Possible Mechanisms and Significance of the Neonatal Surge in Glucagon Secretion: Studies in Newborn Lambs

La, Grajwer; Ma, Santos; Sack, J.; Fisher, Derek J.

doi:10.1203/00006450-197707000-00011

Cited by 46 publications

(21 citation statements)

References 2 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…a. cel!~esponse to adult stimuli such as alanine or hypoglycemia is mimmal, responses to arginine (2) and epineph:ine (2~) have bee~n~ted. A surge .of glucagon secretion occurs immediately after birth m several speCies including the sheep (14) and is associated with an acce~eration~f lipolysis and hepatic gluconeogenesis as well as a fall m hepatic glycogen content (3,14,25), the latter suggesti~&~timulation of acute glycogenolysis. Both Girard, et al (13).~t~hzmg a fet~l rat model, and Schreiner and co-workers (23), utihzmg a chromcally catheterized sheep preparation similar to our own, have documented modest but significant elevations of fetal glucagon concentration after prolonged maternal fasting and have suggested that this hormone may playa role in fetal metabolic homeostasis during times of stress.…”

Section: Discussionmentioning

confidence: 99%

Influence of Exogenous Glucagon on Fetal Glucose Metabolism and Ketone Production

et al. 1983

View full text Add to dashboard Cite

(2, 28) have shown that certain adult glucagon secretogogues such as arginine or epinephrine could produce a significant fetal hyperglucagonemia. Recent work (13) suggests that elevation in fetal glucagon concentration may accompany prolonged maternal fasting.The physiologic function of fetal hyperglucagonemia is also open to question. A hyperglycemic response to pharmacologic injection has been suggested in in vivo preparations (6). In order to clarify the role of glucagon as a possible fetal metabolic regulatory hormone, we utilized the chronically catheterized fetal sheep as our model. Varying degrees of hyperglucagonemia were induced and alterations in fetal glucagon, insulin, glucose and ketone concentrations as well as umbilical glucose and ketone uptakes then noted. Summary SpeculationThe fetus in late gestation may respond to substrate deprivation by secretion of glucagon. If so, a modest but significant hyperglycemia would result, presumably the result of acute fetal glycogenolysis. The acute fetal metabolic adaptation to maternal starvation, however, if modified by glucagon, does not include utilization of ketones as alternate substrates.Acute glucagon injections were performed in chronically catheterized fetal lambs in late gestation to assess the fetal metabolic response to exogenous glucagon infusion. Glucagon dosages between 1 p,g/kg and 1 mg/kg induced significant fetal hyperglycemia by 15-30 min postinjection, with peak glucose values 130-180% of control. Increasing responsivity to the same dose/kg was noted to parallel increasing gestational age. In selected preparations in which umbilical venous catheters were implanted, glucagon injection caused an acute fall in the glucose/oxygen quotient and net umbilical glucose consumption. The fall in glucose consumption to 8% of control values occurred within 15 min of injection and suggests acute fetal glucose excretion, probably secondary to hepatic glycogenolysis. Glucagon injection in the neonatal lamb caused qualitatively similar increases in plasma glucose concentration but the quantitative responses were considerably greater. No change in fetal ,B-hydroxybutyrate (,B-ORD) concentration was noted after injection; nor did the fetal uptake or excretion of this ketone change. The neonatal ,B-ORD concentration was significantly different (P < 0.001) from fetal concentrations and did rise 14% above control after glucagon injection; thus, elevation of plasma glucagon in the fetus causes an acute hyperglycemia but, unlike the adult, does not induce a significant ketogenesis.Experimental design. Eleven pregnant ewes between 118-149 days of gestation were studied (Table 1). Term gestation in the sheep is 147 days. All but two had singleton fetuses. Intravenous sodium pentobarbital and spinal anesthesia were administered to each animal preoperatively. Polyvinyl catheters were then placed in a fetal pedal artery and vein as well as the maternal femoral artery for purposes of sampling and infusion. In five of the fetal lambs umbilical venous catheters were als...

show abstract

Section: Discussionmentioning

confidence: 99%

Influence of Exogenous Glucagon on Fetal Glucose Metabolism and Ketone Production

et al. 1983

View full text Add to dashboard Cite

show abstract

Section: Speculationmentioning

confidence: 99%

“…Similarly, a variety of metabolic events are stimulated including hepatic glucose output, free fatty acid mobilization, nonshivering (chemical) thermogenesis, and production of triiodothyronine by peripheral tissues. We and others have demonstrated the importance of umbilical cord cutting itself in the initiation of these metabolic events (28,17).The present studies were designed to assess the individual effects of delivery and umbilical cord cutting on the stimulation of the sympatho-adrenal system during parturition. The results indicate that umbilical cord cutting is an important stimulus for CAT release.…”

mentioning

confidence: 99%

Neonatal Adaptation: Sympatho-Adrenal Response to Umbilical Cord Cutting

et al. 1981

Self Cite

View full text Add to dashboard Cite

Summaryplasma CAT. In an earlier studv of ~l a s m a CAT in the fetal sheepThe present studies were designed to assess the individual effects of delivery and umbilical cord cutting on the stimulation of the sympatho-adrenal system during parturition. Pregnant ewes with time-dated singleton pregnancies were used in an acutely exteriorized fetal lamb model with an intact umbilical circulation. We observed a minimal, transient elevation in plasma catecholamines (CAT) coincident with the operative procedures and delivery. Subsequent cord clamping was observed to evoke a rapid and marked increase of both norepinephrine and epinephrine (E), maximal at 5 min and persisting over the 4 h r study period. Animals could be grouped on the basis of the observed CAT responses, severity of postpartum acidosis, the extent of free fatty acid (FFA) mobilization and degree of postpartum hypothermia. A blunted FFA response and slower correction of hypothermia were observed in the more acidotic animals despite higher CAT concentrations. One group of four animals had high peak CAT concentrations, 32,000 p g / d norepinephrine and 35,000 p g / d E, a deep nadir in pH of 6.88 k 0.09, a 2-hr delay in maximal FFA mobilization and slower correction of hypothermia. The other group of four animals had peak norepinephrine of 2800 pg/ml and E of 1100 pg/d, a nadir in pH of 7.09 * 0.08, maximal plasma FFA concentration by 1 hr after cord cutting and a higher nadir in body temperature 35.7 versus 32.S°C. The results demonstrate that umbilical cord cutting itself is a potent stimulus for fetal CAT release and FFA mobilization. Acidosis is capable of markedly augmenting E release in the mature fetus and obtunding chemical thermogenesis. SpeculationThe marked catecholamine surge evoked by umbilical cord cutting at the time of birth appears to be a major factor triggering the metabolic events facilitating ada~tation to extrauterine life. The mechanism for the catechoiamine release is uncertain. However, cardiovascular and chemoreceptor mediated activation of autonomic nervous system activity probably are involved. The separate contributions of increased p&tganglionic neurosympathetic activity and adrenal-medullary catecholamine release to n w natal adaptation should be explored further.Previous work in a variety of animals (9) and man (15) suggests that the sympatho-adrenal system is relatively mature at term. Substantial catecholamine release has been observed in the near term fetal sheep in response to a variety of stimuli including hypoxia (8), maternal blood volume depletion (2), and maternal exercise (18). In the human newborn we and others (13,21,23) have shown striking elevations of plasma catecholamine (CAT) in both umbilical blood samples and neonatal blood drawn in the first minutes and hours of life. In each of the studies reported to date there was a marked umbilical artery to umbilical vein CAT concentration difference suggesting a fetal origin for the cord before and during parturition h e demonstrated basal circulating levels at great...

show abstract

“…Because glucagon and insulin are hormones that regulate hepatic P-oxidation of fatty acids, we postulated that they also might influence hepatic carnitine in the newborn period. Although elevated glucagon concentrations have been observed in newborn lambs (34), dog pups (35), and piglets within 48 h of birth (36,37), the temporal pattern through weaning had not been previously established in swine.…”

Section: Discussionmentioning

confidence: 99%

Enterohepatic Distribution of Carnitine in Developing Piglets: Relation to Glucagon and Insulin

et al. 1992

Pediatr Res

View full text Add to dashboard Cite

ABSTRACT. ~Xarnitine plays a crucial role in the perinatal transition from carbohydrate to lipid-derived energy. To examine the potential contribution of assimilated dietary carnitine to the elevated hepatic concentrations in newborns, we measured carnitine concentrations in sow milk, jejunum, and liver, and in vitro jejunal carnitine transport in piglets aged 1-36 d. Hepatic and sow milk total carnitine concentrations peaked soon after birth and declined with age ( p = 0.035 and 0.026, respectively).Although jejunal total carnitine concentrations remained stable, jejunal carnitine flux was higher at 2 d of age than in older piglets. To examine the possible signals that regulate hepatic carnitine, portal enteroinsular hormones were measured by RIA. Portal glucagon ( p = 0.0006), insulin ( p = 0.0001), and g1ucagon:insulin ratio ( p = 0.037) were related to age. Portal glucagon was highest in newborns and during weaning, whereas insulin increased progressively with age; the portal g1ucagon:insulin ratio, like hepatic carnitine, peaked soon after birth and fell with age. A multiple regression analysis indicated a positive association between glucagon and hepatic carnitine and a negative one between insulin and hepatic carnitine (R = 0.802, p = 0.001). An overall pattern of elevated dietary carnitine levels and increased small intestinal absorption and hepatic accumulation of carnitine is noted in early development. The finding of a similar pattern in glucagon-to-insulin ratio suggests that both hormones may participate in the regulation of enterohepatic carnitine distribution in newborns. (Pediatr Res 32: 312-316,1992) Abbreviations PEG, polyethylene glycol SCAC, short-chain acylcarnitine ANOVA, analysis of variance NB, newborn group S, suckling group W, weaning group FW, fully weaned group plays a critical role in the metabolic transition from carbohydrate to lipid-derived energy (2, 3) because hepatic glycogen stores become rapidly depleted and endogenous gluconeogenesis is inadequate in the first 24 h of life (4, 5). As such, carnitine insufficiency has been shown to impair lipid utilization in premature newborns (6, 7). The human newborn is especially susceptible to develop carnitine insufficiency because of low levels in premature infants (8), inadequate dietary intake of carnitine (9), and insufficient endogenous synthesis (10).One marker of the switch from glucose to lipid utilization in the newborn is the increase in hepatic carnitine concentrations compared with the fetus (4). In newborn rats, the Cfold rise in hepatic carnitine has been shown to coincide with enhanced ketone production. Although the origin of hepatic carnitine in newborns has not been fully established, because endogenous synthesis is limited, dietary sources appear to be important. Human and rat milk carnitine concentrations peaked in the first few days after parturition (4, 1 1). In 5-d-old rats, the contribution of milk carnitine to heart (41%) and liver (49%) carnitine stores was substantial (12). We hypothesized that intestinal a...

show abstract

Possible Mechanisms and Significance of the Neonatal Surge in Glucagon Secretion: Studies in Newborn Lambs

Cited by 46 publications

References 2 publications

Influence of Exogenous Glucagon on Fetal Glucose Metabolism and Ketone Production

Influence of Exogenous Glucagon on Fetal Glucose Metabolism and Ketone Production

Neonatal Adaptation: Sympatho-Adrenal Response to Umbilical Cord Cutting

Enterohepatic Distribution of Carnitine in Developing Piglets: Relation to Glucagon and Insulin

Contact Info

Product

Resources

About