NEO052019rev00071 14..29

Glucose Homeostasis in Newborns: An

Endocrinology Perspective

Emir Tas, MD,* Luigi Garibaldi, MD,

†

Radhika Muzumdar, MD

†

*Division of Endocrinology and Diabetes, Department of Pediatrics, Arkansas Children’s Hospital, Little Rock, AR

†

Division of Endocrinology, Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA

Education Gap

Signiﬁcant advances have been made in our understanding of the hormonal

regulation of glucose homeostasis immediately after birth; however,

controversies remain over the deﬁnition of clinically signiﬁcant neonatal

hypoglycemia, and interpretation of hormone concentrations in

asymptomatic neonates with hypoglycemia.

Abstract

Physiologic adaptations in the postnatal period, along with gradual

establishment of enteral feeding, help maintain plasma glucose

concentrations in the neonatal period. The deﬁnition of normal plasma

glucose in t he neonatal period has been a subject of debate because of a

lack of evidence linking a set plasma or blood glucose concentration to

clinical symptoms or predictors of short- and long-term outcomes.

However, there is consensus that maintaining plasma glucose in the

normal range f or age is important to prevent immediate and long-term

neurodevelopmental consequences of hypoglycemia or hyperglycemia.

The speciﬁc management strategy for abnormal gluc ose levels in neonates

depends on the underlying etiology, and interventions could include

nutritional changes, medications, hormone therapy, or even surgery. Here,

we will review the physiological processes that help maintain plasma

glucose in newborns and discuss the approach to a newborn with

disordered glucose homeostasis, with an emphasis on the endocrine basis

of abnormal glucose homeostasis.

Objectives After completing this article, readers should be able to:

1. Describe the physiology of glucose homeostasis in neonates immediately

after

birth.

2. Recognize that hypoglycemia during the ﬁrst 24 to 48 hours after birth is

nonketotic.

AUTHOR DISCLOSURE Drs Tas, Garibaldi,

and Muzu mdar have disclosed no ﬁnancial

relationships relevant to this article. This

commentary does not contain a discussion

of an unapproved/investigative use of a

commercial product/device.

ABBREVIATIONS

ACTH adrenocorticotropic hormone

ATP adenosine triphosphate

CNS central nervous system

DEND developmental delay, epilepsy,

and neonatal diabetes

FFA free fatty acid

GCK glucokinase

GDH glutamate dehydrogenase

GH growth hormone

GIR glucose infusion rate

HI/HA hyperinsulinism/

hyperammonemia

IGF-1 insulinlike growth factor 1

IGFBP-3 IGF-binding protein 3

IUGR intrauterine growth restriction

LGA large for gestational age

NDM neonatal diabetes mellitus

PES Pediatric Endocrine Society

PG plasma glucose

PNDM permanent neonatal diabetes

mellitus

SCHAD short-chain L-3-hydroxyacyl-CoA

dehydrogenase

SGA small for gestational age

TCA tricarboxylic acid

TNDM transient neonatal diabetes

mellitus

VLBW very low birthweight

e14 NeoReviews

at Stony Brook University on July 14, 2021http://neoreviews.aappublications.org/Downloaded from

3. Appreciate the counterregulatory hormonal responses to declining

plasma glucose concentrations in healthy neonates after the transitional

period.

4. Explain the steps and the role of the K-ATP channel in insulin secretion.

5. Describe the most common endocrine etiologies of neonatal

hypoglycemia.

6. Recognize the risk factors for neonatal hyperglycemia.

INTRODUCTION

The deﬁnition of normal plasma glucose in the newborn

period has been a subject of ongoing debate (1) because of a

lack of evidence linking a set plasma glucose (PG) or blood

glucose concentration to clinical symptoms or predictors of

short- and long-term outcomes. PG levels are lower in the

ﬁrst 48 hours after birth. In healthy term newborns with no

risk factors for hypoglycemia, the PG level correlates pos-

itively with postnatal age and birthweight on day 0, (2) and

breastfed babies have lower PG concentrations compared

with formula-fed babies. (3)(4) Although there is no con-

sensus on the PG concentration cutoffs in the ﬁrst 2 days

after birth among neonatologists and endocrinologists, the

Pediatric Endocrine Society (PES) recommends a prepran-

dial cutoff PG concentration of less than 50 mg/dL (2.8

mmol/L) for treatment in all neonates regardless of the

presence of risk factors within the ﬁrst 48 hours. (3) Beyond

the transition period of 48 to 72 hours after birth, neonates

can maintain PG levels similar to those in older children and

adults. (3) Here, we will review the physiological processes

that help maintain PG levels in newborns and discuss the

treatment approach for a newborn with disordered glucose

homeostasis, with an emphasis on the endocrine basis of

abnormal glucose homeostasis.

PHYSIOLOGY OF GLUCOSE HOMEOSTASIS IN THE

NEWBORN

During pregnancy, the fetus is dependent on the mother for

a constant supply of glucose. The relationship between

maternal and fetal PG concentrations is linear in mid and

late gestation, (5) with minimal difference in their PG levels.

However, maternal insulin does not cross the placenta and

the fetus makes its own insulin to maintain blood glucose

levels. (6) Both in utero and in postnatal life, insulin

secretion from the beta cells is tightly linked to PG concen-

trations. Uptake of glucose into the beta cells via a unique

glucose transporter (GLUT2) is the initial step in the insulin

secretory process. Once in the cytoplasm, glucose is phos-

phorylated to glucose-6-phosphate by the enzyme glucoki-

nase (GCK). Further metabolism of glucose through the

tricarboxylic acid (TCA) cycle and oxidative phosphorylation

results in generation of adenosine triphosphate (ATP).

Insulin secretion also occurs in response to other nutrients

such as free fatty acids (FFAs) and amino acids. (7)(8)

Leucine, alanine, and glutamine can undergo metabolism

via a-ketoglutarate and oxaloacetate through the TCA cycle

and generate ATP. (9) Increased ratio of ATP to adenosine

diphosphate causes closure of K-ATP channels, a type of

potassium channel composed of SUR and Kir6.2 subunits,

on the beta cell membrane. Closure of K-ATP channels

results in depolarization of the beta cell, which then triggers

the activation of the voltage-gated calcium channels followed

by calcium inﬂux. An increase in the intracellular calcium

concentration stimulates insulin release via exocytosis. (10)

Metabolic actions of insulin include an increase in cellular

glucose uptake, deposition of glucose as glycogen, lipogen-

esis in adipose tissue, and inhibition of breakdown of

triglycerides (lipolysis) and fatty acids (ketone body forma-

tion or ketogenesis). Importantly, insulin is also a major fetal

growth factor.

With cord clamping at birth, the steady source of glucose

from the mother to the infant is abruptly interrupted. In the

early hours after birth, until enteral intake is established, the

maintenance of PG levels is dependent on the activation of

glycogenolysis (breakdown of stored glycogen). Other mech-

anisms that can provide fuel sources, such as gluconeogen-

esis (formation of new glucose from noncarbohydrate

sources) or ketogenesis, are not established at birth. The

levels of glucagon and epinephrine increase after birth, and

these hormones mobilize glucose through glycogenolysis.

(11) This, along with suppressed insulin levels, maintains

lower but stable PG concentrations in the ﬁrst 4 to 48 hours

after birth. In this period, neonates are hypoketotic. (12)

Whether the reduced ketogenesis is because of immaturity

Vol. 21 No. 1

JANUARY 2020 e15

at Stony Brook University on July 14, 2021http://neoreviews.aappublications.org/Downloaded from

of enzymes, as shown in animal studies, or lower threshold

for insulin release in the immediate postnatal period, as

demonstrated by studies in isolated islets, remains to be

conﬁrmed. (13) Transcription of the gluconeogenic enzymes

and ketogenesis are potentially activated 12 to 24 hours after

birth in response to fatty acid–rich colostrum and changes

in hormonal milieu. (14)

Newborns with low birthweight and intrauterine growth

restriction (IUGR) have decreased glycogen stores at birth

and, therefore, are at risk for hypoglycemia. (15) These

newborns also have low fat stores that further increase their

risk for fuel insufﬁciency. Infants of diabetic mothers, on

the other hand, are at risk for hypoglycemia mainly because

of the presence of high circulating insulin levels and a delay

in glucagon increase. The degree of hyperglycemia and

resultant hyperinsulinemia in the fetus are a direct reﬂec-

tion of the metabolic control of diabetes in the pregnant

woman, with poorly controlled diabetes resulting in macro-

somia. (16) With the establishment of feeding, PG levels

gradually increase in most neonates and reach levels found

in older children and adults by 48 to 72 hours after birth. (3)

The dynamic interplay between nutrient availability and

hormones, such as insulin and other counterregulatory

hormones, helps maintain normoglycemia in fed and fast-

ing states. A low PG concentration triggers a complex, well-

coordinated, and step-wise neuroendocrine response to

counteract hypoglycemia. When the PG concentration

drops below 80 to 85 mg/dL (4.4–4.7 mmol/L), still within

the physiological range, the ﬁrst response is to shut off

insulin secretion to prevent further decrease in glucose

levels. (17)(18) This response also allows the brain to use

available glucose in the circulation because glucose can

easily pass through the blood-brain barrier in an insulin-

independent manner. Furthermore, the decrease in insulin

removes the inhibitory effect on lipolysis and ketogenesis,

thereby providing alternative fuel sources. (3)(12)(18)

Glucagon, growth hormone (GH), catecholamines, and

cortisol are counterregulatory hormones that help mobilize

stored glucose and provide alternative fuel sources for

energy. Hepatic glycogen serves as the ﬁrst and immediate

source of glucose. With a decrease in PG levels, the increase

in glucagon and epinephrine levels promotes hepatic gly-

cogenolysis and provides a source of glucose for a few hours.

(19) Epinephrine also inhibits insulin secretion and stim-

ulates glucagon release from the pancreatic islets. Epineph-

rine and GH promote lipolysis to provide FFAs, which serve

as an energy source for skeletal and cardiac muscle. Further

b-oxidation of fatty acids (mediated through actions of

epinephrine and glucagon) results in the formation of

ketone bodies, an alternative energy source for the brain.

A continuing decline in glucose concentrations stimulates

secretion of other counterregulatory hormones, namely

cortisol and GH. Cortisol, along with epinephrine, increases

gluconeogenesis from noncarbohydrate sources such as

alanine, lactate, and glycerol. Cortisol and GH produce

gluconeogenic substrates alanine and glycerol through mus-

cle breakdown and lipolysis, respectively. Also, cortisol

increases the transcription of enzymes involved in gluco-

neogenesis. The purpose of these complex systems is to

maintain PG within age-appropriate physiologic ranges and

to avoid hypoglycemia-related negative outcomes. The hor-

monal responses to hypoglycemia are s ummarized in

Fig 1.

Glucose is the primary energy source for the central

nervous system (CNS). However, the CNS can use alterna-

tive fuel sources, such as ketone bodies and lactate, for a

limited duration when glucose is scarce. Because the brain

is large compared with the rest of the body in the newborn,

the glucose needs of a newborn are signiﬁcantly higher than

those of older children and adults. Newborns need a glucose

infusion rate (GIR) of 4 to 6 mg/kg per minute compared

with adults who need 1 to 2 mg/kg per minute to maintain

PG levels within the normal range. The brains of newborns

are also more susceptible to the deleterious effects of low PG

levels.

HYPOGLYCEMIA IN THE NEWBORN

Neonates born small or large for gestational age (SGA or

LGA), infants of diabetic mothers, and preterm infants are at

risk for transient hypoglycemia. Screening for hypoglyce-

mia is the standard of care for these newborns. The inci-

dence of neonatal hypoglycemia during the transition

period among at-risk infants varies depending on the cutoff

chosen to identify hypoglycemia, the timing of screening in

relation to feeding, and the laboratory method used to

measure the blood glucose or PG. For instance, Harris

et al (4) used a cutoff of less than 47 mg/dL (2.6 mmol/L)

and reported an incidence of 51%, whereas Stark et al (20)

used a lowe r cuto ff —less than 40 mg/dL (2.2 mmol/L)—

and found a 27% incidence in the at-risk group regardless of

the age of the infant. The 2015 PES guideline on neonatal

hypoglycemia recommends maintaining preprandial PG

concentrations above 50 mg/dL (2.8 mmol/L) in the ﬁrst

48 hours after birth in high-risk neonates without a sus-

pected hypoglycemia disorder. (3) Screening is crucial to

identify and treat hypoglycemia promptly, because a grow-

ing body of evidence has shown a signiﬁcant a ssociation

between neonatal hypoglycemia and long-term negative

neurodevelopmental outcomes. (21)(22) McKinlay and

e16 NeoReviews

at Stony Brook University on July 14, 2021http://neoreviews.aappublications.org/Downloaded from

colleagues reported a ne gative association between the

duration of blood sugar concentrations outside the a rbi-

trary 54 to 72 mg/dL (3–4 mmol/L) range during the ﬁrst

48 hours after birth and neurodevelopmental outcomes

at 2 years of age. (22) Also, in the same cohort, worse

executive and visual-motor integration were noted in

children who h ad more seve re and f requent perio ds of

neonatal hypoglycemia at 4.5 years of age. (21)(22)

A healthy newborn is expected to maintain PG concen-

trations at or above 60 mg/dL (3.3 mmol/L) after 48 hours of

age. (3) Although recurrent hypoglycemia is a common

metabolic problem in neonates, recognizing neonates at

risk for a persistent hypoglycemia disorder is not as straight-

forward because most neonates are asymptomatic or exhibit

nonspeciﬁc symptoms. There is no pathognomonic sign or

symptom for hypoglycemia. Most of the common symp-

toms and signs are nonspeciﬁc, and include abnormal cry,

decreased feeding, jitteriness, irritability, pallor, cyanosis,

hypothermia, or diaphoresis. In severe cases, neonates may

present with lethargy, tachypnea, hemodynamic instabil-

ity, apnea, seizures, or even cardiac arrest. (23) A high

index of suspicion for a hypoglycemia disorder should be

maintained to identify true pathologies and establish

appropriate treatment. Though the presence of symp-

toms or sign s of hypoglycemia has been suggested t o

determine treatment thresholds, current clinical practice

is to treat t he hypoglycemia without any delay even in the

absence of symptoms.

Etiology of Hypoglycemia

A well-coordinated, dynamic balance among intake (feed-

ing), tissue use (glucose uptake, glycolysis, glycogen syn-

thesis), and endogenous production (gluconeogenesis,

glycogenolysis) of glucose is necessary to maintain

euglycemia. Therefore, a diminished exogenous or endog-

enous supply, or increased utilization of glucose can cause

hypoglycemia. Hypoglycemia can be classiﬁed as transient

or permanent, but there is no consensus regarding the

duration of the hypoglycemia to differentiate one form from

the other. Transient hypoglycemia typically resolves within

the ﬁrst few days to weeks.

When hypoglycemia persists beyond the ﬁrst 48 hours,

and hypoglycemia arising from maternal diabetes (the most

common type of transient neonatal hypoglycemia) and other

common etiologies (SGA, LGA, IUGR) are deemed unlikely,

there is a higher risk for permanent pathology. Clinically,

permanent hypoglycemia usually has genetic causes. The

differential diagnosis of persistent hypoglycemia varies

and includes endocrine causes (eg, hyperinsulinemia, GH

deﬁciency, hypocortisolism), as well as nonendocrine causes

(eg, inborn errors of metabolism). (24) The causes of neonatal

hypoglycemia are listed in Table 1. The timing of hypoglyce-

mia in relation to feedings can provide a clue to the

etiology. For instance, postprandial hypoglycemia could

be due to dumping syndrome or inborn errors of metab-

olism, where as fasting or postabsorptive hypoglycemia is

due to hyperinsulinism (HI), defects in glycogenolysis or

gluconeogenesis enzymes, or counterregulatory hormonal

insufﬁciency. (24)(25) Because neonates and young infants

are fed frequently, hypoglycemia may not occur until after

the time between consecutive feedings is spaced out long

enough.

Hyperinsulinism. Congenital HI is the most common

cause of persistent nonketotic hypoglycemia in the newborn

and results from dysregulated insulin secretion. HI could be

acquired or inherited, and it can be transient or permanent.

Initial biochemical tests cannot distinguish the different

forms or types of HI. Demonstrating an elevated insulin

concentration along with suppressed plasma ketones and

FFAs, and a positive response to a glucagon challenge (ie, an

increase in PG concentration over 30 mg/dL [1.6 mmol/L]

above baseline) at the time of the hypoglycemia is gener-

ally enough to establish the diagnosis of HI. (26)(27) In

some cases, the insulin level may be inappropriately nor-

mal (instead of low) despite a low PG level; therefore, the

term hyperinsulinism is preferred over hyperinsulinemia.

(26)(27) Once the diagnosis of HI is established, a trial of

diazoxide, a drug that stabilizes the K-ATP channel in the

open state, should be attempted as the ﬁrst-line medical

therapy. The success or failure of the diazoxide trial depends

on the extent of preservation of K-ATP channel function.

This approach has diagnostic value and may guide future

evaluations.

Figure 1. Hormonal responses to hypoglycemia.

Symptoms mediated

through sympathoadrenal and parasympathetic responses.

Vol. 21 No. 1 JANUARY 2020 e17

at Stony Brook University on July 14, 2021http://neoreviews.aappublications.org/Downloaded from

Stress-induced “transient HI” is an acquired cause of

persistent hypoglycemia (despite its name) and is usually

associated with birth asphyxia, IUGR/SGA infants, and

preeclampsia. (27)(28) The exact pathophysiology is not well

understood. It can last several days to weeks after birth;

however, some reports show that the course can rarely be

prolonged up to a year. (27) Diazoxide is usually effective in the

treatment of perinatal stress-induced HI. (29)

The incidence of inherited HI is estimated to be 1 in

50,000 live births; however, it can be diagnosed more often in

areas with higher rates of consanguineous marriages. (30)

Affected newborns are usually born LGA because of chronic

intrauterine exposure to elevated insulin, a fetal growth factor,

and present with fasting and postprandial hypoglycemia. (31)

HI could be secondary to channelopathies (ABBC8, KCNJ11),

enzyme anomalies (GCK, glutamate dehydrogenase [GDH],

short-chain L-3-hydroxyacyl-CoA dehydrogenase [SCHAD]),

or defects in a transcription factor (HNF4A). (30) Patholog-

ically, the lesion could be focal or diffuse. Inactivating

mutations of the ABCC8 and KNCJ11 as the cause of HI are

estimated to account for 60% of all identiﬁable mutations,

including the majority (85%) of focal or diffuse diazoxide

unresponsive forms. (31)(32) A ctivating mutations of GCK

also result in diazoxide unresponsive HI. (33)

HI resulting from dominant activating mutations of GDH,

encoded by GLUD1, is a common form of diazoxide-responsive

HI. (33) A mild, persistently elevated plasma ammonia level

independent of glucose levels is characteristic. This condition is

also known as hyperinsulinism/hyperammonemia (HI/HA) syn-

drome. Leucine, a branch-chained amino acid, directly regulates

insulin secretion independent of glucose by allosteric activation

of GDH. (34) Affected individuals with HI /HA syndrome have

increased sensitivity to leucine-stimulated insulin release. Another

rare type of diazoxide-responsive HI occurs because of impaired

SCHAD (encoded by HADH) activity that leads to disinhibition

of GDH. (35) Elevated 3-hydroxybutyryl-carnitine, a metabo-

lite that is routinely screened through the newborn screening

programs in some states, is a unique laboratory ﬁnding in

SCHAD-HI. (33)(36) Ammonia levels are normal in this

form. (37) There are a few other but rarer forms of congen-

ital HI, as described elsewhere in the literature. (32)(33)

Hypocortisolism. Adrenal insufﬁciency, primary or

secondary, is a rare cause of persistent neonatal hypogly-

cemia. Cortisol is one o f the key counterregulatory hor-

mones and contributes t o glucose homeostasis through

enhancement of gluconeogen esis. Cortisol deﬁc iency can

lead to hypoglycemia, particularly when enteral feeding

is delayed or not adequately established. There is no

TABLE 1. Etiologies of Neonatal Hypoglycemia

TRANSIENT PERSISTENT

Endocrine Causes

•

Infant of diabetic mother

•

Transient

(perinatal stress-HI)

•

Permanent

•

Channelopathies

•

Activating GLUD1 mutations

•

SCHAD deﬁciency

•

Other rare genetic HI

•

Panhypopituitarism

•

Isolated GH deﬁciency

•

Adrenal insufﬁciency (primary or secondary)

Nonendocrine Causes

•

Delayed enteral feeding

•

Inborn errors of metabolism

•

Prematurity

•

Galactosemia

•

IUGR/SGA

•

Glycogen storage disease

•

Sepsis

•

Gluconeogenic disorders

•

Maternal use of b-blockers

•

Fatty acid oxidation disorders

•

Polycythemia

•

Organic acidurias

•

Hepatic dysfunction

GH¼growth hormone; GLUD¼glutamate dehydrogenase; HI¼hyperinsulinism; IUGR¼intrauterine growth restriction; SCHAD¼short-chain

L-3-hydroxyacyl-CoA dehydrogenase; SGA¼small for gestational age.

Current nomenclature for this type of hypoglycemia, which may, however, last for several weeks or months.

e18 NeoReviews

at Stony Brook University on July 14, 2021http://neoreviews.aappublications.org/Downloaded from

consensus regarding normal values of cortisol and adre-

nocorticotropic hormone (ACTH) within the ﬁrst few

weeks of age. Low cortisol levels are often observed in

neonates, and are possibly caused by im ma tur it y of t he

hypothalamus-pituitary-adrenal axis and underdevel-

oped circadian rhythm. (38) Cortisol deﬁciency should

be suspected as the cause of persistent hypoglycemia in

neonates with midline defects such as holoprosence-

phaly or septo-optic dysplasia. In such circumstances,

cortisol deﬁciency is usually a component of panhypo-

pituitarism. As such, other pituitary hormone concen-

trations should be assessed, and appropriate treatment

should be initiated as applicable. A low cortisol level at

the time of hypoglycemia has poor speciﬁcity for the

diagnosis of adren al ins ufﬁciency. (39) An ACTH sti m-

ulation test will h elp diagnose adrenal i nsufﬁciency

and distinguish primary versus secondary causes of

hypocortisolism.

GH Deﬁciency. GH is another counterregulatory hor-

mone that is secreted from the anterior pituitary. GH

stimulates lipolysis, providing fatty acids and ketone bodies

as alternative fuel sources. GH deﬁciency can be isolated,

but it is mostly present as part of panhypopituitarism,

especially when the infant is born with a midline defect.

GH, cortisol, and thyroxine regulate bilirubin metabolism;

therefore, prolonged jaundice, especially when associated

with hypoglycemia, may be a sign of panhypopituitarism.

(40) A low GH level at the time of hypoglycemia has poor

speciﬁcity for the diagnosis of GH deﬁciency in older chil-

dren. (39) However, GH levels are elevated in neonates

regardless of hypoglycemia. Although a low GH level cannot

prove deﬁciency, a random GH concentration of at least 10

to 15 ng/mL (10–15 mg/L) is considered adequate within the

ﬁrst month after birth. (41) Repeated measurements of GH

levels should be performed (regardless of the glycemic level)

to increase diagnostic value. Provocative tests are rarely

indicated in the newborn period. Insulinlike growth factor

1 (IGF1) and IGF-binding protein 3 (IGFBP3) are produced

in the liver as a function of GH, and are sensitive markers of

circulating GH concentration. The plasma IGF1 level is

directly affected by the nutritional status; therefore, it could

be falsely low in IUGR/SGA neonates. The plasma IGFBP3

concentration, on the other hand, is more stable and is not

affected by the nutritional status. (42) Concomitant mea-

surement of these growth factors may aid in the diagnosis of

GH deﬁciency.

Physical Examination

A thorough physical examination should be performed in all

newborns with hypoglycemia regardless of the presence of

known risk factors for hypoglycemia. This practice will help

guide the diagnostic evaluation, thereby shortening the time

to an accurate diagnosis and initiation of appropriate treat-

ment. The diagnosis of LGA may be a sign of exposure to

high concentrations of insulin in utero as is the case in

infants of diabetic mothers or those born with congenital

HI. (43)(44) A diagnosis of SGA may indicate perinatal

stress, a well-described condition associated with tran-

sient HI. (27) Midline defects or brain malformations (eg,

holoprosencephaly) may suggest a pituitary hormone (eg,

GH, ACTH) deﬁciency, either isolated or combined. (45)

Infants with hypoglycemia and nystagmus may have

septo-optic dysplasia, a well-known midline brain anom-

aly that is highly associated with hypopituitarism. Pres-

ence of syndromic overgrowth conditions (macrocrania

and gigantism in Sotos syndrome, hemihypertrophy and

macroglossia in Beckwith-Wiedemann syndrome) in a

newborn with hypoglycemia may suggest hyperinsulin-

ism. (46)

Laboratory Evaluation

Screening for hypoglycemia is generally done via point-of-

care handheld glucometers. These devices use glucose

oxidase as a reducing agent and measure capillary blood

sugar in a matter of seconds. The capillary blood sugar

concentration measured by glucose meters may be 11%

lower than the PG level. (47) Therefore, a low glucometer

reading should always be veriﬁed with PG estimations to

avoid misinterpretation of the “critical sample” results.

Continuous glucose monitors are widely used in patients

with type 1 diabetes, but they h ave gained attention for

use in newborns only rec ently. They measur e glucose

concentration in the interstitial ﬂuid, which generally

correlates well w ith PG conce ntrations; however, hemo-

dynamic instabilities, including thermoregul ation prob-

lems due to comorbid situations or prematurity, can

potentially affect the reliability of the data. Continuous

glucose monitoring cannot be a substitute for PG mea-

surements for the diagnosis of hypoglycemia, a nd cur-

rently the evidence to suggest routine c linical use is

insufﬁcient. (47)(48)

An infant’s history or physical examination ﬁndings may

guide prioritization of some tests over others, but a consider-

able percentage of affected neonates usually do not have any

identiﬁable risk factors or physical examination ﬁndings.

Considering the limitations in daily blood draw volumes

and the prevalence of different etiologies, it is reasonable

to take a tiered approach (Fig 2). Most endocrinologists

recommend obtaining the following blood tests (critical

Vol. 21 No. 1

JANUARY 2020 e19

at Stony Brook University on July 14, 2021http://neoreviews.aappublications.org/Downloaded from

sample) as ﬁrst tier during a conﬁrmed hypoglycemic

episode (ie, PG concentration <50 mg/dL [2.8 mmol/L])

to rule out endocrin e etiologies: electrolytes, bicarbon-

ate, insulin, b-hydroxybutyrate, FFAs, cortisol, GH, and

lactate. A controlled fasting may be needed to induce

hypoglycemia if the neonate does not develop hypoglycemia

during a frequent feeding schedule. Further evaluation,

including measurement of serum amino acid or acyl car-

nitine proﬁles, urine organic acid proﬁle, advanced tests for

cortisol or GH deﬁciency, and testing for genetic disorders

of hyperinsulinism, will be guided based on clinical course,

associated features, and the results of the critical sample (Fig

2). Recent advances in molecular genetics have enabled

providers to identify the underlying pathology in the insulin

secretory process precisely. Many commercial laboratories

offer a congenital HI panel including the most commonly

implicated genes: ABCC8 (SUR1), KCNJ11 (Kir6.2), GCK

(glucokinase), GLUD1 (GDH), HADH (SCHAD), and

others. (31)(32)(33)

Management of Hypoglycemia

The goal in the management of neonatal hypoglycemia is

to restore PG levels to a safe, age-appropriate range. The

symptoms of the affected neonate will determine the route

of treatment, enteral versus parenteral, to achieve the

desired goal.

Enteral Feeding. Decreased substrate availability, as in

the case of delayed enteral feeding, is one of the most

common causes for hypoglyce mia in all newborns. Enteral

feeding s hould be instituted in all newborns as quickly as

possible unless there are contraindications because of

other m orbidities. Breastfeeding s hould be encouraged

for vari ous health and psychosocial beneﬁts. Breastfed

infants were shown to have signiﬁcantly less recurrent

low glucose concentrations compared with formula-fed

infants. (23) When hypoglycemia persists on a typical

feeding regimen, more frequent feeding regimens or

use of calorically dense formulas or fortiﬁcation of brea st

milk may be t ried.

Recent studies assessed the efﬁcacy of an oral 40%

dextrose gel for the treatment or prevention of asymptom-

atic hypoglycemia in at-risk infants. (49)(50) Harris et al

(51) assessed the efﬁcacy of a dextrose gel for t he treatment

of neonatal hypoglycemia in at-risk neonates. Neonate s

treated with a dextrose gel (200 mg/kg) had less treatment

failure, deﬁned as a blood sugar less than 47 mg/dL (2.6

mmol/L), 30 minutes after the sec ond dose. (51) In addi-

tion, the treatme nt group had less hypoglycemia-related

NICU admissions and highe r breastfeeding s uccess rates 2

weeks after the hypoglycemia event. (51) Importantly, the

groups did not differ with regard to the frequency of

neurosensory impairment at the 2-year follow-up. (52)

Similar ﬁndings of a lack of difference in long-term

Figure 2. N ewborn w ith persistent hypoglyc emia. BOHB¼b-hydroxybutyrate; FFA ¼free fatty acid; GH¼growth hormone; GLUD¼glutamate

dehydrogenase; HI¼hyperinsulinism; K-ATP¼adenosine triphosphate sensitive potassium channel; MCAD¼medium-chain acyl-CoA

dehydrogenase; PG¼plas ma glucose; SCHAD¼short-chain L-3-hydroxya cyl-CoA dehydrogenase; VLCAD ¼very-long-chain acyl-CoA

dehydrogenase.

e20 NeoReviews

at Stony Brook University on July 14, 2021http://neoreviews.aappublications.org/Downloaded from

neurologic outcomes after the use of a glucose gel were

reported at 2-year follow-up by Weston et al. (53) Although a

dextrose gel appears to be a promising modality for the

treatment of asymptomatic hypoglycemia because of its

rapid onset of action , availability, and lower cost, there is no

evidence to support its superiority to other nutritional

approaches including br east milk or formula feeding in

preventing hypoglycemia. Hegarty et al did not ﬁnd the use

of a dextrose gel to be efﬁcacious in preventing neonatal

hypoglycemia in at-risk neonates. (54)

TABLE 2. Etiology of Hyperglycemia in Newborn

Very low birthweight

Sepsis

Stress

Steroid therapy

Parenteral dextrose

Neonatal Diabetes Other Associated Features

Transient neonatal diabetes

6q24 duplication Intrauterine growth restriction

KCNJ11 mutations

ABCC8 mutations

ZFP57 Macroglossia, developmental delay

Permanent neonatal diabetes

Without exocrine pancreas defects

KCNJ11 mutations

ABCC8 mutations

INS gene mutations

Glucokinase mutations

With exocrine pancreas insufﬁciency

EIK2AK3 Skeletal dysplasia, liver disease

GATA4, GATA6 mutations Cardiac defects

PDX1 mutations

PTF1A Neurologic abnormalities, kidney disease

With systemic manifestations

FOXP3 mutations Immune dysregulation, dermopathy,

enteropathy,

Wolframin mutations Diabetes insipidus, optic atrophy, deafness,

cataracts

KCNJ11 DEND syndrome [developmental delay,

epilepsy, neonatal diabetes], neurologic

defects

GLIS3 Hypothyroidism, kidney cysts, liver ﬁbrosis,

glaucoma

NEUROD1 Learning difﬁculty, deafness, neurologic

deﬁcits

NEUROG3 Diarrhea

HNF1beta Urogenital defects

Vol. 21 No. 1 JANUARY 2020 e21

at Stony Brook University on July 14, 2021http://neoreviews.aappublications.org/Downloaded from

Intravenous Dextrose. When enteral feeding is contra-

indicated or the newborn suffers from symptomatic hypo-

glycemia, intravenous dextrose is the treatment of choice for

acute management. The standard approach is to give a 2

mL/kg (200 mg/kg) bolus of 10% dextrose followed by a

continuous dextrose infusion to achieve euglycemia (55);

however, recent evidence recommends caution when using

a dextrose bolus for the treatment of asymptomatic hypo-

glycemia. The main concern with unnecessary bolus treat-

ment is the potential association of rapid correction of

hypoglycemia and wide variability in glucose concentrations

with negative neurodevelopmental outcomes. (22) Under

normal circumstances, a GIR of 4 to 6 mg/kg per minute is

usually sufﬁcient in otherwise healthy full-term infants,

whereas premature infants may need higher rates, up to

6 to 8 mg/kg per minute, to maintain euglycemia. The GIR

should be titrated up to achieve the desired PG range.

Infants with hyperinsulinemia usually require higher

GIR (>15 mg/kg per min) compared to those without

hyperinsulinemia. Placement of a central venous catheter

may be needed to deliver high enough glucose concentra-

tions to stabilize PG levels. When dextrose infusion is not

enough, or a prolonged and persistent type of etiology is

suspected, pharmacologic treatment will be necessary.

Pharmacologic Options. Diazoxide has historically been

the ﬁrst-line treatment for HI and is the only drug approved

by the US Food and Drug Administration for the treatment

of HI. Diazoxide keeps the beta cell K-ATP channel open,

thereby preventing membrane depolarization, a necessary

step for normal insulin secretion. Localization of the defect

in the insulin secretory pathway and the type of genetic

mutation will determine diazoxide responsiveness. For

instance, neonates with recessive mutations of ABCC8

(encoding SUR1 protein) and KCNJ11 (encoding Kir6.2

protein) are unresponsive to diazoxide whereas infants with

activating mutations of GDH or inactivating mutations of

SCHAD are responsive to diazoxide. A typical starting dose

for diazoxide is 5 to 10 mg/kg per day divided in 3 doses. It

may take up to 2 to 3 days until the full therapeutic effect is

seen. The dose is usually titrated up gradually until the

desired effect is achieved with a maximum dose of 15 to 20

mg/kg per day; however, close monitoring is necessary for a

rare but potentially fatal, dose-dependent side effect of ﬂuid

retention and pulmonary hypertension at higher doses. (56)

Chlorothiazide may be added to the regimen to counteract

ﬂuid retention. Hypoalbuminemia was speculated to increase

the risk of diazoxide toxicity because this compound is

typically bound to plasma proteins at a high percentage.

(57) If diazoxide fails to restore euglycemia after a few days

of trial, then octreotide, a long-acting somatostatin analog,

may be considered because it directly inhibits the opening of

voltage-gated calcium channels which are more distal in

the insulin secretory pathway. (44)

Octreotide is used as an off-label treatment for diazoxide-

unresponsive HI; howeve r, its use has been linked to

necrotizing enterocolitis, particularly in preterm infants.

(58) It is usually given as a continuous infusion at a dose

5to40mg/kg per day. (59) Tachyphylaxis may develop after a

few days of use, even at escalating doses. Safety and efﬁcacy

have not been established in the context of HI treatment in

neonates; therefore, octreotide should be used with caution,

and every effort should be made to shorten the duration of

treatment.

Glucagon. Glucagon should be readily available at the

bedside of a neonate who is being treated for hypoglycemia

with labile control. In addition to its therapeutic effect,

glucagon injection also has a diagnostic value. (26) Gluca-

gon can be given in a continuous infusion as a bridge

therapy at a dose of 1 mg/day over 24 hours regardless of

the birthweight and gestational age of the neonate. (60)

Glucagon is generally well-tolerated; however, rebound

hypoglycemia, vomiting, hyponatremia, and a rare skin

reaction, erythema necrolyticum migrans, have been

reported. (61)(62)(63)

Glucocorticoids. Glucocorticoids hypothetically help

with the stabilization of blood sugar via enhancement of

gluconeogenesis; however, studies have shown that in-

fants treated with hydrocortisone or dexamethasone alone

required additional medical treatment to achieve euglyce-

mia. (61)(64)(65) The potential risks associated with the use

of glucocorticoid therapy outweigh the beneﬁts, unless the

etiology of hypoglycemia is adrenal insufﬁciency. The use of

glucocorticoids for the treatment of persistent hypoglycemia

of unknown etiology is not recommended.

rowth Hormone. GH will stabilize PG levels if the

etiology of hypoglycemia is GH deﬁciency. Screening

should be undertaken for other pituitary hormones if the

neonate is suspected to have hypoglycemia resulting from

GH deﬁciency or adrenal insufﬁciency. An endocrinology

consultation early in the course of management should be

considered.

Surgery. Failure of medical intervention to stabilize PG

levels warrants exploration of surgery as an alternative

treatment for hypoglycemia. Specialized imaging using

[

F]ﬂuoro-L-DOPA positron emission tomography with com-

puted tomography distinguishes focal from diffuse lesions

in the pancreas and guides surgical intervention. There are

currently only 2 congenital HI centers (Congenital Hyper-

insulinism Center at the Children’s Hospital of Philadel-

phia, Philadelphia, PA and Cook Children’s Hyperinsulinism

e22 NeoReviews

at Stony Brook University on July 14, 2021http://neoreviews.aappublications.org/Downloaded from

Center, Fort Worth, TX) in the United States where

advanced imaging and precision surgery can be per-

formed, including removal of a focal lesion or near total

pancreatectomy.

When is a Newborn with a History of Hypoglycemia Safe

for Discharge?

The 2015 PES recommendations state that a preprandial PG

level of at least 60 mg/dL (3.3 mmol/L) is within the safe

range for discharge for most infants; but a concentration of

70 mg/dL or higher (‡3.9 mmol/L) is recommended if a

persistent hypoglycemia disorder is suspected, or if the

infant is receiving pharmacologic treatment for hypoglyce-

mia. (3) A safety fast should always be done to determine

whether the neonate could be safely discharged from the

hospital. Duration of a safety fast is typically 6 to 8 hours in

the ﬁrst month after birth, which can be conducted by

skipping a mealtime feeding while closely monitoring the

blood sugar until the test is complete. The infant’s blood

sugar level should remain above 60 mg/dL ([3.3 mmol/L] or

70 mg/dL [3.9 mmol/L] if any medication treatment has

begun or the patient is suspected to have hypoglycemia with

a permanent etiology) before the infant is considered safe to

be discharged.

HYPERGLYCEMIA

In a term newborn, hyperglycemia is a much less common

clinical problem than hypoglycemia. However, it is a com-

mon metabolic abnormality in low-birthweight, preterm,

and critically ill newborns. (23) The deﬁnition of hypergly-

cemia in newborns varies, with the most accepted being any

PG concentration greater than 125 mg/dL (6.9 mmol/L).

However, studies examining consequences of hyperglyce-

mia or treatment thresholds have used varying and higher

glucose thresholds. For instance, Zamir et al set levels more

than 180 mg/dL (10 mmol/L) as the threshold for hyper-

glycemia when evaluating consequences, and Lemelman

et al recommend treatment with insulin if glucose levels are

above 250 mg/dL (13.8 mmol/L). (66)(67)

It is important to recognize and manage hyperglycemia

in newborns as it could have signiﬁcant consequences.

Immediate consequences include dehydration, ketosis, dia-

betic ketoacidosis, poor growth, weight loss, poor perfusion,

and susceptibility to infection; (23) long-term consequences

include negative effects on neurodevelopmental outcomes.

(68)(69) Changes in osmolality and blood ﬂow, endothelial

injury, intracellular acidosis, and increased oxidative stress

have been implicated in hyperglycemia-mediated injury and

its consequences. (70)

Etiology of Hyperglycemia

Risk factors for hyperglycemia in preterm and very-low-

birthweight (VLBW) infants include critical illness, infec-

tion, stress, medications, parenteral glucose administration,

and inadequate pancreatic insulin production. (71) Infec-

tions, sepsis, and stress lead to release of cytokines and

stress hormones that decrease peripheral glucose utilization

as well as increase gluconeogenesis, thereby contributing to

hyperglycemia. (23)(70) When glucose levels are persis-

tently greater than 250 mg/dL (13.8 mmol/L) in the absence

of identiﬁable causes, and persist beyond 7 to 10 days of age,

neonatal diabetes mellitus (NDM) should be considered.

(66)

NDM is rare and estimated to affect 1 in 90,000 to

160,000 live births. (66) By deﬁnition, NDM is diabetes

diagnosed by 12 months of age, though most infants are

diagnosed by 6 months of age. It can result from a range of

defects in the beta cells that affect normal development,

glucose sensing, metabolism, insulin synthesis, insulin

secretion, or enhance beta cell apoptosis. The etiology of

NDM is most often monogenic, especially in term infants.

Preterm infants could also have a monogenic etiology for

their diabetes (31% of cases) and tend to present at an earlier

age than full-term infants. (72) NDM could be transient

(TNDM) or permanent (PNDM).

Infants with TNDM present earlier on average compared

with infants with the permanent form of NDM and outgrow

their need for insulin by 3 to 18 months of age. (73) Diabetes

may recur at puberty, pregnancy, or in older age, and in

some cases, permanent diabetes mellitus may result. The

most common cause of TNDM (70%) is related to the 6q24

region of the chromosome. Normally, 6q24 is only pater-

nally expressed. TNDM occurs when 2 copies of this region

are expressed due to uniparental disomy, duplication of the

paternal allele, or lack of suppression of expression of

maternal allele. Other reported features include IUGR,

umbilical hernia, macroglossia, deafness, hypotonia, and

developmental disabilities. The second most common cause

of TNDM (25%) is heterozygous mutations in ABCC8 or

KCNJ11 (both genes are located in chromosome

Rare causes of TNDM include homozygous or compound

heterozygous mutations in transcription factor Zinc Finger

protein 57 (gene located in chromosome 6p22.

The most common defects leading to PNDM were found

in KCNJ11 and ABCC8, genes that encode subunits of the K-

ATP channel in the beta cell, accounting for 45% of cases

when there is parental consanguinity. (74)(75)(76)(77)

KCNJ11 channels are also found in the brain, and therefore

children with mutations in KCNJ11 may have other

Vol. 21 No. 1

JANUARY 2020 e23

at Stony Brook University on July 14, 2021http://neoreviews.aappublications.org/Downloaded from

neurologic features such as developmental delay, epilepsy,

and neonatal diabetes (DEND syndrome). Indeed, neuro-

logic features are the most common extrapancreatic feature

in infants with NDM. (74) Insulin gene mutations (INS1)

account for 10% to 15% of PNDM cases, (78) and do not

differ in incidence based on parental consanguinity. (74)

Defects in GLUT2 or GCK, leading to impaired or absent

sensing of glucose by the beta cell, and mutations of

voltage-gated calcium channels can also result in NDM.

(79)(80)(81)

Other genes implicated in NDM include genes involved

in beta cell health, immunity, and pancreatic development.

Beta cell destruction is associated with mutations in INS,

EIF2AK3 (Wolcott-Rallison syndrome), IER3IP1, FOXP3

(IPEX syndrome), and WFS1 (Wolfram syndrome). (66)

In these instances, the presence of other clinical features

points to speciﬁc etiologies, though some associated fea-

tures may appear much later. Speciﬁcally, FOXP3 defects

present with immune dysregulation, skin rash, and diar-

rhea, many of which may be noted later in life. (82) Defects

in WFS-1 (Wolfram syndrome) should be considered in an

infant with diabetes, deafness, and ocular manifestations,

though diabetes is usually a later presentation. Generalized

defects in the genes involved in pancreatic development

such as PDX1 (IPF1), PTF1A, HNF1B, RFX6, GATA4, GA-

TA6, GLIS3, NEUROG3, NEUROD1, PAX6, NKX2-2, and

MNX1 can result in exocrine pancreatic insufﬁciency and

neonatal diabetes. (66)

The etiology of hyperglycemia in the newborn is sum-

marized in Table 2.

Diagnosis of Hyperglycemia

Hyperglycemia in the neonate can be insidious and only

detected on routine laboratory tests or urinalysis. Infants are

at risk for dehydration, acidosis, failure to thrive, and poor

weight gain. Symptoms and signs such as tachypnea and

desaturations may be seen if there is progression to diabetic

ketoacidosis. Rarely, features of altered sensorium or stroke

can be seen in response to hyperviscosity and severe

hyperglycemia.

The possibility of an infection should be considered in

neonates with hyperglycemia, especially preterm and VLBW

infants, because hyperglycemia may be a presenting sign of

an infection or sepsis. A thorough family history should be

elicited in newborns with hyperglycemia and suspected

NDM, because the genetic mutations that lead to NDM

may be inherited in an autosomal dominant, autosomal

recessive, or X-linked manner. IUGR and low birthweight

are noted in NDM associated with KCNJ11, ABCC8, 6q24,

INS, and GCK mutations.

The physical examination can offer clues to the etiology

of diabetes, though some of the features of syndromic

diabetes may not become clinically evident until later. In

the context of neonatal hyperglycemia, presence of macro-

glossia and umbilical hernia suggest 6q24-related TNDM;

the presence of cardiac defects may point to mutations in

GATA6 or GATA4; and the presence of diarrhea may point to

exocrine pancreatic insufﬁciency and mutations in NeuroG3

or FOXP3. Neurologic manifestations may occur in NDM of

many genetic etiologies including KCNJ11 mutations. The

ﬁnding of skeletal dysplasia along with NDM suggests

Wolcott-Rallison syndrome. (83) For a more detailed list

of etiologies, we refer the reader to the review on NDM by

Lemelman et al. (66)

Management of Hyperglycemia

The initial management of hyperglycemia should include

decreasing intravenous dextrose concentrations, correc-

tion of dehydration, addressing the underlying conditions

that could contribute to stress (eg, hypoxia, acidosis, poor

perfusion, infections), and if possible, stopping medica-

tionssuchassteroidsorcatecholaminesthatcouldcon-

tribute to hyperglycemia. Increasing the rate of the amino

acid infu sion could increase protein synthesis, anabo-

lism, and insulin secret ion, thereby reducing hype r-

glycemia. Establishing enteral feedings to augment

gut-derived hormones (incretins) and decreasing lipid

infusion rates to d ecrease gluconeogen esis and insulin

resistance have also been sh own t o help correct hyper-

glycemia. (23)(84)

Hyperglycemia may persist in spite of all the aforemen-

tioned interventions, and some preterm neonates may need

short-term insulin therapy. Zamir et al reported a lower

mortality in extremely preterm infants with hyperglycemia

who were treated with insulin (67); however, larger, con-

trolled, prospective studies are needed to validate these

observations. Care should be given to prevent hypoglycemia

with insulin therapy, because hypoglycemia as well as

glucose variability can affect outcomes. (85)

When a diagnosis of NDM is suspected, ultrasonography

of the pancreas should be performed to look for develop-

mental defects. Genetic testing for NDM should be per-

formed to conﬁ rm the diagnosis and establish the etiology,

because therapies vary based on underlying cause. In

infants diagnosed with NDM, insulin or sulfonylureas are

the main lines of therapy. Mutations in K-ATP channel

(KCNJ11 and ABCC8 mutations) may respond to sulfonyl-

ureas. A trial of sulfonylurea in consultation with endocri-

nology may be warranted in neonates with NDM even

before the genetic diagnosis is conﬁrmed. (86)(87)(88)

e24 NeoReviews

at Stony Brook University on July 14, 2021http://neoreviews.aappublications.org/Downloaded from

Sulfonylurea treatment may ameliorate neurologic out-

comes in DEND syndrome. (88)(89) Families with an infant

with IPEX syndrome may need counseling, and early stem

cell transplantation could be beneﬁcial in these cases. (82)

SUMMARY

Concentrations of PG i n the newborn period are mai n-

tained in the normal range for age through postnatal

adaptations and gradual establi shment of enteral feedin g.

In the event of hypoglycemia, a concerted counter re-

gulatory mechanism coordinates various physiological

processes to provide glucose or alternative fuel sources

such as ketone bodies, especiall y to the brain. Maintenance

of PG in the normal range is important to prevent imme-

diate and long-term consequences of hypoglycemia or

hyperglycemia on neurodevelopment. The spec iﬁcman-

agement strategy for abnormal glucose levels depends on

the underlying etiology, and inte rventions could include

nutritional changes, medications, hormone therapy, or

even surgery.

References

1. Hay WW Jr, Raju TN, Higgins RD, Kalhan SC, Devaskar SU.

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;155(5):612–617

2. Swenne I, Ewald U, Gustafsson J, Sandberg E, Ostenson CG. Inter-

relationship between serum concentrations of glucose, glucagon

and insulin during the ﬁrst two days of life in healthy newborns.

Acta Paediatr. 1994;83(9):915–919

3. Thornton PS, Stanley CA, De Leon DD, et al; Pediatric Endocrine

Society. Recommendations from the Pediatric Endocrine Society

for Evaluation and Management of Persistent Hypoglycemia

in Neonates, Infants, and Children. JPediatr.2015;167(2):

238–245

4. Harris DL, Weston PJ, Harding JE. Incidence of neonatal

hypoglycemia in babies identiﬁed as at risk. J Pediatr.

2012;161(5):787–791

5. Bozzetti P, Ferrari MM, Marconi AM, et al. The relationship of

maternal and fetal glucose concentrations in the human from

midgestation until term. Metabolism. 1988;37(4):358–363

6. König S, Vest M, Stahl M. Interrelation of maternal and foetal

glucose and free fatty acids. The role of insulin and glucagon. Eur J

Pediatr. 1978;128(3):187–195

7. Lu M, Li C. Nutrient sensing in pancreatic islets: lessons from

congenital hyperinsulinism and monogenic diabetes. Ann N Y Acad

Sci. 2018;1411(1):65–82

8. Nolan CJ, Madiraju MSR, Delghingaro-Augusto V, Peyot ML,

Prentki M. Fatty acid signaling in the b-cell and insulin secretion.

Diabetes. 2006;55(suppl 2):S16–S23

9. McClenaghan NH, Barnett CR, O’Harte FPM, Flatt PR.

Mechanisms of amino acid-induced insulin secretion from the

glucose-responsive BRIN-BD11 pancreatic B-cell line. J Endocrinol.

1996;151(3):349–357

10. Matschinsky FM. Banting Lecture 1995: a lesson in metabolic

regulation inspired by the glucokinase glucose sensor paradigm.

Diabetes. 1996;45(2):223–241

11. Sperling MA, DeLamater PV, Phelps D, Fiser RH, Oh W, Fisher DA.

Spontaneous and amino acid-stimulated glucagon secretion in the

immediate postnatal period: relation to glucose and insulin. J Clin

Invest. 1974;53(4):1159–1166

12. Stanley CA, Rozance PJ, Thornton PS, et al. Re-evaluating

“transitional neonatal hypoglycemia”: mechanism and implications

for management. J Pediatr. 2015;166(6):1520–5.e1

13. Sodoyez-Goffaux F, Sodoyez JC, De Vos CJ, Foà PP. Insulin and

glucagon secretion by islets isolated from fetal and neonatal rats.

Diabetologia

. 1979;16(2):121–123

14.

Girard J. Metabolic adaptations to change of nutrition at birth. Biol

Neonate. 1990;58(suppl 1):3–15

15. Járai I, Mestyán J, Schultz K, Lázár A, Halász M, Krassy I. Body size

and neonatal hypoglycemia in intrauterine growth retardation.

Early Hum Dev. 1977;1(1):25–38

16. Mallet E, de Menibus CH, Basuyau JP, Brunelle P. Hyperinsulinism

in infants of diabetic mothers: suppression by somatostatin

infusion. Lancet . 1980;1(8171):776–777

17. Bolli GB, Fanelli CG. Physiology of glucose counterregulation to

hypoglycemia. Endocrinol Metab Clin North Am.

1999;28(3):467–493, v

American Board of Pediatrics

Neonatal-Perinatal Content

Speciﬁcations

•

Know the amino acid substrates for gluconeogenesis.

•

Know the fuels used for brain metabolism.

•

Know the relationship of maternal blood glucose to fetal glucose

uptake and metabolism.

•

Know the normal range of endogenous glucose production in

term and preterm infants.

•

Know the causes (including hyperinsulinemic hypoglycemia) of

neonatal hypoglycemia syndromes.

•

Recognize the clinical and laboratory features of neonatal

hypoglycemia.

•

Recognize the approach to therapy and prevention of neonatal

hypoglycemia.

•

Know the potential sequelae of neonatal hypoglycemia.

•

Know the causes, including genetic disorders and other clinical

conditions, of neonatal hyperglycemia, including transient

diabetes mellitus.

•

Know the clinical and laboratory features and approach to

therapy of neonatal hyperglycemia, including transient diabetes

mellitus.

Vol. 21 No. 1 JANUARY 2020 e25

at Stony Brook University on July 14, 2021http://neoreviews.aappublications.org/Downloaded from

18. Tesfaye N, Seaquist ER. Neuroendocrine responses to

hypoglycemia. Ann N Y Acad Sci. 2010;1212:12–28

19. Sprague JE, Arbeláez AM. Glucose counterre gulatory responses to

hypoglycemia. Pediatr Endocrinol Rev. 2011;9(1):463–473, quiz 474–

475

20. Stark J, Simma B, Blassnig-Ezeh A. Incidence of hypoglycemia in

newborn infants identiﬁ ed as at risk [published online ahead of

print January 27]. J Matern Neonatal Med. 2019:1–6. doi: 10.1080/

14767058.2019.1568985

21. McKinlay CJD, Alsweiler JM, Anstice NS , et al; Children With

Hypoglycemia and Their Later Development (CHYLD) Study Team.

Association of neonatal glycemia with neurodevelopmental

outcomes at 4.5 years. JAMA Pediatr. 2017;171(10):972–983

22. McKinlay CJD, Alsweiler JM, Ansell JM, et al; CHYLD Study Group.

Neonatal glycemia and neurodevelopmental outcomes at 2 years. N

Engl J Med. 2015;373(16):1507–1518

23. Hemachandra AH, Cowett RM. Neonatal hyperglycemia. Pediatr

Rev. 1999;20(7):e16–e24. doi: 10.1542/pir.20-7-e16

24. Marles SL, Casiro OG. Persistent neonatal hypoglycemia: diagnosis

and management. Paediatr Child Health. 1998;3(1):16–19

25. Demirbilek H, Hussain K. Congenital hyperi nsulinism: diagnosis

and treatment update. J Clin Res Pediatr Endocrinol. 2017;9(Suppl

2):69–87

26. De León DD, Stanley CA. Determination of insulin for the

diagnosis of hyperinsulinemic hypoglycemia. Best Pract Res Clin

Endocrinol Metab. 2013;27(6):763–769

27. Hoe FM, Thornton PS, Wanner LA, Steinkrauss L, Simmons RA,

Stanley CA. Clinical features and insulin regulation in infants with a

syndrome of prolonged neonatal hyperinsulinism. J Pediatr.

2006;148(2):207–212

28. Palladino AA, Bennett MJ, Stanley CA. Hyperinsulinism in infancy

and childhood: when an insulin level is not always enough. Clin

Chem. 2008;54(2):256–263

29. Palladino A, Ackermann A. Managing congenital hyperinsulinism:

improving outcomes with a multidisciplinary approach. Res Rep

Endocr Disord. 2015;5:103–117. doi: 10.2147/RRED.S56608

30. Arnoux JB, Verkarre V, Saint-Martin C, et al. Congenital

hyperinsulinism: current trends in diagnosis and therapy. Orphanet

J Rare Dis. 2011;6:63

31. Lord K, De León DD. Hyperinsulinism in the neonate. Clin

Perinatol. 2018;45(1):61–74

32. Vajravelu ME, De León DD. Genetic characteristics of patients

with congenital hyperinsulinism. Curr Opin Pediatr.

2018;30(4):568–

575

33.

Stanley CA. Perspective on the genetics and diagnosis of congenital

hyperinsulinism disorders. J Clin Endocrinol Metab.

2016;101(3):815–826

34. Yang J, Chi Y, Burkhardt BR, Guan Y, Wolf BA. Leucine metabolism

in regulation of insulin secretion from pancreatic beta cells. Nutr

Rev. 2010;68(5):270–279

35. Fahien LA, Macdonald MJ. The complex mechanism of glutamate

dehydrogenase in insulin secretion. Diabetes.

2011;60(10):2450–2454

36. Molven A, Matre GE, Duran M, et al. Familial hyperinsulinemic

hypoglycemia caused by a defect in the SCHAD enzyme

of mitochondrial fatty acid oxidation. Diabetes. 2004;53(1):221–227

37. Heslegrave AJ, Hussain K. Novel insights into fatty acid oxidation,

amino acid metabolism, and insulin secretion from studying

patients with loss of function mutations in 3-hydroxyacyl-CoA

dehydrogenase. J Clin Endocrinol Metab. 2013;98(2):496–501

38. Hyman SJ, Novoa Y, Holzman I. Perinatal endocrinology: common

endocrine disorders in the sick and premature newborn. Pediatr

Clin North Am. 2011;58(5):1083–1098, ix

39. Kelly A, Tang R, Becker S, Stanley CA. Poor speciﬁcity of low growth

hormone and cortisol levels during fasting hypoglycemia for the

diagnoses of growth hormone deﬁciency and adrenal insufﬁciency.

Pediatrics. 2008;122(3):e522–e528

40. Eckert M, Bechtold S, Otto R, Ensenauer R, Koletzko S, Schwarz

HP. Panhypopituitarism as a cause for prolonged jaundice and

cholestasis in a newborn with hypoglycemia.

[Panhypopituitarismus als ursache von icterus prolongatus und

cholestase bei einem neugeborenen mit hypoglykämie] Padiatr

Prax. 2011;77(1):55–61

41. Hawkes CP, Grimberg A. Measuring growth hormone and insulin-

like growth factor-I in infants: what is normal? Pediatr Endocrinol

Rev. 2013;11(2):126–146

42. Stanley T. Diagnosis of growth hormone deﬁciency in childhood.

Curr Opin Endocrinol Diabetes Obes. 2012;19(1):47–52

43. Agrawal RK, Lui K, Gupta JM. Neonatal hypoglycaemia in infants of

diabetic mothers. J Paediatr Child Health. 2000;36(4):354–356

44. De León DD, Stanley CA. Mechanisms of disease: advances in

diagnosis and treatment of hyperinsulinism in neonates. Nat Clin

Pract Endocrinol Metab. 2007;3(1):57–68

45. Gandhi K. Approach to hypoglycemia in infants and children. Transl

Pediatr. 2017;6(4):408–420

46. Cohen MM. A comprehensive and critical assessment of

overgrowth and overgrowth syndromes. Adv Hum Genet.

1989;18:181

–303,

373–376. doi: 10.1007/978-1-4613-0785-3_4

47. Cengiz E, Tamborlane WV. A tale of two compartments: interstitial

versus blood glucose monitoring. Diabetes Technol Ther.

2009;11(suppl 1):S11–S16

48. McKinlay CJD, Chase JG, Dickson J, Harris DL, Alsweiler JM,

Harding JE. Continuous glucose monitoring in neonates: a review.

Matern Health Neonatol Perinatol. 2017;3:18

49. Bennett C, Fagan E, Chaharbakhshi E, Zamﬁrova I, Flicker J.

Implementing a protocol using glucose gel to treat neonatal

hypoglycemia. Nurs Womens Health. 2016;20(1):64–74

50. Scheans P, Bennett C, Harris D. Using dextrose (glucose) gel to

reverse neonatal hypoglycemia. Neonatal Netw. 2017;36(4):233–238

51. Harris DL, Weston PJ, Signal M, Chase JG, Harding JE. Dextrose gel

for neonatal hypoglycaemia (the Sugar Babies Study): a

randomised, double-blind, placebo-controlled trial. Lancet.

2013;382(9910):2077–2083

52. Harris DL, Alsweiler JM, Ansell JM, et al. Outcome at 2 years after

dextrose gel treatment for neonatal hypoglycemia: follow-up of a

randomized trial. J Pediatr. 2016;170:54–59.e1-2. doi: 10.1016/

j.jpeds.2015.10.066

53. Weston PJ, Harris DL, Battin M, Brown J, Hegarty JE, Harding JE.

Oral dextrose gel for the treatment of hypoglycaemia in newborn

infants. Cochrane Database Syst Rev. 2016; (5):CD011027

54. Hegarty JE, Harding JE, Crowther CA, Brown J, Alsweiler J. Oral

dextrose gel to prevent hypoglycaemia in at-risk neonates. Cochrane

Database Syst Rev. 2017; 10.1002/14651858.CD012152.pub2

55. Lilien LD, Pildes RS, Srinivasan G, Voora S, Yeh TF. Treatment of

neonatal hypoglycemia with minibolu s and intraveous glucose infus ion.

JPediatr. 1980;97(2):295–29 8 10.1016/S0022-3476(80)80499-9

e26 NeoReviews

at Stony Brook University on July 14, 2021http://neoreviews.aappublications.org/Downloaded from

56. Herrera A, Vajravelu ME, Givler S, et al. Prevalence of adverse

events in children with congenital hyperinsulinism treated with

diazoxide. J Clin Endocrinol Metab. 2018;103(12):4365–4372

57. Tas E, Mahmood B, Garibaldi L, Sperling M. Liver injury may

increase the risk of diazoxide toxicity: a case report. Eur J Pediatr.

2015;174(3):403–406

58. McMahon AW, Wharton GT, Thornton P, De Leon DD. Octreotide

use and safety in infants with hyperinsulinism. Pharmacoepidemiol

Drug Saf. 2017;26(1):26–31

59. Charsha DS, McKinley PS, Whitﬁeld JM. Glucagon infusion for

treatment of hypoglycemia: efﬁcacy and safety in sick, preterm

infants. Pediatrics. 2003;111(1):220–221

60. Miralles RE, Lodha A, Perlman M, Moore AM. Experience with

intravenous glucagon infusions as a treatment for resistant

neonatal hypoglycemia. Arch Pediatr Adolesc Med.

2002;156(10):999–1004

61. Belik J, Musey J, Trussell RA. Continuous infusion of glucagon

induces severe hyponatremia and thrombocytopenia in a premature

neonate. Pediatrics. 2001;107(3):595–597

62. Wald M, Lawrenz K, Luckner D, Seimann R, Mohnike K, Schober E.

Glucagon therapy as a possible cause of erythema necrolyticum

migrans in two neonates with persistent hyperinsulinaemic

hypoglycaemia. Eur J Pediatr. 2002;161(11):600–603

63. Horev Z, Ipp M, Levey P, Daneman D. Familial hyperinsulinism:

successful conservative management. J Pediatr.

1991;119(5):717–720

64. Bhowmick SK, Lewandowski C. Prolonged hyperinsulinism and

hypoglycemia in an asphyxiated, small for gestation infant. Case

management and literature review. Clin Pediatr (Phila).

1989;28(12):575–578

65. Lindley KJ, Dunne MJ, Kane C, et al. Ionic control of beta cell

function in nesidioblastosis. A possible therapeutic role for calcium

channel blockade. Arch Dis Child. 1996;74(5):373–378

66. Lemelman MB, Letourneau L, Greeley SAW. Neonatal diabetes

mellitus: an update on diagnosis and management. Clin Perinatol.

2018;45(1):41–59

67. Zamir I, Tornevi A, Abrahamsson T, et al. Hyperglycemia in

extremely preterm infants—insulin treatment, mortality and

nutrient intakes. J Pediatr. 2018;200:104–110.e1

68. van der Lugt NM, Smits-W intje ns VEHJ, van Zwieten PHT, W alth er FJ.

Short and long term outcome of neonatal hyperglycemia in very preterm

infants: a retrospective follow-up study. BMC Pediatr .2010;10:52

69. Kao LS, Morris BH, Lally KP, Stewart CD, Huseby V, Kennedy KA.

Hyperglycemia and morbidity and mortality in extremely low birth

weight infants. J Perinatol. 2006;26(12):730–

736

70. Brealey D, Singer M. Hyperglycemia in critical illness: a review.

J Diabetes Sci Technol. 2009;3(6):1250–1260

71. Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, et al. Prevalence

and determinants of hyperglycemia in very low birth weight infants:

cohort analyses of the NIRTURE study. J Pediatr. 2010;157(5):715-

9.e1-3. doi: 10.1016/j.jpeds.2010.04.03 2

72. Besser REJ, Flanagan SE, Mackay DGJ, et al. Prematurity and

genetic testing for neonatal diabetes. Pediatrics.

2016;138(3):e20153926

73. Letourneau LR, Carmody D, Wroblewski K, et al. Diabetes

presentation in infancy: high risk of diabetic ketoacidosis. Diabetes

Care. 2017;40(10):e147–e148

74. De Franco E, Flanagan SE, Houghton JAL, et al. The ef fect of early,

comprehensive genomic testing on clinical care in neonatal

diabetes: an international cohort study. Lancet.

2015;386(9997):957–963

75. Hattersley AT, Ashcroft FM. Activating mutations in Kir6.2 and

neonatal diabetes: new clinical syndromes, new scienti ﬁc insights,

and new therapy. Diabetes. 2005;54(9):2503–2513

76. Gloyn AL, Pearson ER, Antcliff JF, et al. Activating mutations in the

gene encoding the ATP-sensitive potassium-channel subunit Kir6.2

and permanent neonatal diabetes. N Engl J Med.

2004;350(18):1838–1849

77. Proks P, Arnold AL, Bruining J, et al. A heterozygous activating

mutation in the sulphonylurea receptor SUR1 (ABCC8) causes

neonatal diabetes. Hum Mol Genet. 2006;15(11):1793–1800

78. McCarthy MI, Hattersley AT. Learning from molecular genetics:

novel insights arising from the deﬁnition of genes for monogenic

and type 2 diabetes. Diabetes. 2008;57(11):2889–2898

79. Sansbury FH, Flanagan SE, Houghton JAL, et al. SLC2A2 mutations

can cause neonatal diabetes, suggesting GLUT2 may have a role in

human insulin secretion. Diabetologia.2012;55(9):2381–2385

80. Bennett K, James C, Mutair A, Al-Shaikh H, Sinani A, Hussain K.

Four novel cases of permanent neonatal diabetes mellitus caused by

homozygous mutations in the glucokinase gene. Pediatr Diabetes.

2011;12(3 Pt 1):192–196

81. Demirbilek H, Galcheva S, Vuralli D, Al-Khawaga S, Hussain K. Ion

transporters, channelopathies, and glucose disorders. Int J Mol Sci.

2019;20(10). doi: 10.3390/ijms20102590

82. Rubio-Cabezas O, Minton JAL, Caswell R, et al. Clinical

heterogeneity in patients with FOXP3 mutations presenting with

permanent neonatal diabetes. Diabetes Care. 2009;32(1):111–116

83. Julier C, Nicolino M. Wolcott-Rallison syndrome. Orphanet J Rare

Dis. 2010;5:29

84. Hay WW Jr, Rozance PJ. Neonatal hyperglycemia: causes,

treatments, and cautions. J Pediatr. 2018;200:6–8

85. Tottman AC, Alsweiler JM, Bloomﬁeld

FH, Pan M, Harding JE.

Relationship between measures of neonatal glycemia, neonatal illness,

and 2-year outcomes in very preterm infants. JPediatr.2017;188:115–121

86. Carmody D, Bell CD, Hwang JL, et al. Sulfonylurea treatment before

genetic testing in neonatal diabetes: pros and cons. J Clin Endocrinol

Metab. 2014;99(12):E2709–E2714

87. Raﬁq M, Flanagan SE, Patch AM, Shields BM, Ellard S, Hattersley

AT; Neonatal Diabetes International Collaborative Group. Effective

treatment with oral sulfonylureas in patients with diabetes due to

sulfonylurea receptor 1 (SUR1) mutations. Diabetes Care.

2008;31(2):204–209

88. Pearson ER, Flechtner I, Njølstad PR, et al; Neonatal Diabetes

International Collaborative Group. Switching from insulin to oral

sulfonylureas in patients with diabetes due to Kir6.2 mutations.

N Engl J Med. 2006;355(5):467–477

89. Thurber BW, Carmody D, Tadie EC, et al; United States

Neonatal Diabetes Working Group. Age at the time of

sulfonylurea initiation inﬂuences treatment outcomes in

KCNJ11-related neonatal diabetes. Diabetologia.

2015;58(7):1430–1435

Vol. 21 No. 1 JANUARY 2020 e27

at Stony Brook University on July 14, 2021http://neoreviews.aappublications.org/Downloaded from

NeoReviews Quiz

Individual CME quizzes are available via the blue CME link in the Table of Contents of any issue.

To learn how to claim MOC points, go to: http://www.aappublications.org/content/moc-credit.

REQUIREMENTS: Learners

can take NeoReviews

quizzes and claim credit

online only at: http://

neoreviews.org/.

To successfully complete

2020 NeoReviews articles for

AMA PRA Category 1

Credit

, learners must

demonstrate a minimum

performance level of 60%

or higher on this

assessm ent. If you score

less than 60% on the

assessment, you will be

given additional

opportunities to answer

questions until an overall

60% or greater score is

achieved.

This journal-based CME

activity is available through

Dec. 31, 2022, however,

credit will be recorded in

the year in which the

learner completes the quiz.

2020 NeoReviews is

approved for a total of

10 Maintenance of

Certiﬁcation (MOC) Part 2

credits by the American

Board of Pediatrics (ABP)

through the AAP MOC

Portfolio Program.

NeoReviews subscribers can

claim up to 10 ABP MOC

Part 2 points upon passing

10 quizzes (and claiming

full credit for each quiz) per

year. Subscribers can start

claiming MOC credits as

early as May 2020. To

learn how to claim MOC

points, go to: http://

www.aappublications.org/

content/moc-credit.

1. Hypoglycemia is a common problem in the newborn period. With the abrupt interruption

of the constant transplacental supply of glucose, rapid metabolic adaptation must occur to

maintain stable plasma glucose levels postnatally. Subsequently, the maintenance of

normoglycemia requires a dynamic balance between nutrient intake and hormones.

Which of the following statements regarding postnatal metabolic adaptation is correct?

A. Gluconeogenesis is an important mechanism of glucose metabolism immediately

after birth.

B. Cortisol decreases the transcription of enzymes involved in glycogenolysis.

C. The levels of glucagon and epinephrine increase after birth, and these hormones

mobilize glucose through glycogenolysis.

D. Growth hormone inhibits lipolysis.

E. Beta oxidation of free fatty acid does not occur during the neonatal period.

2. Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in

the newborn period. HI can be transient or permanent. Which of the following statements

regarding HI is correct?

A. HI is characterized by elevated insulin concentration, plasma ketones, and free fatty

acids.

B. Neonates with HI have a positive response to a glucagon challenge.

C. Neonates with HI are typically small for gestational age.

D. Transient HI secondary to stress is not typically responsive to diazoxide.

E. The most common cause of inherited HI is growth hormone deﬁciency due to

panhypopituitarism.

3. Laboratory evaluations are necessary to establish the etiology of persistent hypoglycemia

in the neonate. First-tier laboratory evaluation, the so-called critical sample, includes the

measurement of insulin, β-hydroxybutyrate, free fatty acid, cortisol, growth hormone and

lactate levels at time of conﬁrmed hypoglycemia (< 50 mg/dL). Which of the following

statements regarding the laboratory evaluation of persistent hypoglycemia in the neonatal

period is correct?

A. Capillary blood sugar measured by glucose meter has been shown to be about 10%

higher than plasma glucose levels.

B. High insulin level during critical laboratory evaluation is most indicative of either

panhypopituitarism or isolated growth hormone deﬁciency.

C. A high free fatty acid level is pathognomonic for a fatty acid oxidation defect.

D. High insulin levels along with absent ketones point toward HI.

E. High lactate levels in the setting of hypoglycemia and low insulin levels are

suggestive of adrenal insufﬁciency.

4. Transient hyperglycemia is a common problem in low-birthweight, preterm, and critically

ill neonates. In contrast, neonatal diabetes mellitus (NDM) is rare and is, by deﬁnition,

diagnosed before age 12 months. NDM should be suspected in neonates with

hyperglycemia greater than 250 mg/dL (13.8 mmol/L) and persisting for more than 7 to 10

days after birth. Which of the following statements regarding NDM is correct?

A. Infants with transient NDM present earlier than those with permanent NDM.

B. Infants with transient NDM typically outgrow their need for insulin by 18 to 24

months of age.

C. Most cases of transient NDM are due to maternal uniparental disomy in chro-

mosomal region 6q24.

D. Insulin gene mutations are a common cause of permanent NDM when there is a

history of parental consanguinity.

E. DEND (developmental delay, epilepsy, neonatal diabetes) syndrome is caused by a

mutation in ABCC8.

e28 NeoReviews

at Stony Brook University on July 14, 2021http://neoreviews.aappublications.org/Downloaded from

5. Hyperglycemia in neonates can be insidious and only detected on routine laboratory tests

or urinalysis. Neonates with hyperglycemia are at risk for dehydration, acidosis, failure to

thrive, and poor weight gain, as well as adverse neurodevelopmental outcomes. Which of

the following mechanisms has not been implicated in hyperglycemia-mediated adverse

consequences?

A. Increased plasma osmolality.

B. Endothelial injury.

C. Dehydration

D. Increased oxidative stress.

E. Intracellular alkalosis.

Vol. 21 No. 1

JANUARY 2020 e29

at Stony Brook University on July 14, 2021http://neoreviews.aappublications.org/Downloaded from

DOI: 10.1542/neo.21-1-e14

2020;21;e14NeoReviews

Emir Tas, Luigi Garibaldi and Radhika Muzumdar

Glucose Homeostasis in Newborns: An Endocrinology Perspective

Services

Updated Information &

http://neoreviews.aappublications.org/content/21/1/e14

including high resolution figures, can be found at:

References

http://neoreviews.aappublications.org/content/21/1/e14.full#ref-list-1

This article cites 85 articles, 18 of which you can access for free at:

Subspecialty Collections

_drug_labeling_update

http://classic.neoreviews.aappublications.org/cgi/collection/pediatric

Pediatric Drug Labeling Update

following collection(s):

This article, along with others on similar topics, appears in the

Permissions & Licensing

https://shop.aap.org/licensing-permissions/

in its entirety can be found online at:

Information about reproducing this article in parts (figures, tables) or

Reprints

http://classic.neoreviews.aappublications.org/content/reprints

Information about ordering reprints can be found online:

at Stony Brook University on July 14, 2021http://neoreviews.aappublications.org/Downloaded from

DOI: 10.1542/neo.21-1-e14

2020;21;e14NeoReviews

Emir Tas, Luigi Garibaldi and Radhika Muzumdar

Glucose Homeostasis in Newborns: An Endocrinology Perspective

http://neoreviews.aappublications.org/content/21/1/e14

located on the World Wide Web at:

The online version of this article, along with updated information and services, is

Online ISSN: 1526-9906.

by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village,

it has been published continuously since 2000. Neoreviews is owned, published, and trademarked

Neoreviews is the official journal of the American Academy of Pediatrics. A monthly publication,

at Stony Brook University on July 14, 2021http://neoreviews.aappublications.org/Downloaded from