Elsevier

The Journal of Pediatrics

Volume 166, Issue 6, June 2015, Pages 1520-1525.e1
The Journal of Pediatrics

Commentary
Re-Evaluating “Transitional Neonatal Hypoglycemia”: Mechanism and Implications for Management

https://doi.org/10.1016/j.jpeds.2015.02.045Get rights and content

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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

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    The authors declare no conflicts of interest.

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