Four days of simulated shift work reduces insulin sensitivity in humans.

AIM: The aim of this study was to investigate the effects of 4 consecutive simulated night shifts on glucose homeostasis, mitochondrial function and central and peripheral rhythmicities compared with a simulated day shift schedule. METHODS: Seventeen healthy adults (8M:9F) matched for sleep, physical activity and dietary/fat intake participated in this study (night shift work n = 9; day shift work n = 8). Glucose tolerance and insulin sensitivity before and after 4 nights of shift work were measured by an intravenous glucose tolerance test and a hyperinsulinaemic euglycaemic clamp respectively. Muscles biopsies were obtained to determine insulin signalling and mitochondrial function. Central and peripheral rhythmicities were assessed by measuring salivary melatonin and expression of circadian genes from hair samples respectively. RESULTS: Fasting plasma glucose increased (4.4 ± 0.1 vs. 4.6 ± 0.1 mmol L-1 ; P = .001) and insulin sensitivity decreased (25 ± 7%, P < .05) following the night shift, with no changes following the day shift. Night shift work had no effect on skeletal muscle protein expression (PGC1α, UCP3, TFAM and mitochondria Complex II-V) or insulin-stimulated pAkt Ser473, pTBC1D4Ser318 and pTBC1D4Thr642. Importantly, the metabolic changes after simulated night shifts occurred despite no changes in the timing of melatonin rhythmicity or hair follicle cell clock gene expression across the wake period (Per3, Per1, Nr1d1 and Nr1d2). CONCLUSION: Only 4 days of simulated night shift work in healthy adults is sufficient to reduce insulin sensitivity which would be expected to increase the risk of T2D.

Small size at birth predicts decreased cardiomyocyte number in the adult ovine heart.

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 individuals may impair their capacity to adapt to additional challenges such as obesity and ageing.

Betamethasone-exposed preterm birth does not impair insulin action in adult sheep.

Preterm birth is associated with increased risk of type 2 diabetes (T2D) in adulthood; however, the underlying mechanisms are poorly understood. We therefore investigated the effect of preterm birth at ~0.9 of term after antenatal maternal betamethasone on insulin sensitivity, secretion and key determinants in adulthood, in a clinically relevant animal model. Glucose tolerance and insulin secretion (intravenous glucose tolerance test) and whole-body insulin sensitivity (hyperinsulinaemic euglycaemic clamp) were measured and tissue collected in young adult sheep (14 months old) after epostane-induced preterm (9M, 7F) or term delivery (11M, 6F). Glucose tolerance and disposition, insulin secretion, ß-cell mass and insulin sensitivity did not differ between term and preterm sheep. Hepatic PRKAG2 expression was greater in preterm than in term males (P = 0.028), but did not differ between preterm and term females. In skeletal muscle, SLC2A4 (P = 0.019), PRKAA2 (P = 0.021) and PRKAG2 (P = 0.049) expression was greater in preterm than in term overall and in males, while INSR (P = 0.047) and AKT2 (P = 0.043) expression was greater in preterm than in term males only. Hepatic PRKAG2 expression correlated positively with whole-body insulin sensitivity in males only. Thus, preterm birth at 0.9 of term after betamethasone does not impair insulin sensitivity or secretion in adult sheep, and has sex-specific effects on gene expression of the insulin signalling pathway. Hence, the increased risk of T2D in preterm humans may be due to factors that initiate preterm delivery or in early neonatal exposures, rather than preterm birth per se.

Spontaneous intrauterine growth restriction due to increased litter size in the guinea pig programmes postnatal growth, appetite and adult body composition.

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<0.005 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.

The effect of antenatal lifestyle advice for women who are overweight or obese on secondary measures of neonatal body composition: the LIMIT randomised trial.

OBJECTIVE: To evaluate the effect of providing antenatal dietary and lifestyle advice on neonatal anthropometry, and to determine the inter-observer variability in obtaining anthropometric measurements. DESIGN: Randomised controlled trial. SETTING: Public maternity hospitals across metropolitan Adelaide, South Australia. POPULATION: Pregnant women with a singleton gestation between 10(+0) and 20(+0) weeks, and body mass index (BMI) ≥25 kg/m(2). METHODS: Women were randomised to either Lifestyle Advice (comprehensive dietary and lifestyle intervention over the course of pregnancy including dietary, exercise and behavioural strategies, delivered by a research dietician and research assistants) or continued Standard Care. Analyses were conducted using intention-to-treat principles. MAIN OUTCOME MEASURES: Secondary outcome measures for the trial included assessment of infant body composition using body circumference and skinfold thickness measurements (SFTM), percentage body fat, and bio-impedance analysis of fat-free mass. RESULTS: Anthropometric measurements were obtained from 970 neonates (488 Lifestyle Advice Group, and 482 Standard Care Group). In 394 of these neonates (215 Lifestyle Advice Group, and 179 Standard Care Group) bio-impedance analysis was also obtained. There were no statistically significant differences identified between those neonates born to women receiving Lifestyle Advice and those receiving Standard Care, in terms of body circumference measures, SFTM, percentage body fat, fat mass, or fat-free mass. The intra-class correlation coefficient for SFTM was moderate to excellent (0.55-0.88). CONCLUSIONS: Among neonates born to women who are overweight or obese, anthropometric measures of body composition were not modified by an antenatal dietary and lifestyle intervention.

Maternal body size prior to pregnancy, gestational diabetes and weight gain: associations with insulin resistance in children at 9-10 years.

AIMS: To investigate whether maternal body size pre-pregnancy, gestational diabetes and weight gain are independently associated with subsequent insulin resistance in children; and to examine the potential mediating role of child's body size in any associations. METHODS: At 9-10 years, 443 children took part in a follow-up of a prospective cohort. Of those, 163 children elected to provide a fasting blood sample and child insulin resistance was estimated by homeostasis model assessment. Generalized linear models with log link function and Gaussian family were used to assess associations with antenatal exposures. Potential confounders were considered as well as the role of the child's size. RESULTS: Prior to pregnancy, 23% of mothers were overweight and another 17% obese. All women were screened for gestational diabetes, with 6% diagnosed. On average, women gained an estimated 14 kg during pregnancy. Gestational diabetes was positively associated with child insulin resistance. In addition, maternal pre-pregnancy body mass index (BMI) was associated with child insulin resistance in a non-linear manner: a positive, progressive association was observed until BMI of 30 kg/m² was reached, but not thereafter. Estimated gestational weight gain was not associated with child insulin resistance. These findings were not accounted for by size of the child at birth or at 9-10 years. CONCLUSIONS: Maternal body size prior to pregnancy is positively associated with increases in child insulin resistance, at least until the 'obese' category is reached. This is independent of gestational diabetes and not mediated by body size of the child, suggesting genetic and/or developmental programming origins.

Circulating IGF1 and IGF2 and SNP genotypes in men and pregnant and non-pregnant women.

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<0.001) and plasma IGF1 and IGF2 concentrations were lower in pregnant women than in non-pregnant women or men (each P<0.001). 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 individuals 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.

Vitamin B12 and homocysteine status during pregnancy in the metformin in gestational diabetes trial: responses to maternal metformin compared with insulin treatment.

AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Diet-induced paternal obesity in the absence of diabetes diminishes the reproductive health of two subsequent generations of mice.

BACKGROUND: Obesity and related conditions, notably subfertility, are increasingly prevalent. Paternal influences are known to influence offspring health outcome, but the impact of paternal obesity and subfertility on the reproductive health of subsequent generations has been overlooked. METHODS: A high-fat diet (HFD) was used to induce obesity but not diabetes in male C57Bl6 mice, which were subsequently mated to normal-weight females. First-generation offspring were raised on a control diet and their gametes were investigated for signs of subfertility. Second-generation offspring were generated from both first generation sexes and their gametes were similarly assessed. RESULTS: We demonstrate a HFD-induced paternal initiation of subfertility in both male and female offspring of two generations of mice. Furthermore, we have shown that diminished reproductive and gamete functions are transmitted through the first generation paternal line to both sexes of the second generation and via the first generation maternal line to second-generation males. Our previous findings that founder male obesity alters the epigenome of sperm, could provide a basis for the developmental programming of subfertility in subsequent generations. CONCLUSIONS: This is the first observation of paternal transmission of diminished reproductive health to future generations and could have significant implications for the transgenerational amplification of subfertility observed worldwide in humans.

Maternal low-dose porcine somatotropin treatment in late gestation increases progeny weight at birth and weaning in sows but not in gilts.

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.

The neglected role of insulin-like growth factors in the maternal circulation regulating fetal growth.

Maternal insulin-like growth factors (IGFs) play a pivotal role in modulating fetal growth via their actions on both the mother and the placenta. Circulating IGFs influence maternal tissue growth and metabolism, thereby regulating nutrient availability for the growth of the conceptus. Maternal IGFs also regulate placental morphogenesis, substrate transport and hormone secretion, all of which influence fetal growth either via indirect effects on maternal substrate availability, or through direct effects on the placenta and its capacity to supply nutrients to the fetus. The extent to which IGFs influence the mother and/or placenta are dependent on the species and maternal factors, including age and nutrition. As altered fetal growth is associated with increased perinatal morbidity and mortality and a greater risk of developing degenerative diseases in adult life, understanding the role of maternal IGFs during pregnancy is essential in order to identify mechanisms underlying altered fetal growth and offspring programming.

Nutrient intake in the bovine during early and mid-gestation causes sex-specific changes in progeny plasma IGF-I, liveweight, height and carcass traits.

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<0.01) and HH (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.

Review: Placental programming of postnatal diabetes and impaired insulin action after IUGR.

Being born small due to poor growth before birth increases the risk of developing metabolic disease, including type 2 diabetes, in later life. Inadequate insulin secretion and decreasing insulin sensitivity contribute to this increased diabetes risk. Impaired placental growth, development and function are major causes of impaired fetal growth and development and therefore of IUGR. Restricted placental growth (PR) and function in non-human animals induces similar changes in insulin secretion and sensitivity as in human IUGR, making these valuable tools to investigate the underlying mechanisms and to test interventions to prevent or ameliorate the risk of disease after IUGR. Epigenetic changes induced by an adverse fetal environment are strongly implicated as causes of later impaired insulin action. These have been well-characterised in the PR rat, where impaired insulin secretion is linked to epigenetic changes at the Pdx-1 promotor and reduced expression of this transcription factor. Present research is particularly focussed on developing intervention strategies to prevent or reverse epigenetic changes, and normalise gene expression and insulin action after PR, in order to translate this to treatments to improve outcomes in human IUGR.

Cross-fostering and improved lactation ameliorates deficits in endocrine pancreatic morphology in growth-restricted adult male rat offspring.

Uteroplacental insufficiency and poor postnatal nutrition impair adult glucose tolerance and insulin secretion in male rat offspring, which can be partially ameliorated by improving postnatal nutrition. Uteroplacental insufficiency was induced in the WKY rat on day 18 of pregnancy (Restricted) compared to sham-operated Controls. Pups were then cross-fostered onto Control or Restricted mothers one day after birth resulting in: (Pup-on-Mother) Control-on-Control, Control-on-Restricted, Restricted-on-Control and Restricted-on-Restricted. Endocrine pancreatic morphology and markers of intrinsic ß-cell function and glucose homeostasis were assessed in male offspring at 6 months. Pancreatic and hepatic gene expression was quantified at postnatal day 7 and 6 months. Restricted pups were born 10-15% lighter than Controls and remained lighter at 6 months. Relative islet and ß-cell mass were 51-65% lower in Restricted-on-Restricted compared to Controls at 6 months. Non-fasting plasma C-reactive protein levels were also increased, suggestive of an inflammatory response. Overall, the average number of islets, small islets and proportion of ß-cells per islet correlated positively with birth weight. Intrinsic ß-cell function, estimated by insulin secretion relative to ß-cell mass, was unaffected by Restriction, suggesting that the in vivo functional deficit was attributable to reduced mass, not function. Importantly, these deficits were ameliorated when lactational nutrition was normalized in Restricted-on-Control offspring, who also showed increased pancreatic Igf1r, Pdx1 and Vegf mRNA expression at 7 days compared to Control-on-Control and Restricted-on-Restricted. This highlights lactation as a critical period for intervention following prenatal restraint, whereby deficits in endocrine pancreatic mass and associated impaired in vivo insulin secretion can be ameliorated.

Maternal responses to daily maternal porcine somatotropin injections during early-mid pregnancy or early-late pregnancy in sows and gilts.

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 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.

Dietary protein during gestation affects maternal insulin-like growth factor, insulin-like growth factor binding protein, leptin concentrations, and fetal growth in heifers.

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.

Effect of variable long-term maternal feed allowance on the development of the ovine placenta and fetus.

Maternal feed allowance during pregnancy can affect the development of the ovine placenta and fetus. The impact of variations in feed allowance prior to as well as throughout pregnancy has received less attention. Ewes were offered 0.6 (R), 1.2 (C) or 1.8 (AL) maintenance requirements from 89 days before conception until day 133 of pregnancy. Ewes were euthanised on days 50, 92 and 133 of pregnancy. Ewe live weight and body condition score, maternal and fetal metabolic and hormonal profiles, fetal body dimensions and organ weights, and the number, weight and morphology of placentomes were measured. Maternal live weight and condition score were lower in R compared to AL ewes at all stages of pregnancy (P<0.05). Plasma glucose and albumin concentrations of R ewes were significantly reduced (P<0.05) at mid and late gestation, respectively. Placental components were generally unresponsive to long term variations in maternal feed allowance. However, placental weight was significantly (P<0.05) correlated with fetal weight at days 50 (r=0.59) and 133 (r=0.69) of gestation. By late gestation growth-retarded singleton fetuses from R ewes were 19% lighter (P<0.05), with reduced abdominal (9%) and thoracic (10%) girths (P<0.05) but of similar crown-rump length compared with fetuses from AL ewes. These differences were associated with significantly reduced IGF-I concentrations in fetal plasma (P<0.05). In conclusion, maternal, placental and fetal adaptations to long established planes of variable maternal feed allowance were able to maintain fetal growth during early and mid-pregnancy while fetal growth restriction, associated with reduced fetal IGF-I levels, became apparent in late pregnancy.

Maternal insulin-like growth factor-II promotes placental functional development via the type 2 IGF receptor in the guinea pig.

In guinea pigs, maternal insulin-like growth factor (IGF) infusion in early-pregnancy enhances placental transport near-term, increasing fetal growth and survival. The effects of IGF-II, but not IGF-I, appear due to enhanced placental labyrinthine (exchange) development. To determine if the type-2 IGF receptor (IGF2R) mediates these distinct actions of exogenous IGF-II in the mother, we compared the impact of IGF-II with an IGF-II analogue, Leu(27)-IGF-II, which only binds the IGF2R. IGF-II, Leu(27)-IGF-II (1mg/kg per day.sc) or vehicle were infused from days 20-38 of pregnancy (term = 67 days) and placental structure and uptake and transfer of [(3)H]-methyl-D-glucose (MG) and [(14)C]-amino-isobutyric acid (AIB) and fetal growth and plasma metabolites, were measured on day 62. Both IGF-II and Leu(27)-IGF-II increased the volume of placental labyrinth, trophoblast and maternal blood space within the labyrinth and total surface area of trophoblast for exchange, compared to vehicle. Leu(27)-IGF-II also reduced the barrier to diffusion (trophoblast thickness) compared to vehicle and IGF-II. Both IGF-II and Leu(27)-IGF-II increased fetal plasma amino acid concentrations and placental transfer of MG to the fetus compared to vehicle, with Leu(27)-IGF-II also increasing AIB transport compared with vehicle and IGF-II. In addition, Leu(27)-IGF-II increased fetal weight compared to vehicle. In conclusion, maternal treatment with IGF-II or Leu(27)-IGF-II in early gestation, induce similar placental and fetal outcomes near term. This suggests that maternal IGF-II in early gestation acts in part via the IGF2R to persistently enhance placental functional development and nutrient delivery and promote fetal growth.

Distinct actions of insulin-like growth factors (IGFs) on placental development and fetal growth: lessons from mice and guinea pigs.

Placental insufficiency is thought to be a key factor in many cases of intrauterine growth restriction which complicates about 6% of pregnancies in western countries. Understanding the molecular control of placental and fetal growth is essential to identifying diagnostic and therapeutic targets to improve pregnancy success. Insulin-like growth factor (IGF)-I and IGF-II gene ablation or maternal food restriction reduce tissue and circulating IGF abundance in the fetus, placenta and mother and are associated with both placental and fetal growth restriction. Conversely, in vivo treatment of the pregnant guinea pig with IGF-I or IGF-II from early to mid pregnancy increases fetal weight and enhances placental transport near term. IGF-II, and an IGF2R specific analogue, enhanced placental structural differentiation, whereas IGF-I altered maternal body composition. These outcomes demonstrate endocrine roles within the mother for both IGFs, as well as autocrine/paracrine effects of IGF-II in enhancing placentation and pregnancy success. Therefore, factors that alter placental expression of IGF-II, or maternal circulating IGF-I or IGF-II in early pregnancy may affect placental exchange function late in gestation when the demands of the fetus escalate. IGF-II within the fetus may also signal its nutrient demands to the placenta to improve its function to suit. Therefore each IGF of endocrine and local origin has important, but distinct, roles in placental development and function.

Intrafetal insulin-like growth factor-I infusion stimulates adrenal growth but not steroidogenesis in the sheep fetus during late gestation.

We investigated the effects of an intrafetal infusion of IGF-I on adrenal growth and expression of the adrenal steroidogenic and catecholamine-synthetic enzyme mRNAs in the sheep fetus during late gestation. Fetal sheep were infused for 10 d with either IGF-I (26 microg/kg.h; n = 14) or saline (n = 10) between 120 and 130 d gestation, and adrenal glands were collected for morphological analysis and determination of the mRNA expression of steroidogenic and catecholamine-synthetic enzymes. Fetal body weight was not altered by IGF-I infusion; however, adrenal weight was significantly increased by 145% after IGF-I infusion. The density of cell nuclei within the fetal adrenal cortex (the zona glomerulosa and zona fasciculata), and within the adrenaline synthesizing zone of the adrenal medulla, was significantly less in the IGF-I-infused fetuses compared with the saline-infused group. Thus, based on cell-density measurements, there was a significant increase in cell size in the zona glomerulosa and zona fasciculata of the adrenal cortex and in the adrenaline-synthesizing zone of the adrenal medulla. There was no effect of IGF-I infusion on the adrenal mRNA expression of the steroidogenic or catecholamine-synthetic enzymes or on fetal plasma cortisol concentrations. In summary, infusion of IGF-I in late gestation resulted in a marked hypertrophy of the steroidogenic and adrenaline-containing cells of the fetal adrenal in the absence of changes in the mRNA levels of adrenal steroidogenic or catecholamine-synthetic enzymes or in fetal plasma cortisol concentrations. Thus, IGF-I infusion results in a dissociation of adrenal growth and function during late gestation.