Neonatal Glucose Homeostasis Research Articles

Relationship of ANGPTL6 With Neonatal Glucose Homeostasis and Fat Mass Is Disrupted in Gestational Diabetic Pregnancies.

Angiopoietin-like protein 6 (ANGPTL6) is a hepatokine, which, in animal studies, improves insulin sensitivity and increases energy expenditure to counteract insulin resistance. Evaluate in a human population, the role of serum ANGPTL6 in gestational diabetes mellitus (GDM) or its presence in fetal circulation. A total of 190 women (115 controls and 75 GDM) and their offspring were studied. Insulin, glucose, ANGPTL6, retinol binding protein 4 (RBP4), and retinol, as well as leptin and adiponectin, were determined in maternal serum obtained at term and from umbilical artery blood at delivery. At term, pregnant women with GDM showed higher serum concentrations of ANGPTL6, insulin, homeostatic model assessment, and apo-RBP4 (free RBP4) than controls but not of glucose, which remained similar in both groups. Also, in arterial cord serum, ANGPTL6 concentration was increased in GDM neonates with respect to the control group (201 ± 12 ng/mL vs 119 ± 8 ng/mL, respectively). No effect of maternal insulin treatment of some GDM mothers in neonates of either sex on ANGPTL6 levels was observed. In GDM, circulating ANGPTL6 showed no correlation with glucose or insulin concentration or with neonatal adiposity. However, in control pregnancies, the variation in glucose concentration was positively correlated with ANGPTL6 concentration, both in maternal and in cord samples, and cord ANGPTL6 was negatively correlated with neonatal fat mass. Furthermore, in control pregnant women, serum concentrations of ANGPTL6 and apo-RBP4 were negatively correlated. Serum ANGPTL6 levels are associated with maternal glucose homeostasis and fetal adiposity in normal pregnancy. ANGPTL6 levels in maternal and cord serum GDM pregnancy at term are increased, although its mechanism and physiological role are unknown yet.

Prenatal or postnatal corticosteroids favor clinical, respiratory, metabolic outcomes and oxidative balance of preterm lambs corticotherapy for premature neonatal lambs

Challenges of the extrauterine environment can be life threatening for a premature fetus with inadequate fetal maturity. Maternal corticosteroids therapy is widely employed to induce fetal pulmonary maturation. Nevertheless, whenever therapeutic pregnancy interruption has to be performed in a time manner insufficient to treat the dam, postnatal corticotherapy can be considered an alternative. However, it is not known if antenatal and postnatal corticotherapy can improve similarly neonatal outcomes and pulmonary function. This research aimed to analyze antenatal and postnatal corticotherapy on premature lambs vitality, pulmonary functioning, metabolic and oxidative status. Lambs were evaluated according to the mode of treatment: Prenatal Corticosteroid Group (8 lambs born after maternal betamethasone treatment 48 h prior to birth), Postnatal Corticosteroid Group (9 lambs subjected to betamethasone treatment 10 min after birth) and Control Group (5 lambs remained untreated). Lambs were medically followed-up from birth to 72 h thereafter through a complete physical examination, as well as lactatemia, glycaemia, blood acid-base balance and antioxidant status. Treated lambs had higher vitality score than the Control Group. Heart rate was higher in postnatal therapy compared to prenatal treatment. Respiratory rate and rectal temperature were higher in treated groups. Treated lambs had hyperglycemia, while the Postnatal Group had higher lactatemia than the Control Group. The Prenatal Group had lower and normal pCO2 from 60 min onwards. The Postnatal Group had higher superoxide dismutase activity than untreated lambs. In conclusion, prenatal and postnatal betamethasone treatments favor neonatal clinical outcome, respiratory function, glucose homeostasis and oxidative balance.

The adipokine FABP4 is a key regulator of neonatal glucose homeostasis.

During pregnancy, fetal glucose production is suppressed, with rapid activation immediately postpartum. Fatty acid–binding protein 4 (FABP4) was recently demonstrated as a regulator of hepatic glucose production and systemic metabolism in animal models. Here, we studied the role of FABP4 in regulating neonatal glucose hemostasis. Serum samples were collected from pregnant women with normoglycemia or gestational diabetes at term, from the umbilical circulation, and from the newborns within 6 hours of life. The level of FABP4 was higher in the fetal versus maternal circulation, with a further rise in neonates after birth of approximately 3-fold. Neonatal FABP4 inversely correlated with blood glucose, with an approximately 10-fold increase of FABP4 in hypoglycemic neonates. When studied in mice, blood glucose of 12-hour-old WT, Fabp4–/+, and Fabp4–/– littermate mice was 59 ± 13 mg/dL, 50 ± 11 mg/dL, and 43 ± 11 mg/dL, respectively. Similar to our observations in humans, FABP4 levels in WT mouse neonates were approximately 8-fold higher compared with those in adult mice. RNA sequencing of the neonatal liver suggested altered expression of multiple glucagon-regulated pathways in Fabp4–/– mice. Indeed, Fabp4–/– liver glycogen was inappropriately intact, despite a marked hypoglycemia, with rapid restoration of normoglycemia upon injection of recombinant FABP4. Our data suggest an important biological role for the adipokine FABP4 in the orchestrated regulation of postnatal glucose metabolism.

Ablation of somatostatin cells leads to impaired pancreatic islet function and neonatal death in rodents

The somatostatin (SST)-secreting cells were mainly distributed in the pancreatic islets, brain, stomach and intestine in mammals and have many physiological functions. In particular, the SST-secreting δ cell is the third most common cell type in the islets of Langerhans. Recent studies have suggested that dysregulation of paracrine interaction between the pancreatic δ cells and β cells results in impaired glucose homeostasis and contributes to diabetes development. However, direct evidence of the functional importance of SST cells in glucose homeostasis control is still lacking. In the present study, we specifically ablated SST-secreting cells by crossing Sst-cre transgenic mice with R26DTA mice (SstCreR26DTA). The SstCreR26DTA mice exhibited neonatal death. The life spans of these mice with severe hypoglycemia were extended by glucose supplementation. Moreover, we observed that SST cells deficiency led to increased insulin content and excessive insulin release, which might contribute to the observed hypoglycemia. Unexpectedly, although SST is critical for the regulation of insulin content, factors other than SST that are produced by pancreatic δ cells via their endogenous corticotropin-releasing hormone receptor 2 (CRHR2) activity play the main roles in maintaining normal insulin release, as well as neonatal glucose homeostasis in the resting state. Taken together, our results identified that the SST cells in neonatal mouse played critical role in control of insulin release and normal islet function. Moreover, we provided direct in vivo evidence of the functional importance of the SST cells, which are essential for neonatal survival and the maintenance of glucose homeostasis.

Alterations in glucose concentrations affect DNA methylation at Lrg1 in an exvivo rat cortical slice model of preterm brain injury.

Preterm birth affects 5-18% of all babies and is associated with neurodevelopmental impairment and increased neuropsychiatric disease risk. Although preterm birth associates with differential DNA methylation at neurodevelopmental genes in buccal DNA, including leucine-rich alpha-2-glycoprotein 1 (LRG1), it is not known whether these differences also occur in the brain, or whether they persist. Thus, there is a need for animal models or invitro systems in which to undertake longitudinal and mechanistic studies. We used a combination of invivo rat studies and exvivo experiments in rat cortical slices to explore their utility in modelling the human preterm brain. We identified temporal changes in DNA methylation at LRG1 in human buccal DNA over the first year of life and found persistent differences in LRG1 methylation between preterm and term infants at 1year. These developmental changes also occurred in rat brains invivo, alongside changes in global DNA hydroxymethylation and expression of the ten-eleven translocation (Tet1) enzyme, and were reproducible in exvivo rat cortical slices. On the basis of the observation that neonatal glucose homeostasis can modify neurodevelopmental outcome, we studied whether glucose concentration affects Lrg1 methylation using cortical slices. Culture of slices in lower glucose concentration was associated with lower Lrg1 methylation, lower global 5hmC and Tet1 expression. Our results suggest that exvivo organotypic cultures may be useful in the study of biological and environmental influences on the epigenome and that perturbations during early life including glucose concentration can affect methylation at specific genes implicated in neurodevelopment.

Apelin Controls Fetal and Neonatal Glucose Homeostasis and Is Altered by Maternal Undernutrition.

The adequate control of glucose homeostasis during both gestation and early postnatal life is crucial for the development of the fetoplacental unit and adaptive physiological responses at birth. Growing evidences indicate that apelin and its receptor, APJ, which are expressed across a wide range of tissues, exert important roles in glucose homeostasis in adults. However, little is known about the function of the apelinergic system during gestation. In this study, we evaluated the activity of this system in rats, the role of apelin in fetal and neonatal glucose homeostasis, and its modulation by maternal food restriction. We found that 1) the apelinergic system was expressed at the fetoplacental interface and in numerous fetal tissues, 2) ex vivo, the placenta released high amounts of apelin in late gestation, 3) intravenous apelin injection in mothers increased the transplacental transport of glucose, and 4) intraperitoneal apelin administration in neonates increased glucose uptake in lung and muscle. Maternal food restriction drastically reduced apelinemia in both mothers and growth-restricted fetuses and altered the expression of the apelinergic system at the fetoplacental interface. Together, our data demonstrate that apelin controls fetal and neonatal glucose homeostasis and is altered by fetal growth restriction induced by maternal undernutrition.

Elevated maternal cortisol leads to relative maternal hyperglycemia and increased stillbirth in ovine pregnancy.

In normal pregnancy, cortisol increases; however, further pathological increases in cortisol are associated with maternal and fetal morbidities. These experiments were designed to test the hypothesis that increased maternal cortisol would increase maternal glucose concentrations, suppress fetal growth, and impair neonatal glucose homeostasis. Ewes were infused with cortisol (1 mg·kg(-1)·day(-1)) from day 115 of gestation to term; maternal glucose, insulin, ovine placental lactogen, estrone, progesterone, nonesterified free fatty acids (NEFA), β-hydroxybutyrate (BHB), and electrolytes were measured. Infusion of cortisol increased maternal glucose concentration and slowed the glucose disappearance after injection of glucose; maternal infusion of cortisol also increased the incidence of fetal death at or near parturition. The design of the study was altered to terminate the study prior to delivery, and post hoc analysis of the data was performed to test the hypothesis that maternal metabolic factors predict the fetal outcome. In cortisol-infused ewes that had stillborn lambs, plasma insulin was increased relative to control ewes or cortisol-infused ewes with live lambs. Maternal cortisol infusion did not alter maternal food intake or plasma NEFA, BHB, estrone, progesterone or placental lactogen concentrations, and it did not alter fetal body weight, ponderal index, or fetal organ weights. Our study suggests that the adverse effect of elevated maternal cortisol on pregnancy outcome may be related to the effects of cortisol on maternal glucose homeostasis, and that chronic maternal stress or adrenal hypersecretion of cortisol may create fetal pathophysiology paralleling some aspects of maternal gestational diabetes.

The effect of hyperglycemia on neonatal immune responses in-vitro

Introduction. Acute hyperglycemia is considered as a pro-inflammatory state and is related to an adverse outcome in critically ill adults. Neonates are susceptible to infections and systemic inflammatory response syndrome induced by pro-inflammatory cytokines. This study focuses on the interaction between neonatal glucose homeostasis and the pro-inflammatory cytokine production in term and preterm infants in-vitro.Methods. We analyzed the pro-inflammatory cytokine production in whole cord blood of term infants (n = 10), preterm infants > 32 weeks (n=16) and preterm infants ≤32 weeks of gestational age (n = 13) and in adult controls (n=14) using an in-vitro sepsis-model. Whole blood was pre-incubated with different concentrations of glucose (0–1000 mg/dl) and insulin (0–62.5 IE/l) and stimulated with lipopolysaccharide. The intracytoplasmatic TNF-α, IL-6, and IL-8 response was measured by flow cytometry.Results. In-vitro hyperglycemia induced a dose-dependent increase of IL-8 in all age groups while TNF-α was demonstrated to be stimulated by glucose in cord blood samples of preterm infants ≤32 weeks of gestational age and term infants. In contrast, insulin showed no significant effects on pro-inflammatory cytokine production in-vitro.Conclusion. Acute hyperglycemia may induce pro-inflammatory cytokine responses in neonatal whole blood in-vitro. These data provide a basis for further in-vitro signal transduction studies and in-vivo investigations about the significance of neonatal glucose homeostasis and its impact on long-term outcome of this susceptible patient cohort.

Apical Na+-d-glucose cotransporter 1 (SGLT1) activity and protein abundance are expressed along the jejunal crypt-villus axis in the neonatal pig

Gut apical Na(+)-glucose cotransporter 1 (SGLT1) activity is high at the birth and during suckling, thus contributing substantially to neonatal glucose homeostasis. We hypothesize that neonates possess high SGLT1 maximal activity by expressing apical SGLT1 protein along the intestinal crypt-villus axis via unique control mechanisms. Kinetics of SGLT1 activity in apical membrane vesicles, prepared from epithelial cells sequentially isolated along the jejunal crypt-villus axis from neonatal piglets by the distended intestinal sac method, were measured. High levels of maximal SGLT1 uptake activity were shown to exist along the jejunal crypt-villus axis in the piglets. Real-time RT-PCR analyses showed that SGLT1 mRNA abundance was lower (P < 0.05) by 30-35% in crypt cells than in villus cells. There were no significant differences in SGLT1 protein abundances on the jejunal apical membrane among upper villus, middle villus, and crypt cells, consistent with the immunohistochemical staining pattern. Higher abundances (P < 0.05) of total eukaryotic initiation factor 4E (eIF4E) protein and eIE4E-binding protein 1 γ-isoform in contrast to a lower (P < 0.05) abundance of phosphorylated (Pi) eukaryotic elongation factor 2 (eEF2) protein and the eEF2-Pi to total eEF2 abundance ratio suggest higher global protein translational efficiency in the crypt cells than in the upper villus cells. In conclusion, neonates have high intestinal apical SGLT1 uptake activity by abundantly expressing SGLT1 protein in the epithelia and on the apical membrane along the entire crypt-villus axis in association with enhanced protein translational control mechanisms in the crypt cells.

In Vitro and In Vivo Effect of Acylated and Unacylated Ghrelin on Neonatal Glucose Homeostasis

Maintenance of normal glucose homeostasis is crucial for survival during the perinatal period. Acylated ghrelin (AG) but not unacylated ghrelin (UAG) inhibits insulin release from pancreatic islets in adult rats. Circulating AG concentrations are low in the fetus and progressively increase in the postnatal period. We tested the hypothesis that AG has insulinostatic effects in vitro and in vivo during the perinatal period. In vitro, AG (10(-10)-10(-8) M) caused a 25-53% decrease in insulin secretion by islets from 5-d-old rat pups under normo- and hyperglycemic conditions, an effect that was mediated through the growth hormone secretagogue receptor (GHSR- 1a). Ghrelin (1-5) amide, [Dap3]-octanoyl, a pentapeptide that is resistant to deacylation and binds the GHSR-1a, had similar effects at 10(-8) M. In vivo, AG, UAG, or GHRP-6 [D-Lys3], a GHSR-1a antagonist, did not affect insulin or glucagon concentrations during the first 3 h of life. In 6-d-old pups, AG, UAG, or ghrelin (1-5) amide, [Dap3]-octanoyl did not affect glucose-induced insulin or C-peptide concentrations. In summary, AG has insulinostatic effects in vitro as early as during the perinatal period. These effects could not be confirmed in vivo, possibly due to the short half-life of AG in rat neonates.

Blood glucose level in preterm infants after antenatal exposure to glucocorticoid

To determine the impact of antenatal glucocorticoid on neonatal glucose homeostasis. This is a retrospective gestationally paired survey followed by a randomized study. On the basis of the interval between last antenatal dexamethasone and birth, 228 preterm infants born before 34 weeks were divided into Short (< 24 h), Intermediate (1-6 days), and Long (> or = 7 days) exposure groups and compared their gestationally paired controls. After a single course of betamethasone, the parturients remaining undelivered for one week were randomized to receive either one dose of betamethasone (n = 52) or placebo (n = 53). Glucose values were recorded at 11 time points in the first 3 days of life. Hypoglycaemic and hyperglycaemic values were counted. There were no overall differences in mean glucose levels between the antenatal glucocorticoid and the control groups. However, the long exposure time to antenatal glucocorticoid was associated with increased risk of hyperglycaemia (OR 4.1; 2.2-7.6). Antenatal glucocorticoid administration was associated with subtle disturbances of glucose homeostasis in preterm infants. These differences were dependent on the length of drug-delivery interval so that long exposition time seemed to increase the incidence of hyperglycaemia during the first days of life.

Neonatal Hypoglycemia: Fifty Years Later, The Questions Remain the Same

Almost 50 years after it was first described, neonatal hypoglycemia remains a commonly encountered clinical problem, particularly among high-risk populations such as preterm infants and infants who experience intrauterine growth restriction. As the articles in this issue demonstrate, our understanding of the metabolic disturbances and genetic defects underlying alterations in neonatal glucose homeostasis has increased dramatically over the past 50 years. However, the growth of knowledge has, if anything, led us farther from an answer to the burning question regarding blood glucose concentrations in the newborn: “How low is too low?” It is clear from all three articles that there is no single answer to this question. The glucose concentration at which physiologic disturbances occur differ between the healthy breastfed term infant who has significant levels of circulating ketone bodies and the infant who has hyperinsulinemia and cannot produce ketones or release stored glycogen from the liver. Unfortunately, our ability to monitor levels of alternate fuels and metabolic demand has not progressed as rapidly as our …

The contribution of glucose to neonatal glucose homeostasis in the lamb.

A multiplicity of substrates and hormones interact to influence neonatal glucose homeostasis. Based on prior studies in our laboratory, we hypothesized that glucose alone does not tightly control neonatal glucose homeostasis. Fifteen spontaneously delivered, mixed-breed term lambs, weighing 4.7 +/- 0.9 kg (mean +/- SD) were studied at 4.7 +/- 0.6 days after birth following administration of 100 microCi D[6,6-(3)H2] glucose in 0.9% NaCl by the prime plus constant infusion technique to measure glucose production. After a baseline period, five lambs received 8.5 mg x kg(-1) x min(-1) glucose in combination with the following to isolate the contribution of glucose: somatostatin to block insulin, glucagon, and growth hormone release; metyrapone to block cortisol release; phentolamine to block alpha-adrenergic release; and propranolol to block beta-adrenergic release (glucose + blockade). Five lambs received the above without the glucose infusion (blockade). Five lambs continued to receive 0.9% NaCl alone as the diluent for the isotopic tracer throughout the study (control). The glucose + blockade group had a significant increase in plasma glucose (P < .0001) and a significant increase in total glucose appearance (P < .0001) compared with both the blockade and control groups. Under conditions of glucose infusion at a rate 49% greater than the basal rate, the endogenous glucose production rate persisted such that there was only an evanescent decrease compared with that of the control group, which was not statistically different over time. As a substrate, glucose does not tightly control neonatal glucose homeostasis.

Insulin injection in the fetal rat: Accelerated intrauterine growth and altered fetal and neonatal glucose homeostasis

Fetal hyperinsulinemia is a well-known correlate of accelerated fetal growth; the consequences of fetal hyperinsulinemia upon fetal and neonatal glucoregulation are less well understood. We injected rat fetuses of a litter on day 18 of gestation with either 5 units of long acting insulin (I) or 154 mmol/L NaCl. Twelve hours after injection, the wet and dry mass of total body and liver of I fetuses significantly exceeded that of controls. At birth (day 21.5), newborn I pups weighed 5.86 ± .08 g, and controls, 5.48 ± .05 g, ( P < .001). On day 18, within one hour of injection, fetal plasma insulin concentrations were significantly elevated and remained so for 24 hours. Mothers of I fetuses had significant elevations of plasma insulin at 1, 3, and 6 hours, and they developed transient hypoglycemia. Plasma glucose concentrations in I fetuses were significantly diminished at 1, 3, and 6 hours and then achieved control levels by 12 hours. Fetal hypoglycemia resulted from an apparent direct effect of insulin upon fetal tissue and from the maternal hypoglycemia. Hypoglycemic I fetuses demonstrated a sluggish α-cell response; they failed to increase plasma glucagon one hour after insulin injection. Values were significantly increased three hours after injection. At birth, I pups became hypoglycemic relative to controls. This was, in part, due to their significantly elevated plasma insulin concentrations at 120 and 240 minutes (120 minutes, 43.8 ± 8 v 17.5 ± 6 μU/mL, P < .001). Plasma glucagon was significantly increased in I pups at 240 minutes. During the neonatal period, pups who had undergone intrauterine insulin injection did not mobilize glycogen or induce hepatic cytosolic phosphoenolpyruvate carboxykinase to the same extent as controls. Insulin injection to the fetus accelerates growth and causes fetal hypoglycemia by decreasing maternal glucose and increasing fetal tissue uptake of glucose. The intriguing observation of sustained neonatal hyperinsulinemia remains unexplained.

Hepatic response to insulin in control of glucose kinetics in the neonatal lamb

Imprecise control of neonatal glucose homeostasis may be partially due to decreased hepatic response to insulin. In prior kinetic studies the effect of that response could not be determined because the hormonal effects of insulin could not be separated from those of glucagon. Somatostatin (SRIF) suppresses secretion of both and has been used to differentiate the hormonal effects. Eighteen term lambs (age 4.2 ± 0.3 days and birth weight 4.0 ± 0.2 kg (M ± SEM)) were infused with 0.9% NaCl at 0.06 mL · kg −1 min −1 plus 100 μCi/kg D[6 - 3H] glucose by prime plus constant infusion. Ra (production) and Rd (utilization) were measured during infusion of SRIF or SRIF plus replacement insulin (0.2 mU · kg −1 min −1). There was a rise in pl. glucose (98 ± 10 to 119 ± 10 mg/dL ( P < .0001)); a fall (46.2%) in pl insulin [13 ± 2 to 7 ± 1 μU/mL ( P < .0004); a rise in Ra (7.8 ± 1.5 to 13.2 ± 4.1 mg · kg −1 min −1 P < .047)); and a rise in Rd (7.7 ± 1.4 to 11.3 ± 3.0 mg · kg −1 min −1 ( P < .047)] in SRIF treated animals compared to nontreated controls. There was no change in plasma glucagon (454 ± 182 to 255 ± 141 pg/mL) in SRIF treated animals compared to nontreated controls. All perturbations were eliminated when SRIF plus replacement insulin produced control insulin levels. Insulin suppression in the neonatal period resulted in glucagon being unopposed which produced an elevated rate of glucose production and elevated plasma glucose concentration.

Gluconeogenesis in late fetal and early neonatal life.

Birth in most mammalian species represents an abrupt change from a high-carbohydrate and low-fat diet to a high-fat and low-carbohydrate diet. Gluconeogenesis is absent from the liver of the fetus of well fed mothers, but can be induced prematurely by prolonged fasting of the mother. Gluconeogenesis increases rapidly in the liver of newborn mammals in parallel with the appearance of phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme of this pathway. The rise in plasma glucagon and the fall in plasma insulin which occur immediately after birth are the main determinants of liver PEPCK induction. When liver PEPCK has reached its adult value, i.e. 24 h after birth, other factors are involved in the regulation of hepatic gluconeogensis. In order to maintain a high gluconeogenic rate, the newborn liver must be supplied with sufficient amount of gluconeogenic substrates and free fatty acids. An active hepatic fatty acid oxidation is necessary to support hepatic gluconeogenesis by providing essential cofactors such as acetyl CoA and NADH. The relevance of animal studies for the understanding of neonatal glucose homeostasis in man is discussed.

Mechanisms of beta sympathomimetic actionon neonatal glucose homeostasis in the lamb

Beta sympathomimetic drugs are used clinically to inhibit premature labor. Significant alterations in glucose homeostasis have been documented in both mother and offspring. To determine the mechanism(s) of beta sympathomimetic drugs on neonatal glucose homeostasis, ritodrine hydrochloride was infused in a newborn term lamb model of glucose kinetics by a crossover design. There was a progressive rise in plasma glucose concentration and plasma insulin concentration during ritodrine hydrochloride infusion compared with the control (saline) infusion. The rise in plasma glucose concentration was associated with a progressive rise in Ra (rate of appearance, production) and Rd (rate of disappearance, utilization). The ritodrine hydrochloride-infused animals had a progressive rise in [insulin/glucose] compared with our prior studies in the newborn lamb, suggesting direct stimulation of pancreatic beta cell secretion. In the neonatal lamb, beta sympathomimetic drugs directly stimulate both hepatic glucose production and pancreatic beta cell secretion. These effects explain, in part, why infants of mothers infused with ritodrine hydrochloride may evidence alterations in neonatal glucose homeostasis.

1204 INSULIN IS THE PRIMARY HORMONE FOR CONTROL OF NEONATAL GLUCOSE HOMEOSTASIS

Immprecise control of neonatal glucose homeostasis may be partially due to hepatic insensitivity for insulin. In prior kinetic studies, the degree of insensitivity could not be determined because the hormonal effects of insulin could not be differentiated from that of glucagon. Somatostatin (SRIF) suppresses secretion of both and has been used to differentiate the hormonal effects. Eighteen term lambs [birth weight 4.0±0.2 kg (M±SEM) and age 4.2±0.3 days] were infused with 0.9% NaCL at 0.06 ml·kg−1 min−1 plus 100 μCi/kg D[6- 3H] glucose by prime plus constant infusion. Ra (production) and Rd (utilization) were measured during infusion of SRIF or SRIF plus replacement insulin. All basal kinetic data was comparable. Kinetic data is shown from the experimental period:There was a rise in pl. glucose (p <.0001), a fall in pl. insulin (p <.004), a rise in Ra (p <.05) and Rd (p<.05) in SIRF compared to controls. All pertubations were eliminated when replacement insulin plus SRIF produced control insulin levels. We suggest that insulin is the primary hormone for control of neonatal glucose homeostasis.

1203 α ADRENERGICS STIMULATE NEONATAL GLUCOSE PRODUCTION LESS THAN ADRENERGICS

Catecholamines are important in maintenance of neonatal glucose homeostasis. The relative contribution of α versus β adrenergics in control of neonatal glucose kinetics has not been established. Twenty-three term lambs [birth weight 4.4±0.2 kg (M±SEM) and age 3.8±0.4 days] were infused with 0.9% NaCL at 0.06 ml kg−1 min−1 plus 100 μCi/kg D[6- 3H] glucose by prime plus constant infusion. Ra (production)(mg · kg min−1) was measured during infusion of variable doses of epinephrine (Epi) (ng·kg−1 min−1,) with or without variable doses of propranolol (Prop) (ug · kg−1 min−1), a competitive β-adrenergic antagonist, to isolate α adrenergic effects. All basal kinetic data was comparable. Kinetic data isThere was a rise in pl. glucose in all groups infused with both epinephrine + propranolol and epinephrine alone compared to controls. While there was no significant rise in Ra with either dose of epinephrine + propranolol, there was a rise in Ra in response to the higher dose of epinephrine alone compared to controls. We conclude that α adrenergics are less important than β adrenergics in control of neonatal glucose production.

Pathophysiology, diagnosis, and management of glucose homeostasis in the neonate

The neonate appears to be in a transitional stage of glucose homeostasis. Maturation of neonatal glucose homeostasis requires coordination of opposing hormonal, neural, and enzymatic controls. The vulnerability of the neonate to carbohydrate disequilibrium has been described by tracing the maturation of carbohydrate homeostasis physiologically. The many examples of neonatal hypoglycemia and hyperglycemia have been enumerated. Much information in recent years has increased our understanding of the mechanism of these conditions in the newborn. Continued research of the biochemical and physiologic bases for alterations of carbohydrate metabolism should further enhance our ability to diagnose and treat the neonate effectively.