Fetal Plasma Insulin Concentrations Research Articles

IGF-1 infusion increases growth in fetal sheep when euinsulinemia is maintained.

Insulin-like growth factor 1 (IGF-1) is a critical fetal anabolic hormone. IGF-1 infusion to the normally growing sheep fetus increases the weight of some organs but does not consistently increase body weight. However, IGF-1 infusion profoundly decreases fetal plasma insulin concentrations, which may limit fetal growth potential. In this study, normally growing late-gestation fetal sheep received an intravenous infusion of either: IGF-1 (IGF), IGF-1 with insulin and dextrose to maintain fetal euinsulinemia and euglycemia (IGF+INS), or vehicle control (CON) for 1 week. The fetus underwent a metabolic study immediately prior to infusion start and after 1 week of the infusion to measure uterine and umbilical uptake rates of nutrients and oxygen. IGF+INS fetuses were 23% heavier than CON (P = 0.0081) and had heavier heart, liver, and adrenal glands than IGF and CON (P < 0.01). By design, final fetal insulin concentrations in IGF were 62% and 65% lower than IGF+INS and CON, respectively. Final glucose concentrations were similar in all groups. IGF+INS had lower final oxygen content than IGF and CON (P < 0.0001) and lower final amino acid concentrations than CON (P = 0.0002). Final umbilical oxygen uptake was higher in IGF+INS compared to IGF and CON (P < 0.05). Final umbilical uptake of several essential amino acids was higher in IGF+INS compared to CON (P < 0.05). In summary, maintaining euinsulinemia and euglycemia during fetal IGF-1 infusion is necessary to maximally support body growth. We speculate that IGF-1 and insulin stimulate placental nutrient transport to support fetal growth.

Cardiac growth and metabolism of the fetal sheep are not vulnerable to a 10 day increase in fetal glucose and insulin concentrations during late gestation

AimsTo evaluate the effects of fetal glucose infusion in late gestation on the mRNA expression and protein abundance of molecules involved in the regulation of cardiac growth and metabolism. Main methodsEither saline or glucose was infused into fetal sheep from 130 to 140 days (d) gestation (term, 150 d). At 140 d gestation, left ventricle tissue samples were collected. Quantitative real-time RT-PCR and Western blot were used to determine the mRNA expression and protein abundance of key signalling molecules within the left ventricle of the fetal heart. Key findingsAlthough intra-fetal glucose infusion increased fetal plasma glucose and insulin concentrations, there was no change in the expression of molecules within the signalling pathways that regulate proliferation, hypertrophy, apoptosis or fibrosis in the fetal heart. Cardiac Solute carrier family 2 member 1 (SLC2A1) mRNA expression was decreased by glucose infusion. Glucose infusion increased cardiac mRNA expression of both Peroxisome proliferator activated receptor alpha (PPARA) and peroxisome proliferator activated receptor gamma (PPARG). However, there was no change in the mRNA expression of PPAR cofactors or molecules with PPAR response elements. Furthermore, glucose infusion did not impact the protein abundance of the 5 oxidative phosphorylation complexes of the electron transport chain. SignificanceDespite a 10-day doubling of fetal plasma glucose and insulin concentrations, the present study suggests that within the fetal left ventricle, the mRNA and protein expression of the signalling molecules involved in cardiac growth, development and metabolism are relatively unaffected.

Attenuated glucose-stimulated insulin secretion during an acute IGF-1 LR3 infusion into fetal sheep does not persist in isolated islets.

Insulin-like growth factor-1 (IGF-1) is a critical fetal growth hormone that has been proposed as a therapy for intrauterine growth restriction. We previously demonstrated that a 1-week IGF-1 LR3 infusion into fetal sheep reduces in vivo and in vitro insulin secretion suggesting an intrinsic islet defect. Our objective herein was to determine whether this intrinsic islet defect was related to chronicity of exposure. We therefore tested the effects of a 90-min IGF-1 LR3 infusion on fetal glucose-stimulated insulin secretion (GSIS) and insulin secretion from isolated fetal islets. We first infused late gestation fetal sheep (n = 10) with either IGF-1 LR3 (IGF-1) or vehicle control (CON) and measured basal insulin secretion and in vivo GSIS utilizing a hyperglycemic clamp. We then isolated fetal islets immediately following a 90-min IGF-1 or CON in vivo infusion and exposed them to glucose or potassium chloride to measure in vitro insulin secretion (IGF-1, n = 6; CON, n = 6). Fetal plasma insulin concentrations decreased with IGF-1 LR3 infusion (P < 0.05), and insulin concentrations during the hyperglycemic clamp were 66% lower with IGF-1 LR3 infusion compared to CON (P < 0.0001). Insulin secretion in isolated fetal islets was not different based on infusion at the time of islet collection. Therefore, we speculate that while acute IGF-1 LR3 infusion may directly suppress insulin secretion, the fetal β-cell in vitro retains the ability to recover GSIS. This may have important implications when considering the long-term effects of treatment modalities for fetal growth restriction.

Reduced glucose-stimulated insulin secretion following a 1-wk IGF-1 infusion in late gestation fetal sheep is due to an intrinsic islet defect.

Insulin and insulin-like growth factor-1 (IGF-1) are fetal hormones critical to establishing normal fetal growth. Experimentally elevated IGF-1 concentrations during late gestation increase fetal weight but lower fetal plasma insulin concentrations. We therefore hypothesized that infusion of an IGF-1 analog for 1 wk into late gestation fetal sheep would attenuate fetal glucose-stimulated insulin secretion (GSIS) and insulin secretion in islets isolated from these fetuses. Late gestation fetal sheep received infusions with IGF-1 LR3 (IGF-1, n = 8), an analog of IGF-1 with low affinity for the IGF binding proteins and high affinity for the IGF-1 receptor, or vehicle control (CON, n = 9). Fetal GSIS was measured with a hyperglycemic clamp (IGF-1, n = 8; CON, n = 7). Fetal islets were isolated, and insulin secretion was assayed in static incubations (IGF-1, n = 8; CON, n = 7). Plasma insulin and glucose concentrations in IGF-1 fetuses were lower compared with CON (P = 0.0135 and P = 0.0012, respectively). During the GSIS study, IGF-1 fetuses had lower insulin secretion compared with CON (P = 0.0453). In vitro, glucose-stimulated insulin secretion remained lower in islets isolated from IGF-1 fetuses (P = 0.0447). In summary, IGF-1 LR3 infusion for 1 wk into fetal sheep lowers insulin concentrations and reduces fetal GSIS. Impaired insulin secretion persists in isolated fetal islets indicating an intrinsic islet defect in insulin release when exposed to IGF-1 LR3 infusion for 1 wk. We speculate this alteration in the insulin/IGF-1 axis contributes to the long-term reduction in β-cell function in neonates born with elevated IGF-1 concentrations following pregnancies complicated by diabetes or other conditions associated with fetal overgrowth.NEW & NOTEWORTHY After a 1-wk infusion of IGF-1 LR3, late gestation fetal sheep had lower plasma insulin and glucose concentrations, reduced fetal glucose-stimulated insulin secretion, and decreased fractional insulin secretion from isolated fetal islets without differences in pancreatic insulin content.

Prolonged amino acid infusion into intrauterine growth-restricted fetal sheep increases leucine oxidation rates.

Overcoming impaired growth in an intrauterine growth-restricted (IUGR) fetus has potential to improve neonatal morbidity, long-term growth, and metabolic health outcomes. The extent to which fetal anabolic capacity persists as the IUGR condition progresses is not known. We subjected fetal sheep to chronic placental insufficiency and tested whether prolonged amino acid infusion would increase protein accretion in these IUGR fetuses. IUGR fetal sheep were infused for 10 days with either mixed amino acids providing ~2 g·kg-1·day-1 (IUGR-AA) or saline (IUGR-Sal) during late gestation. At the end of the infusion, fetal plasma leucine, isoleucine, lysine, methionine, and arginine concentrations were higher in the IUGR-AA than IUGR-Sal group ( P < 0.05). Fetal plasma glucose, oxygen, insulin, IGF-1, cortisol, and norepinephrine concentrations were similar between IUGR groups, but glucagon concentrations were fourfold higher in the IUGR-AA group ( P < 0.05). Net umbilical amino acid uptake rate did not differ between IUGR groups; thus the total amino acid delivery rate (net umbilical amino acid uptake + infusion rate) was higher in the IUGR-AA than IUGR-Sal group (30 ± 4 vs. 19 ± 1 μmol·kg-1·min-1, P < 0.05). Net umbilical glucose, lactate, and oxygen uptake rates were similar between IUGR groups. Fetal leucine oxidation rate, measured using a leucine tracer, was higher in the IUGR-AA than IUGR-Sal group (2.5 ± 0.3 vs. 1.7 ± 0.3 μmol·kg-1·min-1, P < 0.05). Fetal protein accretion rate was not statistically different between the IUGR groups (1.6 ± 0.4 and 0.8 ± 0.3 μmol·kg-1·min-1 in IUGR-AA and IUGR-Sal, respectively) due to variability in response to amino acids. Prolonged amino acid infusion into IUGR fetal sheep increased leucine oxidation rates with variable anabolic response.

Maternal exposure to diluted diesel engine exhaust alters placental function and induces intergenerational effects in rabbits.

BackgroundAirborne pollution is a rising concern in urban areas. Epidemiological studies in humans and animal experiments using rodent models indicate that gestational exposure to airborne pollution, in particular diesel engine exhaust (DE), reduces birth weight, but effects depend on exposure duration, gestational window and nanoparticle (NP) concentration. Our aim was to evaluate the effects of gestational exposure to diluted DE on feto-placental development in a rabbit model.Pregnant females were exposed to diluted (1 mg/m3), filtered DE (NP diameter ≈ 69 nm) or clean air (controls) for 2 h/day, 5 days/week by nose-only exposure (total exposure: 20 days in a 31-day gestation).ResultsDE exposure induced early signs of growth retardation at mid gestation with decreased head length (p = 0.04) and umbilical pulse (p = 0.018). Near term, fetal head length (p = 0.029) and plasma insulin and IGF1 concentrations (p = 0.05 and p = 0.019) were reduced. Placental function was also affected, with reduced placental efficiency (fetal/placental weight) (p = 0.049), decreased placental blood flow (p = 0.009) and fetal vessel volume (p = 0.002). Non-aggregated and “fingerprint” NP were observed at various locations, in maternal blood space, in trophoblastic cells and in the fetal blood, demonstrating transplacental transfer. Adult female offspring were bred with control males. Although fetoplacental biometry was not affected near term, second generation fetal metabolism was modified by grand-dam exposure with decreased plasma cholesterol (p = 0.008) and increased triglyceride concentrations (p = 0.015).ConclusionsRepeated daily gestational exposure to DE at levels close to urban pollution can affect feto-placental development in the first and second generation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12989-016-0151-7) contains supplementary material, which is available to authorized users.

Environmental rather than genetic fetal overgrowth: defining the difference and hints for diagnosis and management

Environmental rather than genetic fetal overgrowth: defining the difference and hints for diagnosis and management

Fetal insulin secretion in late gestation: does size matter?

Fetal insulin secretion in late gestation: does size matter?

Fetal and Amniotic Insulin-Like Growth Factor-I Supplements Improve Growth Rate in Intrauterine Growth Restriction Fetal Sheep

To date, there is no known prenatal treatment for intrauterine growth restriction (IUGR). IGF-I is an important regulator of fetal growth and circulating IGF-I concentrations are reduced in IUGR fetuses. We investigated whether any of three different methods of fetal IGF-I administration would reverse IUGR in sheep. Animals were randomized into five groups: control (n = 17), IUGR + saline (SAL, n = 17), IUGR + iv IGF-I (IGF-IV, n = 14), IUGR + intraamniotic IGF-I (IGF-AF, n = 14), or IUGR + intraamniotic IGF-I with nutrients (IGF-NUT, n = 16). Weekly IGF-I dose was 360 microg in each treatment group. IUGR was induced by placental embolization between 93 and 99 d and treatment was from 100-128 d gestation (term = 147 d). Embolization caused asymmetrical IUGR with reduced fetal growth rates and body and organ weights, but increased brain to liver weight ratio, at post mortem. Embolized fetuses were also hypoxemic and hypoglycemic and had reduced circulating IGF-I and insulin concentrations. IGF-AF and IGF-IV significantly increased fetal growth rates, but only IGF-AF significantly increased fetal liver weight, compared with saline-treated fetuses. Fetal weights and brain to liver weight ratios in all IGF-I-treated fetuses were intermediate between the control and SAL groups. Addition of nutrients reduced the effects of amniotic IGF-I treatment and increased fetal hemoglobin and lactate concentrations. Treatments did not change fetal plasma IGF-I and insulin concentrations. This is the first report of an intrauterine treatment significantly increasing fetal growth rate in established IUGR. Amniotic IGF-I administration may provide the basis for a clinically applicable prenatal treatment for the IUGR fetus.

Relationship between Maternal and Fetal Plasma Glucose and Insulin Concentrations during Graded Maternal Hyperglycemic States in Primates

Our goal was to conduct a controlled study using an established timed-pregnant baboon model to describe the maternal and fetal plasma glucose and insulin concentrations during graded increases in maternal circulating glucose levels. Timed-pregnant baboons were operated on during the second half of pregnancy, and after recovery from surgery, maternal glucose infusions were started. To determine changes in plasma glucose and insulin concentrations, maternal and fetal blood samples were obtained before glucose infusion and at 30-minute intervals to include 30 minutes postinfusion. Maternal plasma glucose concentrations ranged from 97 to 392 mg/dL and fetal plasma glucose concentrations from 78 to 278 mg/dL. Maternal plasma insulin concentrations ranged from 123 to 1384 U/mL, and the fetal plasma insulin concentrations from 76 to 260 U/mL. Significant correlations were noted between maternal plasma glucose and insulin concentrations (N = 10; R(2), 80%; P < 0.001), as well as maternal and fetal plasma glucose concentrations (N = 10; R(2), 97%; P < 0.001). Maternal-to-fetal glucose gradient ranged from 16 to 34% (mean, 23%) and did not correlate with maternal plasma glucose concentration. No correlation was found between fetal plasma glucose and insulin concentration. Maternal-to-fetal insulin gradient ranged from 31 to 87% (mean, 70.7%) and was significantly different from the glucose gradient ( P < 0.0001). Results from this study suggests that (1) there is a relatively steady transplacental glucose transfer during the second half of pregnancy at maternal plasma glucose concentrations ranging from 97 to 392 mg/dL; and (2) there is also a relative incapacity of the fetal pancreas, compared with the maternal pancreas, to respond to graded increases of hyperglycemia. Studies aimed at determining whether particular thresholds of maternal hyperglycemia at different gestational ages can lead to transitory hyperosmolar and polyuric fetal states could provide further insights into the mechanisms leading to idiopathic polyhydramnios.

Developmental Changes in Ovine Myocardial Glucose Transporters and Insulin Signaling Following Hyperthermia-Induced Intrauterine Fetal Growth Restriction

Developmental changes in ovine myocardial glucose transporters and insulin signaling following hyperthermia-induced intrauterine fetal growth restriction (IUGR) were the focus of our study. Our objective was to test the hypothesis that the fetal ovine myocardium adapts during an IUGR gestation by increasing glucose transporter protein expression, plasma membrane-bound glucose transporter protein concentrations, and insulin signal transduction protein concentrations. Growth measurements and whole heart tissue were obtained at 55 days gestational age (dGA), 90 dGA, and 135 dGA (term = 145 dGA) in fetuses from control (C) and hyperthermic (HT) pregnant sheep. Additionally, in 135 dGA animals, arterial blood was obtained and Doppler ultrasound was used to determine umbilical artery systolic (S) and diastolic (D) flow velocity waveform profiles to calculate pulsatility (S - D/mean) and resistance (S - D/S) indices. Myocardial Glut-1, Glut-4, insulin signal transduction proteins involved in Glut-4 translocation, and glycogen content were measured. Compared to age-matched controls, HT 90-dGA fetal body weights and HT 135-dGA fetal weights and gross heart weights were lower. Heart weights as a percent of body weights were similar between C and HT sheep at 135 dGA. HT 135-dGA animals had (i) lower fetal arterial plasma glucose and insulin concentrations, (ii) lower arterial blood oxygen content and higher plasma lactate concentrations, (iii) higher myocardial Glut-4 plasma membrane (PM) protein and insulin receptor beta protein (IRbeta ) concentrations, (iv) higher myocardial glycogen content, and (v) higher umbilical artery Doppler pulsatility and resistance indices. The HT ovine fetal myocardium adapts to reduced circulating glucose and insulin concentrations by increasing plasma membrane Glut-4 and IRbeta protein concentrations. The increased myocardial Glut-4 PM and IRbeta protein concentrations likely contribute to or increase the intracellular delivery of glucose and, together with the increased lactate concentrations, enhance glycogen synthesis, which allows for maintained myocardial growth commensurate with fetal body growth.

Effects of acute hyperinsulinemia on insulin signal transduction and glucose transporters in ovine fetal skeletal muscle

To test the effects of acute fetal hyperinsulinemia on the pattern and time course of insulin signaling in ovine fetal skeletal muscle, we measured selected signal transduction proteins in the mitogenic, protein synthetic, and metabolic pathways in the skeletal muscle of normally growing fetal sheep in utero. In experiment 1, 4-h hyperinsulinemic-euglycemic clamps were conducted in anesthetized twin fetuses to produce selective fetal hyperinsulinemia-euglycemia in one twin and euinsulinemia-euglycemia in the other. Serial skeletal muscle biopsies were taken from each fetus during the clamp and assayed by Western blot for selected insulin signal transduction proteins. Tyrosine phosphorylation of the insulin receptor, insulin receptor substrate-1, and the p85 subunit of phosphatidylinositol 3-kinase doubled at 30 min and gradually returned to control values by 240 min. Phosphorylation of extracellular signal-regulated kinase 1,2 was increased fivefold through 120 min of insulin infusion and decreased to control concentration by 240 min. Protein kinase B phosphorylation doubled at 30 min and remained elevated throughout the study. Phosphorylation of p70 S6K increased fourfold at 30, 60, and 120 min. In the second experiment, a separate group of nonanesthetized singleton fetuses was clamped to intermediate and high hyperinsulinemic-euglycemic conditions for 1 h. GLUT4 increased fourfold in the plasma membrane at 1 h, and hindlimb glucose uptake increased significantly at the higher insulin concentration. These data demonstrate that an acute increase in fetal plasma insulin concentration stimulates a unique pattern of insulin signal transduction proteins in intact skeletal muscle, thereby increasing pathways for mRNA translation, glucose transport, and cell growth.

Recovery in the fetal pancreatic islet following fetal administration of streptozotocin in the rat in vivo and in vitro

In our previous study, after direct administration of streptozotocin (STZ; 400 microg/g) to fetuses on day 19 of gestation, the B-cell volume in fetal pancreatic islets showed a marked decrease, but gradually recovered with electron microscopic confirmation of B-cell regeneration. However, STZ at this dose often caused fetal death. In this study, therefore, we determined whether B-cells are newly generated after treatment with STZ at a smaller dose in vivo and in vitro. For in vivo experiment, fetuses were administered STZ at 40 microg/g on day 19 of gestation. The B-cell volume in pancreatic islets decreased markedly 3 hr after the administration of STZ, but it began to increase after 6 hr. The fetal plasma insulin concentration decreased from 6 to 12 hr after the administration, but recovered after 48 hr. The cell division index in fetal pancreatic islets of the STZ-treated group began to be significantly larger after 6 hr. For in vitro experiment, fetal pancreases on day 18 of gestation were pretreated with 10 mM STZ for 6 hr and cultured for 98 hr. B-cells were completely destroyed with STZ treatment; however, as these pancreases were cultured in a medium free of STZ, B-cells began to appear and insulin secretion was detected after 48 hr. After 72 hr, the cell division index was significantly greater. These results suggest that the fetal pancreas treated with STZ has the ability to regenerate B-cells both in vivo and in vitro.

Factors Influencing Fetal Growth

After completing this article, readers should be able to: 1. Describe the roles of insulin-like growth factor on fetal growth and development. 2. Delineate components of “maternal constraint.” 3. Explain the role of the placenta in regulating fetal growth. 4. Describe the effects of fetal glucose, amino acid, and fat supply on fetal growth. The principal determinants of fetal growth are fetal genotype and in utero environment. Environmental factors include maternal and paternal genetics, maternal size, and the capacity of the placenta to provide nutrients to the fetus. These environmental factors interact with the intrinsic growth pattern of the fetus, yielding a particular rate and composition of fetal growth. Most of the variation in fetal growth in a population is due to variations in environmental factors, not the fetal genome, although a genetically abnormal fetus clearly might not grow as well as a normal fetus if affected genes include those that are important for growth. Many genes contribute to fetal growth and birthweight. Techniques in which specific genes can either be deleted (“knockouts”) or overexpressed have led to greater understanding of how some of these genes regulate fetal growth. Such studies have shown that both maternal and paternal influences are present during fetal development and are passed on to the developing fetus by spermatozoa or oogonia by a mechanism called imprinting. Although the maternal genetic composition exerts greater influence than fetal genotype in the overall regulation of fetal growth, both maternal and paternal genomes are important in fetal growth and development (1)(2). For example, gynogenetic zygotes (two maternal genome copies) lead to underdeveloped extraembryonic tissues but well-developed embryos. The more modest regulation offered by the paternal genotype is essential for trophoblast development. For example, zygote nuclear transfer experiments have shown that androgenetic zygotes (two paternal genome copies) develop extensive trophoblast tissues but …

Maturation of Glucose-Stimulated Insulin Secretion in Fetal Sheep

To determine the gestational maturation of fetal insulin response to glucose and arginine and the effects of sustained hyperglycemia on these processes, we measured insulin secretion in different groups of fetal sheep at 75, 100, 122, and 137 days of gestation (50, 67, 81, and 91% of term gestation, respectively). The basal glucose concentration decreased progressively from 1.36 ± 0.16 mM at 75 days to 1.00 ± 0.07 mM at 137 days (p < 0.05). The fetal plasma insulin concentration did not change (54 ± 11 pM at 75 days, 68 ± 8 pM at 137 days), but there was a significant increase in the increment in plasma insulin concentration in response to a hyperglycemic clamp over this same period (ΔI pM/ΔG mM) from 20 ± 3 at 75 days to 105 ± 8 at 137 days (p < 0.001). The ΔI (pM) in response to arginine also increased from 129 ± 17 pM at 75 days to 635 ± 103 pM at 137 days (p < 0.001). Sustained hyperglycemia from 90 to 100 days reduced the ΔI (pM)/ΔG (mM) to glucose (13 ± 2, p < 0.01) and the ΔI pM to arginine (369 ± 86, p < 0.05) to values less than those found in euglycemic animals (ΔI/ΔG = 58 ± 4 to glucose, ΔI = 525 ± 71 to arginine). Thus, glucose and arginine stimulate insulin secretion at midgestation at 20% of the rate near term, and there is a consistently positive developmental pattern of insulin secretion to these secretagogues over the second half of gestation. Furthermore, chronic, high, relatively constant hyperglycemia blunts insulin secretion to glucose and arginine close to midgestation, similar to the effect seen near term. Such developmental and adaptive capacities may account for an important part of the variability in fetal glucose metabolism observed in animal models and human cases of diabetes during pregnancy.

Translocation of Fetal Ovine Skeletal Muscle Glut 1 and Glut 4 in Response to Selective Hyperglycemia and Selective Hyperinsulinemia • 1494

Previous studies have defined separate and interactive effects of fetal plasma glucose (Gf) and insulin (If) concentrations on increasing fetal glucose utilization. To determine the role of glucose transporter proteins in enhancing net fetal tissue glucose uptake, we simultaneously measured fetal ovine glucose uptake and assessed the subcellular distribution of skeletal muscle Glut 1 (basal) and Glut 4 (insulin responsive) after “clamp” periods of 30-60 minutes, 2.5 hours, and 24 hours of selective hyperglycemia (↑G) or selective hyperinsulinemia(↑I). During the 2.5 hour period of ↑G, Gf increased from 20 to 39 mg/dl (p<0.01) without a change in If. In 2.5 hours of ↑I, If increased from 16 to 73 uU/ml (p<0.01) without a change in Gf. Under both study conditions, fetal glucose uptake increased, from 6.7 to 9.5 mg/min/kg (↑G) and from 7.5 to 11.4 mg/min/kg (↑I). Similar responses were observed at 30-60 minutes and 24 hours. Semi-quantitation of immunohistochemical analysis of hind limb skeletal muscle Glut 1 and Glut 4 revealed a sarcolemmal (SL) association of Glut 1 and an intracellular (IC) aggregation of Glut 4 at zero time. ↑G caused an 8-fold increase at 24 hours and ↑I caused a 4-fold increase at 30-60 minutes in the number of cells showing an SL association of Glut 1. In contrast, neither ↑G or ↑I altered the SL association of Glut 4 at any of the three time points. We conclude that high glucose and insulin concentrations independently translocate fetal ovine Glut 1 to the SL in a time dependent fashion, while not affecting Glut 4 translocation. Under both conditions, translocation of Glut 1 may contribute toward increasing net fetal glucose uptake.

Perinatal energy stores and excessive fat deposition in genetically obese (fa/fa) rats.

To find out whether perinatal differences in energy stores are essential for the phenotypic manifestation of the fa/fa genotype in 16-day-old rats, we investigated Zucker rats (13M) x Brown Norway (BN) hybrids. +/fa and fa/fa hybrids were identified by molecular polymorphisms approximately 1 cM from the fa locus. The fat content of all pups increased rapidly after birth, and differences between +/fa and fa/fa hybrid pups were significant in 7- and 16-day-old rats but not at 0, 1, and 4 days of age. For 16-day-old 13MBN hybrids as well as 13M Zucker rats, plots of carcass fat vs. body mass were closely fitted by parallel regression lines, with carcass fat similarily higher in fa/fa than +/fa pups of both strains. Fetal and neonatal plasma insulin concentration and hepatic glycogen in the 13MBN hybrid pups did not differ between +/fa and fa/fa litter-mates, nor did the hepatic and adipose tissue triglycerides in 24-h-old 13MBN hybrid pups. The manifest differences between fatty and lean 16-day-old pups thus do not depend on differences in perinatal energy stores.

Glucose Suppression of Insulin Secretion in Chronically Hyperglycemic Fetal Sheep

Previous observations in fetal sheep indicate that glucose may inhibit as well as enhance insulin secretion. To study conditions involved in inhibition of insulin secretion, we compared changes in plasma insulin concentration in response to acute increases in glucose and arginine concentrations in a group of normal, late gestation fetal sheep (euglycemic controls, EC) and a comparable group made chronically hyperglycemic by constant maternal glucose infusion (hyperglycemics, HG). After 7-10 d of maternal and fetal hyperglycemia, fetal glucose concentrations (G) were significantly increased in the HG group (0.98 +/- 0.07 mM EC, 2.00 +/- 0.11 mM HG, p < 0.001) but fetal plasma insulin concentrations (I) were not significantly different (57 +/- 7 pM EC, 71 +/- 9 pM HG, p = 0.2). Furthermore, the I/G ratio was significantly decreased in the HG group (60 +/- 9 EC, 40 +/- 4 HG, p = 0.03) and during a hyperglycemic glucose clamp (delta G approximately equal to 1.4 mM), glucose-stimulated increase in steady state I was less in the HG than in the EC fetuses (mean delta I/delta G = 106 +/- 15 EC, 61 +/- 10 HG, p = 0.01). An arginine infusion at the end of the clamp produced similar increases in I in the EC and HG groups (delta I = 824 +/- 116 pM EC, 906 +/- 131 pM HG, p = 0.45). There were no differences between groups for blood oxygen saturation and content, pH, or lactate concentration. After 14-17 d of hyperglycemia, glucose-stimulated increase in I was even more reduced in the HG fetuses than observed at 7-10 d. Decreased insulin response to arginine also was present, although pancreatic insulin concentration was not decreased. Glucose-stimulated increase in I returned to normal after 7 d of no glucose infusion and euglycemia. These data indicate that glucose-stimulated insulin secretion is reversibly decreased by marked, chronic hyperglycemia. Because pharmacologic inhibitors of insulin secretion (e.g. streptozotocin or alloxan) were not used, and oxygenation, pH, and lactate values were similar between the two groups, this decrease of insulin secretion appears to be glucose-specific, although mechanisms involved can include both glucose and amino acid (arginine) stimulation processes. Such decrease in fetal insulin secretion may limit the rate of fetal glucose utilization during chronic hyperglycemia and thereby modulate the rate of fetal growth.

Differential effects of short and long durations of insulin-induced maternal hypoglycemia upon fetal rat tissue growth and glucose utilization.

We studied the effects of short and long durations of insulin-induced maternal hypoglycemia upon in vivo glucose utilization of several fetal tissues in the rat. Osmotic minipumps filled with insulin were implanted in pregnant rats on d 15 or 18 of gestation (term 21.5 d), and radiolabeled 2-deoxyglucose was used to measure relative glucose utilization rates (rGU) of fetal liver, lung, muscle, kidney, heart, placenta, and brain on d 20 of gestation after 2 or 5 d of hypoglycemia. Maternal plasma glucose concentrations decreased within 24 h of pump placement and remained less than controls throughout gestation. Fetal plasma glucose and insulin concentrations on d 20 were equally reduced after 2 and 5 d of hypoglycemia. Both 2 and 5 d of hypoglycemia were associated with significant reductions in the rGU of fetal liver, lung, and muscle. Reductions in fetal kidney rGU also occurred after 2 and 5 d of hypoglycemia but to a smaller degree. rGU of fetal heart was reduced after 2 d of hypoglycemia, but was normal after 5 d of hypoglycemia. Both 2 and 5 d of hypoglycemia were associated with increased rGU of fetal brain. Five d, but not 2 d of hypoglycemia resulted in decreased fetal weight on d 20 of gestation. However, at term, newborn pups delivered of hypoglycemic mothers weighed significantly less than controls regardless of the timing of minipump placement. Liver, lung, and carcass of these growth-retarded pups weighed less than control tissues, whereas kidney, heart, and brain weights were not affected.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of prostaglandins in the metabolic responses of the fetus to hypoxia

The effect of inhibiting prostaglandin synthesis on the fetal metabolic response to hypoxemia was examined by infusing indomethacin during periods of reduced maternal uterine blood flow. In seven fetal sheep we administered a 6-hour infusion of either indomethacin (n = 5), indomethacin plus prostaglandin E2, or a vehicle solution (n = 5). The last 4 hours of each infusion period coincided with a period of fetal hypoxemia induced by reduced maternal uterine blood flow. During reduced maternal uterine blood flow indomethacin infusions caused a significantly greater reduction in pHA (reduced from 7.36 +/- 0.01 to 7.10 +/- 0.02) than both the vehicle (from 7.36 +/- 0.01 to 7.20 +/- 0.03) and indomethacin plus prostaglandin E2 infusions (from 7.36 +/- 0.01 to 7.18 +/- 0.02). Before reduced maternal uterine blood flow was induced, indomethacin significantly elevated fetal plasma glucose and lactate concentrations from 0.6 +/- 0.04 and 2.2 +/- 0.1 to 1.3 +/- 0.2 and 6.7 +/- 0.7 mmol/L, respectively. During reduced maternal uterine blood flow indomethacin caused a significantly greater increase in plasma glucose and lactate concentrations than the vehicle; plasma glucose and lactate concentrations increased to a maximum of 1.8 +/- 0.2 and 22.7 +/- 0.8 mmol/L, respectively, during indomethacin infusions compared with 1.1 +/- 0.1 and 15.7 +/- 1.7 mmol/L, respectively, during vehicle infusions. The addition of prostaglandin E2 to the indomethacin infusion prevented the enhanced increase in glucose and lactate concentrations during reduced maternal uterine blood flow and caused a significant increase in fetal plasma insulin concentrations from 12.6 +/- 0.7 to 60.9 +/- 28.1 microU/ml. The inhibition of prostaglandin synthesis during fetal hypoxemia alters the metabolic response of the fetus, leading to a severe metabolic acidosis.