CommentaryRe-Evaluating “Transitional Neonatal Hypoglycemia”: Mechanism and Implications for Management
Section snippets
Patterns of Plasma Glucose Concentrations in Normal Newborns during the First Days of Life
Prior to birth, fetal fuel metabolism is based primarily on oxidation of glucose, which is supplied from maternal plasma glucose whose levels are regulated by maternal insulin secretion.9 The fetal brain is exposed to circulating glucose concentrations only slightly below those of maternal plasma; with normal maternal glucose concentrations of 70-90 mg/dL (3.9-5.0 mmol/L), the mean fetal-maternal plasma glucose difference at term is only 9 mg/dL (0.5 mmol/L).10 Fetal insulin secretion is
Transitional Neonatal Hypoglycemia in Normal Newborns Is a Hypoketotic Hypoglycemia
As noted above, the underlying mechanisms of hypoglycemia are best elucidated by examining the hormonal and metabolic fuel responses as hypoglycemia develops. The approach was applied in 3 studies of transitional neonatal hypoglycemia in normal newborns between 1974 and 199215, 19, 22; more recent studies are not available. They all demonstrate that low glucose concentrations on the first day of life are associated with remarkably low concentrations of plasma ketones.
For example, in the study
Insulin Secretion in Transitional Neonatal Hypoglycemia in Normal Newborns
Using umbilical venous infusions, Isles et al in 1968,28 demonstrated that normal newborn infants at 2 hours of age have brisk acute insulin responses to glucose, which are comparable with the responses of older children and adults.29 In addition, these studies showed that portal vein insulin levels (49 ± 19 μU/mL) were not suppressed at low plasma glucose levels of 44 ± 20 mg/dL. Other reports also indicate that plasma insulin concentrations are not completely suppressed at the lower levels of
Transitional Neonatal Hypoglycemia in Normal Newborns Is Associated with Inappropriate Preservation of Liver Glycogen Reserves
As shown in the Figure, an important test to confirm hyperinsulinism is the demonstration of inappropriate retention of liver glycogen stores by a glycemic response to glucagon or epinephrine of greater than 30 mg/dL (1.7 mmol/L).33 Studies of the glycemic response to epinephrine by Desmond in 195020 showed increments in normal newborns (adjusted to plasma glucose values) ranging from 52-83 mg/dL (2.9-4.6 mmol/L); this included neonates whose baseline plasma glucose concentrations were as low
Transitional Neonatal Hypoglycemia in Normal Newborns Resembles Congenital Hyperinsulinism Caused by Regulatory Defects in Glucokinase Activity
The combination of features in transitional neonatal hypoglycemia in normal term, AGA newborns (stable hypoglycemia irrespective of feeding or fasting, suppressed plasma ketones and FFA, incomplete suppression of plasma insulin concentrations, and inappropriately large glycemic responses to glucagon or epinephrine) are well-recognized features of congenital hyperinsulinism caused by activating mutations of glucokinase.40 Glucokinase plays a key role in setting the glucose threshold for
Brain Responses to Transitional Neonatal Hypoglycemia in Normal Newborns
In older children and adults, after suppression of insulin secretion, the second hormonal defense against hypoglycemia is activation of glucagon secretion and a sympatho-adrenal discharge (reflected by elevations of plasma epinephrine concentrations) when glucose becomes limiting for brain metabolism.42 Secretion of both glucagon and epinephrine appear to also be activated in transitional neonatal hypoglycemia in normal neonates. Data from 3 reports suggest that normal and SGA neonates activate
Speculation on Beta-Cell Insulin Regulatory Differences in the Newborn and Possible Mechanism of Transitional Neonatal Hypoglycemia
Recent studies of insulin secretion in rodent newborn models suggest a potential mechanism for the apparent lower glucose threshold for insulin release in the period of transitional neonatal hypoglycemia. Islets from newborn rodents have long been known to respond to lower concentrations of glucose than adult islets. For example, in a recent report, postnatal day 1 (P1) mouse islets released insulin in response to a low concentration of glucose (2.8 mmol/L) that had no effect on adult islets,
Does a Low Glucose Threshold for Insulin Release Play an Adaptive Role in the Fetus?
It may be important for fetal growth that the glucose threshold for insulin secretion in fetal islets be set lower than in the maternal islets. Continuous fetal secretion of insulin would be important to maintain fetal growth, especially when maternal glucose levels are decreased (eg, during overnight fasting; pregnant women have markedly reduced fasting tolerance and develop hyperketonemia much earlier than nonpregnant women52). The generation by the mother of high plasma ketone levels would
Discussion
Transitional neonatal hypoglycemia in normal newborns is a hypoketotic form of hypoglycemia, which appears to be caused by a lower glucose threshold for suppression of insulin secretion than would be normal for infants, children, or adults. This interpretation of previously published data could not have been made until recently when the clinical phenotypes of a wide range of genetic forms of hyperinsulinism were described. There may be additional factors contributing to transitional neonatal
References (54)
- et al.
Symptomatic neonatal hypoglycemia associated with toxemia of pregnancy
J Pediatr
(1959) - et al.
Neonatal hypoglycemia-answers, but more questions
J Pediatr
(2012) - et al.
Knowledge gaps and research needs for understanding and treating neonatal hypoglycemia: workshop report from Eunice Kennedy Shriver National Institute of Child Health and Human Development
J Pediatr
(2009) - et al.
The impact of gestational age and fetal growth on the maternal-fetal glucose concentration difference
Obstet Gynecol
(1996) - et al.
Clinical features and insulin regulation in infants with a syndrome of prolonged neonatal hyperinsulinism
J Pediatr
(2006) - et al.
Serum glucose levels in term neonates during the first 48 hours of life
J Pediatr
(1987) - et al.
The glycemic response of the newborn infant to epinephrine administration: a preliminary report
J Pediatr
(1950) - et al.
The effects of anesthesia and surgery on metabolic homeostasis in infancy and childhood
J Pediatr Surg
(1990) - et al.
Hyperinsulinism in infants and children: diagnosis and therapy
Adv Pediatr
(1976) - et al.
Determination of insulin for the diagnosis of hyperinsulinemic hypoglycemia
Best Pract Res Clin Endocrinol Metab
(2013)
Glycemic response to glucagon during fasting hypoglycemia: an aid in the diagnosis of hyperinsulinism
J Pediatr
Glucose production in response to glucagon is comparable in preterm AGA and SGA infants
Clin Nutr
Exaggerated epinephrine responses to hypoglycemia in normal and insulin-dependent diabetic children
J Pediatr
Hypoglycemic brain injury
Semin Neonatol
Neonatal symptomatic and asymptomatic hypoglycaemia: a follow-up study of 151 children
Dev Med Child Neurol
Fuels, hormones, and liver metabolism at term and during the early postnatal period in the rat
J Clin Invest
Development of hepatic fatty acid oxidation and ketogenesis in the newborn guinea pig
Pediatr Res
Blood glucose in the neonate and its clinical significance
N Engl J Med
Hyperinsulinism in infancy: diagnosis by demonstration of abnormal response to fasting hypoglycemia
Pediatrics
Glucose production in pregnant women at term gestation. Sources of glucose for human fetus
J Clin Invest
Mutations in the glucokinase gene of the fetus result in reduced birth weight
Nat Genet
Incidence of hypoglycemia in newborn infants classified by birth weight and gestational age
Pediatrics
Hyperinsulinaemic hypoglycaemia in small for dates babies
Arch Dis Child
Patterns of metabolic adaptation for preterm and term infants in the first neonatal week
Arch Dis Child
Blood glucose levels in a population of healthy, breast fed, term infants of appropriate size for gestational age
Arch Dis Child Fetal Neonatal Ed
Population meta-analysis of low plasma glucose thresholds in full-term normal newborns
Am J Perinatol
Metabolic fuel and hormone responses to fasting in newborn infants
Pediatrics
Cited by (163)
Infants of Diabetic Mothers
2023, Principles of NeonatologyNeonatal Hypoglycemia
2023, Principles of NeonatologyNeonatal Hypoglycemia and Hyperglycemia
2023, Avery's Diseases of the NewbornAssociation between pregnant women fasting duration and neonatal hypoglycemia: A prospective cohort study
2024, International Journal of Gynecology and Obstetrics
The authors declare no conflicts of interest.