and insulin (+115%, P = 0.009). PR reduced whole-body insulin sensitivity (−43%, P & 0.001) and skeletal muscle expression of INSR (−36%), IRS1 (−28%), AKT2 (−44%), GLUT4 (−88%), GSK3α (−35%), and GYS1 (−31%) overall (each P & 0.05) and decreased AMPKγ3 expression in females (P = 0.030). PR did not alter hepatic expression of insulin signaling and related genes but increased GLUT2 expression (P = 0.047) in males. Whole-body insulin sensitivity correlated positively with skeletal muscle expression of IRS1, AKT2, HK, AMPKγ2, and AMPKγ3 in PR lambs only (each P & 0.05) but not with hepatic gene expression in control or PR lambs. Onset of insulin resistance after PR and IUGR is accompanied by, and can be accounted for by, reduced expression of insulin signaling and metabolic genes in skeletal muscle but not liver.
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1111/AJT.16898
Abstract: Deceased donor kidneys are a scarce community resource therefore, the principles underpinning organ allocation should reflect societal values. This study aimed to elicit community and healthcare professional preferences for principles guiding the allocation of kidneys from deceased donors and compare how these differed across the populations. A best-worst scaling survey including 29 principles in a balanced incomplete block design was conducted among a representative s le of the general community (n = 1237) and healthcare professionals working in transplantation (n = 206). Sequential best-worst multinomial logistic regression was used to derive scaled preference scores (PS) (range 0-100). Thematic analysis of free text responses was performed. Five of the six most valued principles among members of the community related to equity, including priority for the longest waiting (PS 100), difficult to transplant (PS 94.5) and sickest (PS 93.9), and equitable access for men and women (PS 94.0), whereas the top four principles for healthcare professional focused on maximizing utility (PS 89.9-100). Latent class analysis identified unmeasured class membership among community members. There are discordant views between community members and healthcare professionals. These should be considered in the design, evaluation, and implementation of deceased donor kidney allocation protocols.
Publisher: Springer Science and Business Media LLC
Date: 06-2010
Publisher: Cambridge University Press (CUP)
Date: 06-04-2017
DOI: 10.1017/S2040174417000137
Abstract: Most in iduals whose growth was restricted before birth undergo accelerated or catch-up neonatal growth. This is an independent risk factor for later metabolic disease, but the underlying mechanisms are poorly understood. This study aimed to test the hypothesis that natural and experimentally induced in utero growth restriction increase neonatal appetite and milk intake. Control (CON) and placentally restricted (PR) ewes carrying multiple fetuses delivered naturally at term. Outcomes were compared between CON ( n =14) and PR ( n =12) progeny and within twin lamb pairs. Lamb milk intake and feeding behaviour and ewe milk composition were determined using a modified weigh-suckle-weigh procedure on days 15 and 23. PR lambs tended to have lower birth weights than CON (−15%, P =0.052). Neonatal growth rates were similar in CON and PR, whilst heavier twins grew faster in absolute but not fractional terms than their co-twins. At day 23, milk protein content was higher in PR than CON ewes ( P =0.038). At day 15, PR lambs had fewer suckling bouts than CON lambs and in females light twins had more suckling attempts than their heavier co-twins. Birth weight differences between twins positively predicted differences in milk intakes. Lactational constraint and natural prenatal growth restriction in twins may explain the similar milk intakes in CON and PR. Within twin comparisons support the hypothesis that prenatal constraint increases lamb appetite, although this did not increase milk intake. We suggest that future mechanistic studies of catch-up growth be performed in singletons and be powered to assess effects in each sex.
Publisher: Japanese Society of Animal Reproduction
Date: 2010
DOI: 10.1262/JRD.10-060T
Abstract: Litter size and progeny birth weights are lower in gilts than in sows. Somatotropin (ST) is an important regulator of ovulation, fetal growth and survival. We therefore investigated effects of pST treatment of gilts for two to four weeks before mating on ovulation rate, behavioural estrus, fetal growth and survival, litter size and birth weights. In Experiment One, gilts were injected with 0, 30, 60 or 90 µg pST/kg/day for 14 days commencing 7 days after first estrus. Reproductive tracts were collected and corpora lutea and follicle numbers counted 5.5 days after second estrus. Ovulation rate (P=0.031) and number of medium-sized follicles (P=0.059) correlated positively with pST dose. In Experiment Two, gilts were injected with 0, 12.5, 25 or 50 µg pST/kg/day for 21 days from first estrus, and mated at second estrus. Numbers of corpora lutea, follicles and fetuses were counted at day 31 of pregnancy. Numbers of medium follicles and ovary weights were positively related to pST dose. In Experiment Three, 31 week old (1(st) replicate) or 27 week old (2(nd) replicate) gilts were injected daily with 0 or 12.5 µg pST/kg/day until mating 25.9 ± 0.6 days later, and delivered at term. Pre-mating pST increased total litter size in younger gilts in the 2(nd) replicate only (P<0.05). In conclusion, injecting gilts with pST before mating does not consistently alter ovulation rate, increases the number of medium follicles available for recruitment at the second mating after treatment and increases subsequent litter size in younger gilts.
Publisher: American Physiological Society
Date: 02-2018
DOI: 10.1152/AJPREGU.00248.2017
Abstract: The in utero environment is inherently rhythmic, with the fetus subjected to circadian changes in temperature, substrates, and various maternal hormones. Meanwhile, the fetus is developing an endogenous circadian timing system, preparing for life in an external environment where light, food availability, and other environmental factors change predictably and repeatedly every 24 h. In humans, there are many situations that can disrupt circadian rhythms, including shift work, international travel, insomnias, and circadian rhythm disorders (e.g., advanced/delayed sleep phase disorder), with a growing consensus that this chronodisruption can have deleterious consequences for an in idual’s health and well-being. However, the impact of chronodisruption during pregnancy on the health of both the mother and fetus is not well understood. In this review, we outline circadian timing system ontogeny in mammals and examine emerging research from animal models demonstrating long-term negative implications for progeny health following maternal chronodisruption during pregnancy.
Publisher: American Physiological Society
Date: 02-2007
DOI: 10.1152/AJPENDO.00269.2006
Abstract: Maternal ethanol intake during pregnancy impairs fetal growth, but mechanisms are not clearly defined. Reduced IGF abundance or bioavailability in the fetus and/or mother may contribute to this growth restriction. We hypothesized that an episode of acute ethanol exposure, mimicking binge drinking would restrict fetal growth and perturb the maternal and fetal IGF axes. Pregnant sheep were infused intravenously with saline or ethanol (1 g/kg maternal wt) over 1 h, on days 116, 117, and 118 of gestation (start of 1st infusion = time 0, term is 147 days). Maternal and fetal plasma IGF and IGF-binding protein (IGFBP) concentrations were measured before and after each infusion. Compared with controls, ethanol exposure reduced fetal weight at day 120 by 19%, transiently reduced maternal plasma IGF-I (−35%) at 30 h, and decreased fetal plasma IGF-II (−28%) from 24 to 54 h after the first infusion. Ethanol exposure did not alter maternal or fetal plasma concentrations of IGFBP-2 and IGFBP-3, measured by Western ligand blotting. We conclude that suppression of maternal and fetal IGF abundance may contribute to fetal growth restriction induced by acute or binge ethanol exposure.
Publisher: American Physiological Society
Date: 07-2008
DOI: 10.1152/AJPENDO.00047.2008
Abstract: Exposure to synthetic glucocorticoids in utero markedly improves survival after preterm birth, but repeated exposures impair fetal and postnatal growth and are associated with evidence of insulin resistance in later life. The insulin-like growth factor (IGF) axis is an important regulator of growth and metabolism before and after birth. We have therefore investigated the effects of repeated maternal betamethasone injections on plasma IGF-I, IGF-II, and IGF-binding proteins (IGFBP) in fetal and postnatal progeny in the sheep. Pregnant sheep carrying male fetuses were injected with saline or betamethasone at 104, 111, and 118 days of gestation (dG, term ∼150 dG). Plasma s les were collected postmortem from fetuses before (75, 84, 101 dG) or after one (109 dG), two (116 dG), or three (121–122, 132–133, 145–147 dG) doses of saline or betamethasone and from progeny at 42 and 84 days of age. Fetal weight was reduced after two or more maternal betamethasone injections, and this effect persisted to term. Repeated betamethasone exposures reduced plasma IGF-I and total IGFBP in fetuses at 133 dG and progeny at 84 days, and reduced plasma IGFBP-3 at 84 days. Fetal plasma IGF-II tended to increase transiently at 109 dG following the first betamethasone injection. Fetal, placental, and/or postnatal weights correlated positively with concomitant plasma IGF-I, IGF-II, and total IGFBP. We conclude that repeated exposure to synthetic glucocorticoids in utero programs the IGF axis before and after birth, which may contribute to the adverse effects of betamethasone exposure on growth and metabolism.
Publisher: Wiley
Date: 18-07-2018
DOI: 10.1113/JP276679
Publisher: Bioscientifica
Date: 03-08-2009
DOI: 10.1677/JOE-09-0131
Abstract: Fetal growth is restricted in primiparous pigs (gilts) compared with dams who have had previous pregnancies (sows), as in other species. In gilts, daily maternal porcine GH (pGH) injections from day 25 to 50 of pregnancy (term ∼115 day) increase fetal growth and progeny muscularity, and responses in sows are unknown. Whether feeding the β 2 -adrenergic agonist ractopamine during this period increases progeny growth rates in either parity and fetal responses in gilts, have not been investigated. We hypothesised that fetal and placental growth and fetal muscle development would be increased more by maternal pGH and/or ractopamine during early–mid pregnancy in gilts than sows, since fetal growth is restricted in gilts causing lower birth weights. Large White×Landrace gilts and sows were injected daily with water (controls) or pGH (∼15 μg/kg per day), or were fed 20 ppm ractopamine, between day 25 and 50 of pregnancy. Maternal pGH increased litter average fetal weight (11%, P =0.007) and length (3%, P =0.022), but not placental weight, at day 50 of pregnancy, irrespective of parity, and had the greatest effects in the heaviest fetuses of each litter. Maternal ractopamine increased average fetal weight (9%, P =0.018), but not length. Muscle fiber diameter was increased by pGH in heavy littermates and by ractopamine in median littermates. Similar fetal growth responses to pGH and ractopamine in gilts and sows suggest that these hormones increase fetal nutrient availability similarly in both parities. We therefore predict that sustained pGH treatment will increase progeny birth weight, postnatal growth and survival, in both sows and gilts.
Publisher: CRC Press
Date: 20-12-2005
DOI: 10.1201/B14625-11
Publisher: Canadian Science Publishing
Date: 06-2007
DOI: 10.1139/Y07-047
Abstract: We imposed a sustained reduction in glucose supply to late-gestation fetal sheep to see whether the reduction in glucose and insulin levels affected renal growth, renin expression and synthesis, and renal function. Maternal glucose concentrations were lowered to 1.7–1.9 mmol/L for 12–13 days by i.v. insulin infusion (n = 9, 121 days gestation, term = 150 days). Control ewes (n = 7) received vehicle. Maternal and fetal glucose concentrations were 40% and 31% lower than in controls (p 0.001), respectively. Fetal plasma insulin levels fell 36% ± 7% by day 7 (p 0.05) IGF-I levels were unchanged. Arterial PO 2 and pH increased and PCO 2 fell (p 0.05). Renal function was largely unaffected. Longitudinal growth was 28% slower and spleen weights were 36% smaller (p 0.05) body and kidney weights were not affected. Renal renin levels and renin, angiotensinogen, and angiotensin receptor mRNA levels were similar to those of controls. Plasma renin levels increased from 2.1 ± 0.6 to 7.6 ± 2.8 ng angiotensin I·mL –1 ·h –1 (p = 0.01). Thus reductions in fetal glucose and insulin levels in late gestation that were sufficient to retard skeletal growth had no effect on kidney growth or function or the renal renin–angiotensin system, possibly because IGF-I levels were not reduced. There was, however, increased activity of the circulating renin–angiotensin system similar to that seen during insulin-induced hypoglycaemia.
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.PHYSBEH.2014.11.037
Abstract: Brain development and function are susceptible to perturbation by environmental factors. Sheep are increasingly being used as a neurodevelopmental model due to timing similarities with humans, but effects of age, experience and sex on cognition are not well characterised in this species. We therefore studied memory and reversal learning in sheep using a modified Y-maze at two ages: naive 18 weeks old (18N: 23 male, 17 female), experienced 40 week old sheep that had previously been tested at 18 weeks (40E: 22 male, 17 female), and naive 40 weeks old (40N: 4 male, 10 female). Younger naive animals (18N) required more trials and time to solve the first reversal task (task R1) than 40E (P=0.007 and P<0.001 respectively). Experience also improved outcomes, with 40N sheep requiring more time to solve tasks L (P=0.034) and R1 (P=0.002) than 40E. Increasing age (40N cf. 18N) decreased bleat frequency in tasks R1, M2 and R2 (each P<0.05). In 40N females, outcomes also differed by exit method in task R1, with those that exited via an indirect route taking less time to pass tasks R1 (P=0.009) and R2 (P=0.015) than those that used a direct route. Age plus experience improved learning outcomes, demonstrating knowledge retention for 22 weeks in this species, whilst age alone affected mostly behavioral responses. These results provide comparison data, and can be utilised to improve experimental design, for studies of neurodevelopment in the sheep.
Publisher: CSIRO Publishing
Date: 1999
DOI: 10.1071/A98131
Abstract: We report the effects of spray-topping annual grass pasture with glyphosate (180 g a.i./ha as Roundup CT, at the seed head emergence stage) on the nutritive value of herbage and on subsequent performance of grazing sheep. Eight 1-ha plots, consisting of 4 sprayed and 4 unsprayed (control) plots, were set-stocked with Merino wethers (18 months old, 12 sheep/ha) from 8 days after anthesis in the control plots (late spring) until 165 days after anthesis (mid-autumn). In 4 periods (15–20, 36–41, 71–76, and 99–104 days after anthesis Periods 1–4, respectively) sheep were dosed with synthetic alkanes and herbage and faecal s les were taken, in order to estimate diet composition (in terms of plant parts), faecal output, herbage intake, and the digestibility of the whole diet. As described in our earlier papers, spray-topping reduced the yield of pasture dry matter, but also slowed the loss of water-soluble carbohydrate (WSC) and digestibility during pasture senescence. The present paper shows that as a result, sheep grazing sprayed herbage in Periods 1 and 2 consumed significantly more organic matter (OM) and digestible OM (DOM) than sheep grazing the control pasture. Their diet contained a higher proportion of stem with a higher WSC concentration than that of the sheep grazing the control plots. The proportions of different plant parts (leaf blade+sheath, stem, seed head) in the diet of both the plot sheep and oesophageally fistulated (OF) sheep, which grazed treatments for short periods, differed significantly between treatments in all periods. However, the compositions of the diets selected by plot and OF sheep were similar. These results confirmed diet preferences measured using housed sheep and demonstrate the usefulness of alkane-based procedures for quantifying diet composition and intake in grazing animals. As a result of their higher intake of DOM, sheep grazing sprayed herbage had a significantly higher liveweight gain over the first 2 periods (40 g/day). In Period 3, sheep grazing sprayed herbage consumed more OM than sheep grazing control herbage. However, DOM intakes from sprayed or control plots were not significantly different in either Period 3 or Period 4, and were lower than in Periods 1 and 2. Sheep grazing both treatments lost liveweight at a similar rate over this time. Wool growth in sheep grazing sprayed herbage was improved by 10% during the experimental period wool strength was also improved significantly. The implications for the management of sheep grazing spray-topped pastures over summer are discussed.
Publisher: CSIRO Publishing
Date: 1999
DOI: 10.1071/A98130
Abstract: Previous papers in this series have demonstrated that, when annual pastures were sprayed at seed head emergence with low rates of the herbicide glyphosate, the nutritive value of the sprayed herbage was improved. Housed sheep preferred sprayed herbage to unsprayed herbage and, within sprayed herbage, appeared to have a preference for stem material. The housed sheep ate more of the sprayed material and their weight gains were improved. If such responses occurred in grazing animals, they could result in substantial improvements in animal liveweights or wool production. The present paper describes the alkane-based procedures used to investigate diet selection and herbage intake in grazing animals, with the emphasis placed on methodological and statistical issues. The alkane concentrations in the plant fractions (leaf, leaf sheath, stem, seed head) of sprayed and unsprayed herbage are reported. Similarly, the alkane concentrations in extrusa s les collected by oesophageally fistulated sheep given access to the grazed areas, and in the faeces of sheep grazing the areas, are reported. Patterns of alkane concentrations in extrusa and faeces were similar and indicated that, in the short term, oesophageally fistulated animals consumed a diet of similar composition to that selected by the animals resident on the plots. Using these data for alkane concentrations, multivariate statistical analyses are presented which provide an objective basis for selecting the alkanes to be used in the estimation of diet selection. The results of the first of 4 grazing periods are presented, as an ex le of the application of the alkane-based procedures for estimating herbage intake and, in particular, diet composition. Use of these techniques indicated that, when given access to sprayed senescent pasture, sheep consumed more digestible dry matter and selected more of it from the stem fraction than was the case with unsprayed herbage. These results are similar to those found with housed animals and demonstrate that patterns of herbage and faecal alkane concentrations can be used to estimate diet composition of grazing animals in terms of the plant parts on offer
Publisher: American Physiological Society
Date: 06-2007
DOI: 10.1152/AJPENDO.00706.2006
Abstract: Prenatal and early postnatal life experiences, reflected by size at birth and postnatal catch-up growth, contribute to the risk of developing the metabolic syndrome in adulthood, but their relative importance is unclear. Therefore, we determined the effects of restricted placental and fetal growth on components of the metabolic syndrome in young adult sheep and the relationships of the latter to size at birth and early postnatal growth. Fasting plasma metabolites, glucose tolerance (by intravenous glucose tolerance test, IVGTT), insulin secretion and sensitivity, and resting blood pressure were measured in 22 control and 20 placentally restricted (PR) 1-yr-old sheep. In male sheep, PR increased the initial rise in glucose during an IVGTT and reduced diastolic blood pressure, and small size at birth independently predicted reduced adult size, glucose tolerance, and fasting plasma insulin and insulin disposition of glucose metabolism but increased insulin disposition of circulating FFAs. Also in males, high fractional growth rates in early postnatal life independently predicted impaired early glucose clearance during an IVGTT. In female animals, PR increased insulin sensitivity of glucose metabolism and reduced fasting plasma FFAs, and thinness at birth predicted increased adult size, fasting blood glucose, and pulse pressure. In conclusion, PR and small size at birth are associated with more components of the metabolic syndrome in adult male than in adult female sheep, with few independent effects of early postnatal growth. These sex differences in the onset and extent of adverse metabolic consequences after prenatal restraint in the sheep are consistent with observations in humans.
Publisher: Elsevier BV
Date: 09-2010
DOI: 10.1016/J.ANIREPROSCI.2010.05.017
Abstract: Fetal and postnatal growth are mediated by insulin-like growth factors (IGFs) and their binding proteins (IGFBPs). Maternal nutrient intake during gestation can program the postnatal IGF-axis. This may have significant economic implications for beef cattle production. We investigated the effect of high (H=240%) and low (L=70%) levels of recommended daily crude protein (CP) intake for heifers during the first and second trimesters of gestation in a two-by-two factorial design on progeny (n=68) plasma IGF-I, IGF-II, total IGFBP (tIGFBP), postnatal growth and carcass traits. Calves were heavier at birth following high CP diets during the second trimester (P=0.03) and this persisted to 29d. Plasma IGF-I concentrations of males were greater for HL compared to LL (P 0.04) from 29 to 657d, and for LH compared to LL from 29 until 379d (P=0.02). Exposure to low CP diets during the first trimester resulted in heavier males from 191d onwards (P=0.04) but a tendency for lighter females from 552d onwards (P=0.07) that had lighter carcass weights (P=0.04). Longissimus dorsi cross-sectional area of all carcasses was greater following exposure to low CP diets during the second trimester (P=0.04). Heifer nutrient intake during the first and second trimesters causes persistent and sex-specific programming of progeny plasma IGF-I, postnatal liveweight and carcass weight. Refining heifer nutritional programs during early gestation may optimize production objectives in progeny.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 12-2019
DOI: 10.1200/JGO.18.00191
Abstract: The objectives of this study were to report the oncologic outcomes and the treatment-related toxicities after reirradiation (re-RT) for recurrent nasopharyngeal carcinoma (rNPC) at our institution and to apply a recently published prognostic model for survival in rNPC in our cohort. Thirty-two patients with rNPC treated at the authors' institution with re-RT were retrospectively reviewed. Treatment modalities for re-RT were intensity-modulated radiotherapy (n = 14), three-dimensional conformal radiotherapy (n = 9), single-fraction stereotactic radiosurgery (n = 6), fractionated stereotactic radiotherapy (n = 2), and high dose rate intracavitary brachytherapy (n = 1). Twenty-seven patients received re-RT with curative intent, whereas five patients were treated palliatively. Median follow-up time was 15.5 months (range, 1 to 123 months) for the entire cohort and 20 months (range, 3 to 123 months) for patients treated with curative intent. For the entire cohort, median locoregional recurrence-free survival (LRRFS) was 14 months, with actuarial 1- and 2-year LRRFS estimates of 67.5% and 44.0%, respectively. Median overall survival (OS) time was 38 months, with actuarial 1- and 2-year estimates of 74.2% and 57.2%, respectively. For patients treated with curative intent, median LRRFS was not reached. Actuarial 1- and 2-year LRRFS estimates were 68.2% and 54.5%, respectively. Median OS time after curative intent re-RT was 42 months, with actuarial 1- and 2-year estimates of 75.4% and 63.8%, respectively. One- and 2-year OS estimates based on risk stratification were 68.6% for high risk compared with 80.8% for low risk and 34.3% for high risk compared with 70.7% for low risk, respectively ( P = .223). Three patients (9.4%) developed symptomatic temporal lobe necrosis. There was no reported grade 5 treatment-related toxicity. Results of the study suggest that re-RT is an effective and safe salvage treatment strategy for rNPC. Re-RT to a maximum equivalent dose in 2-Gy fractions of 60 Gy may yield good LRRFS and translate to prolonged OS.
Publisher: American Physiological Society
Date: 06-2004
DOI: 10.1152/AJPENDO.00340.2003
Abstract: Glucose tolerance declines with maturation and aging in several species, but the time of onset and extent of changes in insulin sensitivity and insulin secretion and their contribution to changes in glucose tolerance are unclear. We therefore determined the effect of maturation on glucose tolerance, insulin secretion, and insulin sensitivity in a longitudinal study of male and female sheep from preweaning to adulthood, and whether these measures were related across age. Glucose tolerance was assessed by intravenous glucose tolerance test (IVGTT, 0.25 g glucose/kg), insulin secretion as the integrated insulin concentration during IVGTT, and insulin sensitivity by hyperinsulinemic-euglycemic cl (2 mU insulin·kg −1 ·min −1 ). Glucose tolerance, relative insulin secretion, and insulin sensitivity each decreased with age ( P 0.001). The disposition index, the product of insulin sensitivity, and various measures of insulin secretion during fasting or IVGTT also decreased with age ( P 0.001). Glucose tolerance in young adult sheep was independently predicted by insulin sensitivity ( P = 0.012) and by insulin secretion relative to integrated glucose during IVGTT ( P = 0.005). Relative insulin secretion before weaning was correlated positively with that in the adult ( P = 0.023), whereas glucose tolerance, insulin sensitivity, and disposition indexes in the adult did not correlate with those at earlier ages. We conclude that glucose tolerance declines between the first month of life and early adulthood in the sheep, reflecting decreasing insulin sensitivity and absence of compensatory insulin secretion. Nevertheless, the capacity for insulin secretion in the adult reflects that early in life, suggesting that it is determined genetically or by persistent influences of the perinatal environment.
Publisher: American Physiological Society
Date: 04-2014
DOI: 10.1152/AJPREGU.00432.2013
Abstract: Prenatal and early childhood exposures are implicated as causes of allergy, but the effects of intrauterine growth restriction on immune function and allergy are poorly defined. We therefore evaluated effects of experimental restriction of fetal growth on immune function and allergic sensitization in adolescent sheep. Immune function (circulating total red and white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, and basophils, and the antibody response to Clostridial vaccination) and responses to house dust mite (HDM) allergen and ovalbumin (OVA) antigen sensitization (specific total Ig, IgG 1 , and IgE antibodies, and cutaneous hypersensitivity) were investigated in adolescent sheep from placentally restricted (PR, n = 23) and control ( n = 40) pregnancies. Increases in circulating HDM-specific IgE ( P = 0.007) and OVA-specific IgE ( P = 0.038) were greater in PR than control progeny. PR did not alter total Ig, IgG 1 , or IgM responses to either antigen. PR increased OVA-specific but not HDM-specific IgA responses in females only ( P = 0.023). Multiple birth increased Ig responses to OVA in a sex-specific manner. PR decreased the proportion of positive cutaneous hypersensitivity responders to OVA at 24 h ( P = 0.030) but had no effect on cutaneous responses to HDM. Acute wheal responses to intradermal histamine correlated positively with birth weight in singletons ( P = 0.023). Intrauterine growth restriction may suppress inflammatory responses in skin downstream of IgE induction, without impairment in antibody responses to a nonpolysaccharide vaccine. Discord between cutaneous and IgE responses following sensitization suggests new mechanisms for prenatal allergy programming.
Publisher: American Physiological Society
Date: 02-2007
DOI: 10.1152/AJPREGU.00430.2006
Abstract: Intrauterine growth restriction (IUGR) is associated with accelerated growth after birth. Together, IUGR and accelerated growth after birth predict reduced lean tissue mass and increased obesity in later life. Although placental insufficiency is a major cause of IUGR, whether it alters growth and adiposity in early postnatal life is not known. We hypothesized that placental restriction (PR) in the sheep would reduce size at birth and increase postnatal growth rate, fat mass, and feeding activity in the young lamb. PR reduced survival rate and size at birth, with soft tissues reduced to a greater extent than skeletal tissues and relative sparing of head width ( P 0.05 for all). PR did not alter absolute growth rates (i.e., the slope of the line of best fit for age vs. parameter size from birth to 45 days of age) but increased neonatal fractional growth rates (absolute growth rate relative to size at birth) for body weight (+24%), tibia (+15%) and metatarsal (+18%) lengths, hindlimb (+23%) and abdominal (+19%) circumferences, and fractional growth rates for current weight ( P 0.05) weekly throughout the first 45 days of life. PR and small size at birth reduced in idual skeletal muscle weights and increased visceral adiposity in absolute and relative terms. PR also altered feeding activity, which increased with decreasing size at birth and was predictive of increased postnatal growth and adiposity. In conclusion, PR reduced size at birth and induced catch-up growth postnatally, normalizing weight and length but increasing adiposity in early postnatal life. Increased feeding activity may contribute to these alterations in growth and body composition following prenatal restraint and, if they persist, may lead to adverse metabolic and cardiovascular outcomes in later life.
Publisher: American Physiological Society
Date: 10-2017
DOI: 10.1152/AJPENDO.00033.2017
Abstract: Restricted growth before birth (IUGR) increases adult risk of Type 2 diabetes by impairing insulin sensitivity and secretion. Altered fetal one-carbon metabolism is implicated in developmental programming of adult health and disease by IUGR. Therefore, we evaluated effects of maternal dietary supplementation with methyl donors and cofactors (MMDS), designed to increase fetal supply, on insulin action in the spontaneously IUGR twin lamb. In vivo glucose-stimulated insulin secretion and insulin sensitivity were measured at
Publisher: The Endocrine Society
Date: 05-06-2008
DOI: 10.1210/EN.2008-0233
Abstract: Poor growth before birth increases the risk of non-insulin-dependent diabetes mellitus (NIDDM) and impairs insulin secretion relative to sensitivity. We investigated the effects of intrauterine growth restriction in sheep on insulin secretion, β-cell mass, and function from before birth to young adulthood and its molecular basis. Pancreas was collected from control and placentally restricted sheep as fetuses (d 143 gestation), lambs (aged 42 d), and young adults (aged 556 d), following independent measures of in vivo insulin secretion and sensitivity. β-Cells and islets were counted after immunohistochemical staining for insulin. In lambs, gene expression was measured by RT-PCR and expressed relative to 18S. β-Cell mass correlated positively with fetal weight but negatively with birth weight in adult males. Glucose-stimulated insulin disposition and β-cell function correlated negatively with fetal weight but positively with birth weight in adult males. Placental restriction increased pancreatic expression of IGF-II and IGF-I but decreased that of voltage-gated calcium channel, α1D subunit (CACNA1D) in lambs. In male lambs, pancreatic IGF-II and insulin receptor expression correlated strongly and positively with β-cell mass and CACNA1D expression with glucose-stimulated insulin disposition. Restricted growth before birth in the sheep does not impair insulin secretion, relative to sensitivity, before birth or in young offspring. IGF-II and insulin receptor are implicated as key molecular regulators of β-cell mass compensation, whereas impaired expression of the voltage-gated calcium channel may underlie impaired β-cell function after intrauterine growth restriction. With aging, the insulin secretory capacity of the β-cell is impaired in males, and their increases in β-cell mass are inadequate to maintain adequate insulin secretion relative to sensitivity.
Publisher: Wiley
Date: 06-04-2023
DOI: 10.1113/EP091040
Abstract: What is the central question of this study? Body mass and food intake change during the female ovarian cycle: does glucose transport by the small intestine also vary? What is the main finding and its importance? We have optimised Ussing chamber methodology to measure region‐specific active glucose transport in the small intestine of adult C57BL/6 mice. Our study provides the first evidence that jejunal active glucose transport changes during the oestrous cycle in mice, and is higher at pro‐oestrus than oestrus. These results demonstrate adaptation in active glucose uptake, concurrent with previously reported changes in food intake. Food intake changes across the ovarian cycle in rodents and humans, with a nadir during the pre‐ovulatory phase and a peak during the luteal phase. However, it is unknown whether the rate of intestinal glucose absorption also changes. We therefore mounted small intestinal sections from C57BL/6 female mice (8–9 weeks old) in Ussing chambers and measured active ex vivo glucose transport via the change in short‐circuit current (∆ I sc ) induced by glucose. Tissue viability was confirmed by a positive ∆ I sc response to 100 µM carbachol following each experiment. Active glucose transport, assessed after addition of 5, 10, 25 or 45 mM d ‐glucose to the mucosal chamber, was highest at 45 mM glucose in the distal jejunum compared to duodenum and ileum ( P 0.01). Incubation with the sodium–glucose cotransporter 1 (SGLT1) inhibitor phlorizin reduced active glucose transport in a dose‐dependent manner in all regions ( P 0.01). Active glucose uptake induced by addition of 45 mM glucose to the mucosal chamber in the absence or presence of phlorizin was assessed in jejunum at each oestrous cycle stage ( n = 9–10 mice per stage). Overall, active glucose uptake was lower at oestrus compared to pro‐oestrus ( P = 0.025). This study establishes an ex vivo method to measure region‐specific glucose transport in the mouse small intestine. Our results provide the first direct evidence that SGLT1‐mediated glucose transport in the jejunum changes across the ovarian cycle. The mechanisms underlying these adaptations in nutrient absorption remain to be elucidated.
Publisher: Oxford University Press (OUP)
Date: 04-2010
Abstract: Piglet neonatal survival and postnatal growth and efficiency are positively related to birth weight. In gilts, daily maternal porcine ST (pST) injections from d 25 to 100 (term approximately 115 d), but not d 25 to 50, of pregnancy increase progeny birth weight. Daily maternal pST injections from d 25 to 50 increase fetal weight at d 50 in gilts and sows. We therefore hypothesized that daily pST injections from d 25 to 100, but not d 25 to 50, of pregnancy would increase birth weight similarly in both parities. Landrace x Large White gilts and sows were uninjected (controls) or were injected daily with pST (gilts: 2.5 mg/d sows: 4.0 mg/d, each approximately 15 microg of pST/kg per day) from d 25 to 50 or 100 of pregnancy. Litter size and BW were recorded at birth, midlactation, and weaning. Dams were followed through the subsequent mating and pregnancy. Maternal pST injections from d 25 to 100, but not d 25 to 50, increased mean piglet birth weight by 11.6% in sows (P <or= 0.001) and by 5.6% in gilts (P = 0.008). Both pST treatments decreased litter size by approximately 0.6 live-born piglets (each P 0.1) the weaning-remating interval, conception rate, or subsequent litter size. Greater pST-induced birth weight increases in sows than in gilts may mean that underlying metabolic or placental mechanisms for pST action are constrained by maternal competition for nutrients in rapidly growing gilts.
Publisher: American Physiological Society
Date: 04-2019
DOI: 10.1152/AJPREGU.00341.2018
Abstract: Intrauterine growth restriction (IUGR) and subsequent neonatal catch-up growth are implicated in programming of insulin resistance later in life. Spontaneous IUGR in the guinea pig, due to natural variation in litter size, produces offspring with asymmetric IUGR and neonatal catch-up growth. We hypothesized that spontaneous IUGR and/or accelerated neonatal growth would impair insulin sensitivity in adult guinea pigs. Insulin sensitivity of glucose metabolism was determined by hyperinsulinemic-euglycemic cl (HEC) in 38 (21 male, 17 female) young adult guinea pigs from litters of two-to-four pups. A subset (10 male, 8 female) were infused with d-[3- 3 H]glucose before and during the HEC to determine rates of basal and insulin-stimulated glucose utilization, storage, glycolysis, and endogenous glucose production. n males, the insulin sensitivity of whole body glucose uptake ( r = 0.657, P = 0.002) and glucose utilization ( r = 0.884, P = 0.004) correlated positively and independently with birth weight, but not with neonatal fractional growth rate (FGR 10–28 ). In females, the insulin sensitivity of whole body and partitioned glucose metabolism was not related to birth weight, but that of endogenous glucose production correlated negatively and independently with FGR 10–28 ( r = −0.815, P = 0.025). Thus, perinatal growth programs insulin sensitivity of glucose metabolism in the young adult guinea pig and in a sex-specific manner impaired insulin sensitivity, including glucose utilization, occurs after IUGR in males and impaired hepatic insulin sensitivity after rapid neonatal growth in females.
Publisher: Bioscientifica
Date: 1997
Abstract: Factors contributing to sex differences in the somatotrophic axis were investigated in growing lambs. In the first experiment, circulating patterns of GH in venous blood, pituitary content of GH and GH mRNA, and median eminence (ME) contents of GH-releasing factor (GRF) and somatostatin (SRIF) were characterized in prepubertal ram and ewe lambs which were pair-fed to remove sex differences in feed intake. Mean and baseline plasma GH concentrations, GH pulse litude, and integrated plasma GH were greater in ram lambs than in ewe lambs, but GH interpulse interval did not differ between sexes. The pituitary GH content and ME contents of GRF and SRIF were greater in rams than in ewes, but steady-state levels of mRNA for GH in the pituitary gland did not differ between sexes. A second experiment investigated sex effects on the levels of SRIF in hypophysial portal blood, and found that these did not differ between sexes. We concluded that the presence of sexually dimorphic patterns of GH secretion in the growing lamb is independent of feed-intake differences between sexes. The lack of sex differences in circulating patterns of SRIF in portal plasma implies that there may be a difference in GRF secretion which may produce sexually dimorphic patterns of GH secretion in lambs. Journal of Endocrinology (1997) 152, 19–27
Publisher: Oxford University Press (OUP)
Date: 17-07-2009
Abstract: The influence of supplemental protein during gestation on maternal hormones and fetal growth was determined in composite beef heifers. At AI, 118 heifers were stratified by BW within each composite genotype (BeefX = 1/2 Senepol, 1/4 Brahman, 1/8 Charolais, 1/8 Red Angus and CBX = 1/2 Senepol, 1/4 Brahman, 1/4 Charolais) into 4 treatment groups: high high (HH = 1.4 kg CP/d for first and second trimesters of gestation), high low (HL = 1.4 kg of CP/d for first trimester and 0.4 kg of CP/d for second trimester), low high (lowH = 0.4 kg CP/d for first trimester and 1.4 kg of CP/d and for second trimester), or low low (LL = 0.4 kg CP/d for first and second trimesters). Maternal plasma IGF-I and -II, total IGFBP, and leptin concentrations were determined at 14 d before AI and at d 28, 82, 179, and 271 post-AI (mean gestation length 286 d), and leptin concentrations were also determined at calving. Increased dietary protein increased maternal plasma IGF-I (P < 0.001 on d 28, 82, and 179), IGF-II (P = 0.01 on d 82 P = 0.04 on d 271), and total IGFBP (P = 0.002 on d 82 P = 0.005 on d 179 P = 0.03 on d 271). Maternal plasma IGF-I at d 271 was negatively associated with calf crown-rump length at birth (P = 0.003). BeefX had greater birth weight calves (P = 0.01), greater IGF-II (P < 0.001), increased ratios of IGF-I:total IGFBP (P = 0.008) and IGF-II:total IGFBP (P < 0.001), and reduced total IGFBP compared with CBX (P = 0.02). Increased dietary protein during second trimester increased maternal plasma leptin at calving (P = 0.005). Maternal plasma leptin near term was positively associated with heifer BCS (P = 0.02) and with calf birth weight (P = 0.04), and at calving was positively associated with heifer age at AI (P = 0.02). These findings suggest that maternal dietary protein, age, and genotype influence plasma concentrations of metabolic hormones and fetal growth in Bos indicus-influenced heifers.
Publisher: Elsevier BV
Date: 09-2007
Publisher: Bioscientifica
Date: 04-2002
Abstract: Poor prenatal growth is associated with limited evidence of GH deficiency in adult humans, which may contribute to their increased risk of cardiovascular and metabolic disease. We therefore examined the effects of placental restriction of fetal growth (PR) on size at birth, neonatal fractional growth rate (FGR) and the circulating GH profile in adolescent and young adult sheep of both sexes. Moderate or severe PR decreased birth size and increased neonatal FGR of weight, crown-rump length and abdominal circumference. In adolescent males, mean and baseline GH concentrations correlated negatively and independently with birth weight and FGR of weight, and mean GH concentrations correlated negatively with current weight. In young adult males, mean GH concentrations correlated negatively and independently with birth shoulder height and FGR of shoulder height whilst, in young adult females, these correlations were positive. This suggests that restricted fetal growth and reduced neonatal growth rate in sheep are followed by elevated circulating GH in adolescent and adult males, but GH deficiency or increased GH clearance in adult females.
Publisher: Cambridge University Press (CUP)
Date: 08-2003
DOI: 10.1079/BJN2003893
Abstract: Maternal nutrition and growth hormone (GH) treatment during early- to mid-pregnancy can each alter the subsequent growth and differentiation of muscle in progeny. We have investigated the effects of varying maternal nutrition and maternal treatment with porcine (p) GH during the second quarter of pregnancy in gilts on semitendinosus muscle cross-sectional area and fibre composition of progeny, and relationships between maternal and progeny measures and progeny muscularity. Fifty-three Large White×Landrace gilts, pregnant to Large White×Duroc boars, were fed either 2·2 kg (about 35 % ad libitum intake) or 3·0 kg commercial ration (13·5 MJ digestible energy, 150 g crude protein (N×6·25)/kg DM)/d and injected with 0, 4 or 8 mg pGH/d from day 25 to 50 of pregnancy, then all were fed 2·2 kg/d for the remainder of pregnancy. The higher maternal feed allowance from day 25 to 50 of pregnancy increased the densities of total and secondary fibres and the secondary:primary fibre ratio in semitendinosus muscles of their female progeny at 61 d of age postnatally. The densities of secondary and total muscle fibres in semitendinosus muscles of progeny were predicted by maternal weight before treatment and maternal plasma insulin-like growth factor-II during treatment. Maternal pGH treatment from day 25 to day 50 of pregnancy did not alter fibre densities, but increased the cross-sectional area of the semitendinosus muscle this may be partially explained by increased maternal plasma glucose. Thus, maternal nutrition and pGH treatment during the second quarter of pregnancy in pigs independently alter muscle characteristics in progeny.
Publisher: Wiley
Date: 03-07-2019
DOI: 10.1113/JP277952
Publisher: Elsevier BV
Date: 09-2007
Publisher: Oxford University Press (OUP)
Date: 1999
Abstract: Previous studies have reported conflicting data on gender differences in plasma IGF-I in postnatal pigs. There is also debate over the role of IGF-II in regulation of postnatal growth. We have, therefore, determined the concentrations of plasma IGF-I, IGF-II, and IGF-binding protein-3 (IGFBP-3) in boars, barrows, and gilts and related these to postnatal growth characteristics. Plasma concentrations of IGF-I were higher in boars than in gilts or barrows from 13 wk. of age, and plasma IGF-II levels were generally higher in barrows than in boars or gilts. Plasma IGFBP-3 levels were higher in boars than in gilts or barrows at most ages. Between 15 and 23 wk. of age, IGF-I and IGFBP-3, but not IGF-II, were positively associated with growth rate, voluntary feed intake, and gain:feed ratio. Plasma IGF-II, but not IGF-I or IGFBP-3, was positively associated with backfat depth during this period. These results support the hypothesis that circulating IGF-I and IGF-II are regulators of lean and adipose tissue growth, respectively.
Publisher: Oxford University Press (OUP)
Date: 05-2012
Abstract: Birth weight positively predicts postnatal growth and performance in pigs and can be increased by sustained maternal porcine ST (pST) treatment from d 25 to 100 of pregnancy (term ∼115 d). The objective of this study was to test whether a shorter period of maternal pST treatment in late pregnancy (d 75 to 100) could also increase birth and weaning weights of progeny under commercial conditions. Gilts (parity 0) and sows (parities 2 and 3) were not injected (controls) or injected daily with pST (gilts: 2.5 mg•d(-1), sows: 4.0 mg•d(-1), both ∼13 to 14 μg•kg(-1)•d(-1)) from d 75 to 100 of pregnancy. Litter size and BW were recorded at birth and weaning, and dams were followed through the subsequent mating and pregnancy. Maternal pST injections from d 75 to 100 increased litter average progeny weight at birth (+96 g, P = 0.034) and weaning (+430 g, P = 0.038) in sows, but had no effect on progeny weight in gilts (each P > 0.5). Maternal pST treatment did not affect numbers of live-born piglets and increased numbers of stillborn piglets in sows only (+0.4 pigs/litter, P = 0.034). Maternal pST treatment did not affect subsequent reproduction of dams. Together with our previous data, these results suggest that sustained increases in maternal pST are required to increase fetal and postnatal growth in gilt progeny, but that increasing maternal pST in late pregnancy may only be an effective strategy to increase fetal and possibly postnatal growth in sow progeny.
Publisher: Wiley
Date: 07-2018
DOI: 10.1111/NEP.13166
Publisher: Elsevier BV
Date: 04-2023
Publisher: Bioscientifica
Date: 06-2000
Abstract: Birth weight is a determinant of blood leptin concentrations in adults. Since nutrition during pregnancy can affect birth weight, the hypothesis that feed intake during pregnancy alters leptin expression in progeny was examined. Leptin mRNA was measured in subcutaneous adipose tissue and leptin protein was measuredin blood plasma from 59 day old female pigs whose mothers were fed at the same restricted rate except that half were permitted to consume 35% more feed during the second quarter of pregnancy. Leptin mRNA abundance in adipose tissue (P=0.015) and plasma leptin concentration (P=0.01) were higher in progeny from mothers provided with more feed. Body weight at birth was negatively correlated with the abundance of leptin mRNA in subcutaneous fat at 59 days of age (P=0.01). This study shows for the first time that maternal nutrition during pregnancy programs postnatal leptin expression in offspring.
Publisher: American Physiological Society
Date: 07-2017
DOI: 10.1152/AJPREGU.00028.2017
Abstract: The guinea pig is an alternate small animal model for the study of metabolism, including insulin sensitivity. However, only one study to date has reported the use of the hyperinsulinemic euglycemic cl in anesthetized animals in this species, and the dose response has not been reported. We therefore characterized the dose-response curve for whole body glucose uptake using recombinant human insulin in the adult guinea pig. Interspecies comparisons with published data showed species differences in maximal whole body responses (guinea pig ≈ human rat mouse) and the insulin concentrations at which half-maximal insulin responses occurred (guinea pig human ≈ rat mouse). In subsequent studies, we used concomitant d-[3- 3 H]glucose infusion to characterize insulin sensitivities of whole body glucose uptake, utilization, production, storage, and glycolysis in young adult guinea pigs at human insulin doses that produced approximately half-maximal (7.5 mU·min −1 ·kg −1 ) and near-maximal whole body responses (30 mU·min −1 ·kg −1 ). Although human insulin infusion increased rates of glucose utilization (up to 68%) and storage and, at high concentrations, increased rates of glycolysis in females, glucose production was only partially suppressed (~23%), even at high insulin doses. Fasting glucose, metabolic clearance of insulin, and rates of glucose utilization, storage, and production during insulin stimulation were higher in female than in male guinea pigs ( P 0.05), but insulin sensitivity of these and whole body glucose uptake did not differ between sexes. This study establishes a method for measuring partitioned glucose metabolism in chronically catheterized conscious guinea pigs, allowing studies of regulation of insulin sensitivity in this species.
Publisher: Elsevier BV
Date: 03-2010
Publisher: CSIRO Publishing
Date: 2017
Publisher: Oxford University Press (OUP)
Date: 11-2012
DOI: 10.1095/BIOLREPROD.112.100222
Abstract: Growth hormone (GH) is important in maternal adaptation to pregnancy, and maternal circulating GH concentrations are reduced in human growth-restricted pregnancies. In the pig, maternal GH treatment throughout early to mid pregnancy increases fetal growth, despite constraining effects of adolescent and primiparous pregnancy, high litter size, and restricted maternal nutrition. Because GH cannot cross the placenta and does not increase placental weight, we hypothesized that its effects on fetal growth might be via improved placental structure or function. We therefore investigated effects of maternal GH treatment in pigs on structural correlates of placental function and placental expression of nutrient transporters important to fetal growth. Multiparous (sows) and primiparous pregnant pigs (gilts) were treated with GH (~15 μg kg(-1) day(-1)) or vehicle from Days 25-50 of gestation (n = 7-8 per group, term ~115 days). Placentas were collected at Day 50 of gestation, and we measured structural correlates of function and expression of SLC2A1 (previously known as GLUT1) and SLC38A2 (previously known as SNAT2) nutrient transporters. Maternal GH treatment did not alter placental size or structure, increased protein expression of SLC2A1 in trophoblast (+35% P = 0.037) and on its basal membrane (+44% P = 0.011), and increased SLC38A2 protein expression in the basal (+44% P = 0.001) but not the apical cytoplasm of trophoblast. Our findings suggest that maternal GH treatment increases fetal growth, in part, by enhancing placental nutrient transporter protein expression and hence fetal nutrient supply as well as trophoblast proliferation and differentiation and may have the potential to ameliorate intrauterine growth restriction.
Publisher: Oxford University Press (OUP)
Date: 2022
DOI: 10.1093/GIGASCIENCE/GIAC071
Abstract: Survival analysis is a branch of statistics that deals with both the tracking of time and the survival status simultaneously as the dependent response. Current comparisons of survival model performance mostly center on clinical data with classic statistical survival models, with prediction accuracy often serving as the sole metric of model performance. Moreover, survival analysis approaches for censored omics data have not been thoroughly investigated. The common approach is to binarize the survival time and perform a classification analysis. Here, we develop a benchmarking design, SurvBenchmark, that evaluates a erse collection of survival models for both clinical and omics data sets. SurvBenchmark not only focuses on classical approaches such as the Cox model but also evaluates state-of-the-art machine learning survival models. All approaches were assessed using multiple performance metrics these include model predictability, stability, flexibility, and computational issues. Our systematic comparison design with 320 comparisons (20 methods over 16 data sets) shows that the performances of survival models vary in practice over real-world data sets and over the choice of the evaluation metric. In particular, we highlight that using multiple performance metrics is critical in providing a balanced assessment of various models. The results in our study will provide practical guidelines for translational scientists and clinicians, as well as define possible areas of investigation in both survival technique and benchmarking strategies.
Publisher: Wiley
Date: 12-11-2019
DOI: 10.1113/JP279051
Publisher: Bioscientifica
Date: 10-1997
Abstract: The ontogeny of the IGF endocrine system was investigated in 15 young lambs before and after weaning at 62 days of age. Before weaning, plasma IGF-I concentrations were higher in rams than ewes, and plasma concentrations of IGF-II and IGF-binding protein-3 (IGFBP-3) also tended to be higher in rams than in ewes. Feed intake of ewes and rams was restricted after weaning to remove sex differences in feed intake. Plasma concentrations of IGF-I and IGFBP-3 did not differ between rams and ewes at 100 days of age, but plasma IGF-II was higher in rams than in ewes at this time. Since circulating concentrations of GH were higher in rams than in ewes at 100 days of age, this implies that the restricted feed intake blocked the IGF-I and IGFBP-3 responses to GH. We conclude that sex differences in circulating IGF-I and IGFBP-3 concentrations in the growing lamb alter with age, and are not present when nutrition is restricted.
Publisher: CSIRO Publishing
Date: 2018
DOI: 10.1071/AN17014
Abstract: Animal producers are well aware that a low-birthweight animal is more likely to die in the first few days of life, and, if it survives, it is likely to perform poorly. We are now coming to appreciate that early life events can permanently change an animal’s developmental trajectory, also often referred to as developmental programming. This is an area of current interest in biomedicine, where the concept is known as the ‘developmental origins of health and disease’ (DOHaD). Current gaps in understanding include many of the underlying mechanisms, and whether and how we might intervene and restore the potential for healthy and productive development. This review introduces the biomedical perspective of developmental programming, reviews some of the evidence for long-term effects of early life exposures on welfare and productivity in animal production, with a focus on prenatal growth and maternal stress in pig production, and discusses options for intervening to improve long-term outcomes.
Publisher: CSIRO Publishing
Date: 2013
DOI: 10.1071/RD12329
Abstract: Inclusion of high levels of the high-fibre ingredient sugar-beet pulp in pre-mating diets has been shown to increase gonadotrophin concentrations and improve oocyte quality in nulliparous pigs (gilts). This study evaluated the effects of two alternative fibre sources on reproductive performance in gilts. Gilts received one of three diets from 3 weeks before puberty stimulation until Day 19 of the first oestrous cycle: control (39 g kg–1 fibre), bran (500 g kg–1 wheat bran, 65 g kg–1 fibre) or lupin (350 g kg–1 lupin, 118 g kg–1 crude fibre). Diet did not affect circulating LH concentrations or ovarian follicle size. However, a higher percentage of oocytes collected from lupin-supplemented gilts reached metaphase II in vitro compared with those collected from bran-fed or control gilts (89 ± 5% versus 72 ± 5% and 66 ± 5%, respectively P 0.05). Furthermore, in a second experiment, gilts fed the same lupin-based diet before mating had improved embryo survival (92 ± 5%) on Day 28 after mating compared with control gilts (76 ± 4% P 0.05). Therefore, feeding a high-fibre diet before mating can improve oocyte quality in gilts without changes in circulating LH, but this effect is dependent on the fibre source.
Publisher: Wiley
Date: 04-2019
DOI: 10.1113/JP277186
Publisher: Wiley
Date: 31-10-2007
Publisher: Cambridge University Press (CUP)
Date: 23-06-2016
DOI: 10.1017/S2040174416000295
Abstract: Intrauterine growth restriction (IUGR) and subsequent neonatal catch-up growth are implicated in the programming of increased appetite, adiposity and cardiometabolic diseases. Guinea pigs provide an alternate small animal model to rodents to investigate mechanisms underlying prenatal programming, being relatively precocial at birth, with smaller litter sizes and undergoing neonatal catch-up growth after IUGR. The current study, therefore, investigated postnatal consequences of spontaneous IUGR due to varying litter size in this species. Size at birth, neonatal, juvenile (post-weaning, 30–60 days) and adolescent (60–90 days) growth, juvenile and adolescent food intake, and body composition of young adults (120 days) were measured in 158 male and female guinea pigs from litter sizes of one to five pups. Compared with singleton pups, birth weight of pups from litters of five was reduced by 38%. Other birth size measures were reduced to lesser degrees with head dimensions being relatively conserved. Pups from larger litters had faster fractional neonatal growth and faster absolute and fractional juvenile growth rates ( P .005 for all). Relationships of post-weaning growth, feed intakes and adult body composition with size at birth and neonatal growth rate were sex specific, with neonatal growth rates strongly and positively correlated with adiposity in males only. In conclusion, spontaneous IUGR due to large litter sizes in the guinea pig causes many of the programmed sequelae of IUGR reported in other species, including human. This may therefore be a useful model to investigate the mechanisms underpinning perinatal programming of hyperphagia, obesity and longer-term metabolic consequences.
Publisher: American Diabetes Association
Date: 12-06-2013
DOI: 10.2337/DC12-2132
Abstract: Factors associated with increasing maternal triglyceride concentrations in late pregnancy include gestational age, obesity, preecl sia, and altered glucose metabolism. In a subgroup of women in the Metformin in Gestational Diabetes (MiG) trial, maternal plasma triglycerides increased more between enrollment (30 weeks) and 36 weeks in those treated with metformin compared with insulin. The aim of this study was to explain this finding by examining factors potentially related to triglycerides in these women. Of the 733 women randomized to metformin or insulin in the MiG trial, 432 (219 metformin and 213 insulin) had fasting plasma triglycerides measured at enrollment and at 36 weeks. Factors associated with maternal triglycerides were assessed using general linear modeling. Mean plasma triglyceride concentrations were 2.43 (95% CI 2.35–2.51) mmol/L at enrollment. Triglycerides were higher at 36 weeks in women randomized to metformin (2.94 [2.80–3.08] mmol/L +23.13% [18.72–27.53%]) than insulin (2.65 [2.54–2.77] mmol/L, P = 0.002 +14.36% [10.91–17.82%], P = 0.002). At 36 weeks, triglycerides were associated with HbA1c (P = 0.03), ethnicity (P = 0.001), and treatment allocation (P = 0.005). In insulin-treated women, 36-week triglycerides were associated with 36-week HbA1c (P = 0.02), and in metformin-treated women, they were related to ethnicity. At 36 weeks, maternal triglycerides were related to glucose control in women treated with insulin and ethnicity in women treated with metformin. Whether there are ethnicity-related dietary changes or differences in metformin response that alter the relationship between glucose control and triglycerides requires further study.
Publisher: Impact Journals, LLC
Date: 02-2018
Publisher: American Physiological Society
Date: 15-09-2015
DOI: 10.1152/AJPENDO.00487.2014
Abstract: Intrauterine growth restriction (IUGR) increases the risk of adult type 2 diabetes (T2D) and obesity. Neonatal exendin-4 treatment can prevent diabetes in the IUGR rat, but whether this will be effective in a species where the pancreas is more mature at birth is unknown. Therefore, we evaluated the effects of neonatal exendin-4 administration after experimental restriction of placental and fetal growth on growth and adult metabolic outcomes in sheep. Body composition, glucose tolerance, and insulin secretion and sensitivity were assessed in singleton-born adult sheep from control (CON n = 6 females and 4 males) and placentally restricted pregnancies (PR n = 13 females and 7 males) and in sheep from PR pregnancies that were treated with exendin-4 as neonates (daily sc injections of 1 nmol/kg exendin-4 PR + exendin-4 n = 11 females and 7 males). Placental restriction reduced birth weight (by 29%) and impaired glucose tolerance in the adult but did not affect adult adiposity, insulin secretion, or insulin sensitivity. Neonatal exendin-4 suppressed growth during treatment, followed by delayed catchup growth and unchanged adult adiposity. Neonatal exendin-4 partially restored glucose tolerance in PR progeny but did not affect insulin secretion or sensitivity. Although the effects on glucose tolerance are promising, the lack of effects on adult body composition, insulin secretion, and insulin sensitivity suggest that the neonatal period may be too late to fully reprogram the metabolic consequences of IUGR in species that are more mature at birth than rodents.
Publisher: Wiley
Date: 28-02-2013
DOI: 10.1111/DOM.12080
Abstract: The aim of the study is to compare the effects of metformin and insulin treatment for gestational diabetes mellitus (GDM) on vitamin B12 and homocysteine (Hcy) status. Women with GDM, who met criteria for insulin treatment, were randomly assigned to metformin (n = 89) or insulin (n = 91) in the Adelaide cohort of the metformin in gestational diabetes (MiG) trial. Fasting serum total vitamin B12 (TB12), holotranscobalamin (HoloTC), a marker of functional B12 status and plasma Hcy concentrations were measured at 20-34 weeks (at randomization) and 36 weeks gestation, then at 6-8 weeks postpartum. Circulating TB12, HoloTC and Hcy were similar in both treatment groups at each time point. Women who were taking dietary folate supplements at randomization had higher serum TB12 and HoloTC at randomization than those not taking folate. Overall, serum TB12 fell more between randomization and 36 weeks gestation in the metformin group than in the insulin group (metformin: -19.7 ± 4.7 pmol/l, insulin: -6.4 ± 3.6 pmol/l, p = 0.004). The decrease in serum TB12 during treatment was greater with increasing treatment duration in metformin-treated (p < 0.001), but not in insulin-treated women. Total, but not bioavailable, vitamin B12 stores were depleted during pregnancy to a greater extent in metformin-treated than in insulin-treated women with GDM, but neither analyte differed between groups at any stage. This adds further evidence supporting metformin as a safe alternative treatment to insulin in GDM. Further investigation is needed to evaluate whether women treated with metformin for longer periods in pregnancy require additional B12 or other supplementation.
No related grants have been discovered for Kathryn Gatford.