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Neonatal Hyperglycemia

Anusha H. Hemachandra and Richard M. Cowett


Pediatr. Rev. 1999;20;e16-e24
DOI: 10.1542/pir.20-7-e16

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pedsinreview.aappublications.org/cgi/content/full/20/7/e16

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned,
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Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 1999 by the American Academy of
Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.

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ARTICLE

Neonatal Hyperglycemia
Anusha H. Hemachandra, MD, MPH* and Richard M. Cowett, MD*†
Questions to consider (feel free to
OBJECTIVES send in your answers to these ques-
After completing this article, readers should be able to: tions and any questions of your own
for the “experts” to consider and
1. Explain the relationship of the frequency of hyperglycemia with the discuss about this case)
birthweight and gestational age of the neonate. 1. Why did this infant develop
2. List factors that may decrease glucose tolerance in the neonate. hyperglycemia?
3. Describe the major mechanism(s) contributing to altered regulation of 2. What role did the infant’s
neonatal glucose metabolism.
intrauterine growth restriction play
4. List the untoward effects of hyperglycemia in the neonate.
5. Describe the beneficial effects of insulin infusion in selected neonates. in the pathogenesis of
hyperglycemia?
3. Did the clinicians decrease the
IV glucose infusion rate sufficiently
Case Study the intravenous (IV) fluid rate was to correct the hyperglycemia?
A preterm male infant was born at 225 mL/kg per day (“to maintain 4. Did the IV amino acids play a
26 weeks’ gestation weighing 900 g, hydration”) and the glucose infusion role in treating the hyperglycemia?
with a birthweight percentile below rate was 16 mg/kg per minute. The 5. Should the clinicians have
the 3rd percentile and a head cir- IV solution was changed to 5% dex- used insulin?
cumference at about the 25th per- trose, but the glucose concentration 6. Why did the infant develop
centile. His Apgar scores were 4 and remained high, increasing to hypoglycemia and possibly a hypo-
5 at 1 and 5 minutes, respectively, 17.76 mmol/L (320 mg/dL), then glycemic seizure when the IV line
and he required intubation and ven- 22.65 mmol/L (410 mg/dL). Insulin infiltrated?
tilation in the delivery room. The treatment was started at 0.05 U/kg 7. Was the delayed development
infant was given artificial surfactant per hour, along with an IV infusion in this infant directly related to the
and maintained on a respirator with of 1 g/kg per day of amino acids. hyperglycemia?
“moderate to high settings.” Several By the fourth day of life, the William W. Hay, Jr, MD
saline boluses were administered for infant continued to receive IV insu- Coeditor
hypotension, and dopamine was lin and was tolerating total paren-
started to maintain a mean arterial teral nutrition (TPN) with 5% dex-
blood pressure above 30 mm Hg. trose providing 12 mg/kg per minute Introduction
Initial serum glucose concentrations and 2 g/kg per day of amino acids Hyperglycemia has become a signif-
were in the range of 1.67 to via a central venous catheter. Glu- icant risk factor for morbidity and
2.76 mmol/L (30 to 50 mg/dL). The cose concentrations remained in the mortality as smaller and more frag-
infant was given 10% dextrose at a range of 5.55 to 8.33 mmol/L ile infants survive during the neona-
rate of 100 mL/kg per day. (100 to 150 mg/dL). One episode tal period. Historically, hyperglyce-
By the second day of life, the of hypoglycemia (glucose, mia has been attributed to excessive
serum glucose concentration was in ,0.56 mmol/L [,10 mg/dL]) with IV glucose infusion. More recent
the range of 5.55 to 8.33 mmol/L an apparent seizure was noted after studies indicate that physiologic and
(100 to 150 mg/dL), and the dex- the infant was switched to a periph- biochemical mechanisms, leading to
trose infusion, which now contained eral catheter for the TPN solution
sodium chloride and potassium ace- and it infiltrated, probably for
tate, was increased to 150 mL/kg 2 hours before being discovered.
Enteral feeding was started on the ABBREVIATIONS
per day because of polyuria of
6 mL/kg per hour. The infant 10th day of life. Other than the AGA: appropriate for gestational
age
remained NPO. Subsequent glucose development of chronic lung dis-
ELBW: extremely low birthweight
concentrations over the next ease, one episode of suspected
GLUT: glucose transporter
24 hours increased to more than necrotizing enterocolitis without
LBW: low birthweight
13.88 mmol/L (250 mg/dL), and pneumotosis intestinalis, and one
PNDM: permanent neonatal
glycosuria was noted. At this time, episode of Staphylococcus epidermi- diabetes mellitus
dis sepsis, the infant’s course was RQ: respiratory quotient
relatively uncomplicated. At term SGA: small for gestational age
*Department of Neonatology, The gestation, his weight remained much TNDM: transient neonatal diabetes
Children’s Hospital; Division of Pediatrics, less than the 3rd percentile, growth mellitus
The Cleveland Clinic Foundation, had shown no catch-up, and he was TPN: total parenteral nutrition
Cleveland, OH. not yet approaching a standard

The Robert Schwartz, MD Center for VLBW: very low birthweight
Metabolism and Nutrition and the Division growth curve for infants of YSI: Yellow Springs Instrument
of Neonatology, Department of Pediatrics, 26 weeks’ gestation. Subsequent Company glucose analyzer
MetroHealth Medical Center, Cleveland, OH. development was markedly delayed.

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ENDOCRINOLOGY
Hyperglycemia

excess glucose production, insulin the YSI with glucose reflectance weak. In addition, the time lag
resistance, or glucose intolerance, meters among randomly selected between glucose entering the blood-
underlie the development of hyper- infants. The reflectance meters have stream and its excretion into body
glycemia in preterm infants and correlations with the YSI ranging fluids is not well documented in the
sometimes inhibit efforts to maintain from r50.88 to 0.96 for cord blood neonate. Thus, analysis of body flu-
normal glycemia in the neonate. The and from r50.64 to 0.86 for capil- ids other than blood is inappropriate
sequelae of these disturbances in lary blood (Table 1), demonstrating for the diagnosis and management
glucose metabolism are extensive. a fundamental shortcoming of hand- of hyperglycemia in the neonate.
held glucose reflectance meters to
determine blood glucose concentra-
Diagnosis tion in the neonate. More recently, Epidemiology
Hyperglycemia generally is defined improved glucose reflectance meters The incidence of hyperglycemia var-
as a whole blood glucose concentra- have become available. As with all ies widely, but nearly all studies
tion greater than 6.66 to reflectance meters, however, consis- show that low birthweight (LBW) is
6.94 mmol/L (.120 to 125 mg/dL) tently careful and accurate use is the primary significant risk factor at
or a plasma glucose concentration necessary to achieve optimal any gestational age; preterm birth
greater than 8.05 to 8.33 mmol/L performance. ranks a close second. Thus, the inci-
(.145 to 150 mg/dL), regardless of Several noninvasive techniques dence of hyperglycemia is related
the neonate’s gestational age, for measuring glucose concentration inversely to birthweight in the pre-
weight, or postnatal age. Although have been proposed and evaluated. term infant, ranging from about 2%
affected neonates often are “asymp- The first used near-infrared spectros- in infants who weigh more than
tomatic” or have signs indicative of copy, usually on a finger, the inner 2,000 g to 45% in those who weigh
other disease processes, recognizable lip, or oral mucosa. However, this less than 1,000 g and up to 80% in
signs specific to hyperglycemia may method is not very accurate. Cross- extremely low-birthweight (ELBW)
include dehydration due to an validated standard errors of predic- infants weighing less than 750 g.
osmotic diuresis, weight loss, failure tion have ranged from 2.16 to Many other factors also are asso-
to thrive, fever, glycosuria, ketosis, 3.05 mmol/L (39 to 55 mg/dL) in ciated with hyperglycemia. In most
and metabolic acidosis. The latter normoglycemic adults. More tradi- studies there is a significant relation-
three signs are particularly common tional ultraviolet and infrared spec- ship between blood glucose concen-
among infants who have transient or troscopy are impractical because of tration and the initial rates of IV
permanent neonatal diabetes limited depth of penetration and the glucose administration (Fig. 1). Over
mellitus. interfering absorption of these wave- longer periods of observation, how-
Because such clinical signs are lengths of light by many photoreac- ever, the correlation between blood
unreliable indicators of the presence tive substances. Another form of glucose concentration and the rate of
or degree of hyperglycemia, it is noninvasive glucose measurement glucose infusion decreases, as clini-
necessary to measure glucose con- involves direct analysis of body flu- cians attempt to treat the hypergly-
centration by glucose analyzers. ids other than blood (eg, saliva, cemia by decreasing the rate of glu-
Considerable controversy surrounds sweat, urine, or tears). Unfortu- cose infusion. In fact, glucose
the use of different instruments that nately, the correlation between blood administration rates as low as 3 to
have highly variable degrees of glucose concentration and glucose 4 mg/kg per minute have been asso-
accuracy and reliability. The spec- concentration in excreted fluids is ciated with persistent hyperglycemia.
trophotometric glucose oxidase
method is the gold standard, but
using a central hospital laboratory to TABLE 1. Accuracy of Reflectance Meters Versus the Yellow
analyze the repeated blood samples Springs Instruments Co. Glucose Analyzer
necessary to manage the sick neo-
nate, often moment to moment, may DIFFERENCE BETWEEN CORD HEEL STICK
be impractical. One alternative may MEANS (%) BLOOD BLOOD P VALUE
be the use in the nursery of the Yel- Refectance meter
low Springs Instrument Company Glucometer M 29.3 223.2
glucose analyzer (YSI), which has Diascan S 0.4 20.4
excellent correlation (r50.99) with Accu-Chek II 1.2 16.4
the manual, laboratory-performed One Touch 35.2 25.6
spectrophotometric glucose oxidase
method. In contrast, glucose reagent Correlation coefficient
strips and glucose reflectance Glucometer M 0.88 0.64 ,0.05
meters, whether read visually or Diascan S 0.96 0.71 ,0.01
using a built-in algorithm, have Accu-Chek II 0.91 0.71 ,0.05
much weaker correlations with the One Touch 0.92 0.86 NS
laboratory glucose oxidase method From Lin HC, Maguire C, Oh W, Cowett R. Accuracy and reliability of glucose reflec-
(r50.70 to 0.83). tance meters in the high risk neonate. J Pediatr. 1989;115:998 –1000.
Several studies have compared

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ENDOCRINOLOGY
Hyperglycemia

steady and sustained increase in


serum glucose concentrations devel-
ops during the infusion and up to
1 hour postinfusion. These exceed-
ingly high lipid infusion rates are
not used in preterm or term infants,
but the results demonstrate that lip-
ids and lipid components, especially
free fatty acids, can promote hyper-
glycemia. Increased plasma free
fatty acid concentrations decrease
FIGURE 1. The plasma glucose concentration relative to the rate of IV glucose peripheral glucose utilization, pri-
administered in a representative neonate in the 500-g birthweight category (a) and
marily by substituting carbon and
in one in the 900-g birthweight category (b). From Cowett AA, Farrag HM, Gelardi
NL, Cowett RM. Hyperglycemia in the micropremie: evaluation of the metabolic altering enzymatic activity that pref-
disequilibrium during the neonatal period. Prenat Neonatal Med. 1997;2:360 –365. erentially leads to fatty acid carbon
oxidation rather than glucose oxida-
Positive relationships also have been infants receiving continuous glucose tion. Fatty acids also inhibit the
found between hyperglycemia and infusions at 8 mg/kg per minute, effect of insulin to suppress hepatic
the severity of clinical problems in 11 mg/kg per minute, or 14 mg/kg glucose production. These two con-
the neonate, as estimated by the per minute, practically none of the ditions—peripheral glucose intoler-
Apgar score, the fractional concen- infants in the lowest glucose infu- ance and central (hepatic) insulin
tration of inspired oxygen, and the sion group developed hyperglyce- resistance—increase glucose concen-
respiratory distress score. A negative mia. In contrast, 50% or more of the trations in the plasma. As a result,
correlation also exists between blood infants in the middle infusion group insulin concentrations often are par-
glucose concentration and blood and all of the infants in the highest adoxically greater after lipid infu-
hematocrit, serum billirubin concen- infusion group developed increased sion. This seemingly contradictory
tration, and plasma total protein blood glucose concentrations (Fig. 2). trend in glucose and insulin concen-
concentration. trations may be explained by the
LIPIDS direct effect of fatty acids on pro-
It is important to point out, how- moting insulin secretion as well as
Etiology ever, that critically ill neonates who the inhibition of insulin action in the
are receiving even lower rates of periphery.
GLUCOSE INFUSION
glucose infusion also have devel-
Exogenous glucose infusion has a oped hyperglycemia, which has led
major impact on the development of to speculation about alternative eti- STRESS
hyperglycemia. Among preterm ologies. For Stress, as measured by increased
example, the plasma cortisol concentrations, also
lipid component appears to be an important risk fac-
of parenteral tor for the development of hypergly-
nutrition may cemia. Sick neonates frequently suf-
contribute to the fer physiologic stress from both
glycemic their disease processes and the med-
response apart ical interventions provided (eg, pain-
from that of the ful procedures such as venipuncture
exogenous glu- and cutdowns, endotracheal tube
cose (dextrose) irritation during ventilator treatment,
component. Sev- catecholamine infusions). However,
eral studies have the relationship between cortisol as
shown a dose- an indicator of stress and the devel-
response rela- opment of hyperglycemia can be
tionship between confusing because the cortisol
the plasma con- response may be suppressed by
centration of hyperglycemia in a negative feed-
lipid and blood back relationship. Neonates also can
glucose. In pre- develop marked hyperglycemia dur-
FIGURE 2. Incidence of glycosuria among three groups of term infants ing and after surgical procedures.
infants categorized according to maximal plasma glucose receiving either
concentration obtained during steady state. From Cowett RM, Postsurgical hyperglycemia appears
Oh W, Pollak A, Schwartz R, Stonestreet BS. Glucose disposal
0.25 or 0.5 g/kg to be due to increased cortisol secre-
of low birthweight infants: steady state hyperglycemia per hour of tion during surgery; hyperglycemia
produced by constant intravenous glucose infusion. Pediatrics. Intralipid® lipid noted immediately after the start of
1979;63:389 –396. emulsion, a anesthesia appears to be due to cate-

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ENDOCRINOLOGY
Hyperglycemia

cholamine release in response to utilization, despite lower concentra- OTHER


induction. tions of insulin receptors on hepato- Other causes of hyperglycemia
In support of these factors caus- cytes. Furthermore, IV infusions of include the use of medications such
ing or amplifying hyperglycemia insulin in infants who have hyper- as theophylline and dexamethasone.
after surgery or stressful invasive glycemia usually produce prompt Individual cases reported in the liter-
procedures, fentanyl treatment dur- and rapid decreases in plasma glu- ature associate hyperglycemia with
ing and after surgery has decreased cose concentration. prostaglandin E1 and chromosome
the incidence of hyperglycemia and deletion (46,xxDq- on number 13).
increased circulating concentrations Sepsis also has been implicated.
of epinephrine, glucocorticoids, and INSULIN-DEPENDENT DIABETES
glucagon as well as the insulin:glu- MELLITUS
cagon ratio. Epinephrine decreases An unusual, but important, etiology
insulin secretion from the pancreatic of hyperglycemia in the infant is Pathophysiology
beta cell and interferes with periph- insulin-dependent diabetes mellitus. As described previously, glucose
eral insulin action. Glucagon pro- Transient neonatal diabetes mellitus homeostasis becomes more disor-
motes glycogenolysis and release of (TNDM) presents early in postnatal dered with decreasing maturity of
hepatic glucose. Glucocorticoids life; 75% of cases present in the the neonate. In human fetuses, insu-
promote gluconeogenesis by increas- first 10 days of life with weight lin is produced in the pancreas as
ing protein breakdown and, thus, the loss, polyuria, dehydration, glycos- early as the 11th week of gestation.
supply of amino acids. Glucocorti- uria, and hyperglycemia. Concentra- However, this insulin is not released
coids also enhance hepatic enzyme tions of C-peptide and plasma insu- readily in response to hyperglycemia
activity in the gluconeogenic path- lin are low. TNDM usually does not even as late as the 20th week of
way, particularly phosphoenolpyru- resolve for several weeks to months. gestation. Unresponsiveness to insu-
vate carboxykinase, which is the A rebound in C-peptide concentra- lin action may continue even later in
rate-limiting enzyme for gluconeo- tion typically marks the resolution. gestation. Studies using the euglyce-
genesis, and glucose-6-phosphatase, When TNDM does not resolve, mic hyperinsulinemic clamp tech-
which releases glucose into the which is much rarer, it is known as nique in neonates born at 31 to
circulation. permanent neonatal diabetes mellitus 34 weeks’ gestational age have
(PNDM). Both conditions are caused shown persistent glucose production
by endogenous insulin deficiency during steady-state insulin infusions.
INSULIN RESISTANCE due to failure of pancreatic beta This endogenous glucose production
The theory of insulin resistance in cells. The pathogenesis is unknown; occurs at even very high rates of
peripheral tissues, especially skeletal anti-islet antibodies and typical insulin infusion that range from
muscle, causing hyperglycemia has human lymphocyte antigen types 0.2 up to 4.0 mU/kg per min (Fig.
been tested repeatedly. In general, have not been reported in infants 3). Although a postinsulin receptor
LBW infants given a glucose chal- who have either TNDM or PNDM. defect may be responsible, such as
lenge (eg, 1 g/kg IV bolus) have A family history of diabetes is glucose transporter or enzyme regu-
shown variable increases in plasma found in about one third of cases of lation in the glycolytic, glycogeno-
insulin concentration. Among pre- TNDM, with the condition occurring lytic, or gluconeogenic pathways,
term small for gestational age more frequently among siblings and there is no specific evidence for
(SGA) and preterm appropriate for even in mother and offspring. There these possible mechanisms. Others
gestational age (AGA) infants who has been no evidence of common have suggested that such delays in
have relatively normal insulin secre- loci associated with diabetes melli- insulin sensitivity leading to hyper-
tion, however, plasma free fatty acid tus in such families nor have tissue glycemia are the result of obscure or
and beta-hydroxybutyrate concentra- antibodies associated with autoim- poorly manifested cases of stress
tions still increase significantly. mune causes of diabetes been and counterregulatory hormonal
These observations indicate that fat detected. Detailed evaluations of action. Clearly there is considerable
mobilization, with release of fatty isolated cases of familial PNDM need for definitive studies of such
acids and their subsequent beta oxi- have shown the infants to have nor- possible mechanisms responsible for
dation in the liver, is not suppressed mal secretion of glucagon, cortisol, insulin sensitivity in these preterm
by glucose-stimulated insulin secre- and growth hormone. Insulin secre- infants as well as in developing
tion. Such findings are consistent tion has not been assessed, but fetuses and otherwise normal pre-
with a decreased sensitivity to insu- C-peptide concentrations are low. term infants.
lin among LBW infants, particularly Results of insulin-binding studies in Excessive or inappropriate (for
those who are sufficiently mature to fibroblasts, erythrocytes, and B lym- insulin secretion rates and plasma
have adipose tissue stores, even if phocytes appear normal and do not insulin concentrations) glucose pro-
SGA, and the enzymatic capacity to suggest end-organ insulin receptor duction also can promote or prolong
mobilize fatty acids from adipose insensitivity. Such cases of PNDM hyperglycemia. Very low-
tissue. This subject remains contro- may be the result of genetic inheri- birthweight (VLBW) and ELBW
versial. Animal data indicate normal tance (a dominant trait with variable infants can develop surprisingly high
or even increased insulin action in penetrance) and may represent a rates of glucose production, both
early gestation in relation to glucose unique form of diabetes mellitus. from glycogenolysis and from glu-

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ENDOCRINOLOGY
Hyperglycemia

high affinity for glucose compared


with other GLUTs, meaning that
GLUT-1 and GLUT-3 can be effec-
tive even at low glucose concentra-
tions. This characteristic is particu-
larly important in the central
nervous system (CNS), where
GLUT-1 and GLUT-3 are the pri-
mary transporters for glial and neu-
ronal cells, respectively. Gene
expressions of GLUT-2 and
GLUT-3 are determined by the met-
abolic needs of the CNS. Because
these transporters are not sensitive
to insulin, CNS glucose uptake is
not affected by plasma insulin con-
centrations. The glucose transport
capacity of the combined brain vas-
FIGURE 3. Percent decrease in endogenous glucose production (A) and cular endothelial cell GLUT-1 and
percent increase in glucose utilization (B) subdivided by various insulin neuronal GLUT-3 expression
infusion rates administered to neonates and 2 mU/kg per minute administered appears to be great enough to allow
to adults. From Farrag HM, Nawrath LM, Healy JE, et al. Persistent glucose sufficient glucose uptake for most of
production and greater peripheral sensitivity to insulin in the neonate versus the brain’s glucose needs, even in
the adult. Am J Physiol. 1997;272:E86 –E93. the presence of modest
hypoglycemia.
coneogenesis, relatively soon after Hyperglycemia may be more com- GLUT-2 occurs only in hepato-
preterm birth. Studies of endogenous mon in very preterm infants due to cytes and pancreatic beta cells; its
glucose production in ELBW neo- inadequate development of the expression and effect on glucose
nates during steady-state infusion of insulin-dependent GLUT-4-mediated uptake are regulated developmen-
stable isotope tracers of glucose glucose transport system. GLUT-4 tally and by plasma glucose and
have documented hepatic glucose develops progressively during gesta- insulin concentrations. GLUT-2 is a
production rates as great as tion, coincident with the growth of low-affinity transporter, allowing
0.05 mg/g (liver weight) per minute, insulin-sensitive tissues, primarily glycogenolysis and gluconeogenesis
which is comparable to values skeletal muscle, as well as the pro- to release glucose into the plasma in
reported in fasting adults. Correla- duction of insulin and the concentra- response to small reductions in glu-
tion between glucose production tion of insulin in the plasma. Fetal cose concentration, even in the nor-
rates and plasma insulin concentra- hyperglycemia has been shown to mal glucose concentration range,
tions is seldom significant, perhaps decrease GLUT-4 expression, which which helps to prevent hypoglyce-
because only relatively narrow would tend to produce insulin resis- mia. Similarly, the low affinity of
ranges of both plasma glucose and tance, and to decrease skeletal mus- GLUT-2, in concert with glucoki-
insulin concentrations have been cle GLUT-1, which would tend to nase function, allows pancreatic beta
studied. Interestingly, glycerol is a produce glucose intolerance. Hypo- cells to recognize modest increases
principal source of gluconeogenesis glycemia either has no effect or in plasma glucose concentration,
when early gluconeogenesis in pre- increases GLUT-1 and GLUT-4. leading to increased insulin secre-
term infants is active. This observa- Studies among different species, tion, which helps prevent hypergly-
tion is consistent with previous stud- different tissues, and different dura- cemia. Although the beta cells of
ies that have shown only limited tions of glycemic change demon- preterm infants respond to hypergly-
conversion of alanine (and other strate considerable variation in cemia by increasing insulin secre-
amino acids) to glucose in preterm GLUT expression and relation to tion, this process is diminished, in
infants, indicating that amino acid glucose metabolism. Thus, study of part due to decreased expression or
conversion to glucose is a develop- GLUTs, the regulation of their function of the immature glucose
mental process that occurs later. expression and activity, and their sensor (GLUT-2 plus glucokinase)
effect on glucose metabolism, partic- and in part due to decreased activity
ularly with conditions such as of other metabolic linkages in beta
Glucose Homeostasis and hyperglycemia, are important and cells. The resulting increase in
Glucose Transporters should be helpful in understanding plasma insulin concentration often is
Glucose is transported across the molecular aspects of pathologic gly- not adequate to prevent
plasma membrane of cells by a fam- cemic conditions in neonates. hyperglycemia.
ily of structurally similar proteins GLUT-1 and GLUT-3 are consti- Hyperglycemia also may be due
called glucose transporters (GLUTs). tutive transporters responsible for to hepatic and peripheral insulin
The GLUTs are expressed in a basal glucose uptake in many tis- resistance that results in diminished
tissue-specific manner (Table 2). sues. They are characterized by a effectiveness of insulin in inhibiting

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ENDOCRINOLOGY
Hyperglycemia

TABLE 2. Glucose Transporters


GLUCOSE CHARACTERISTIC RELATIVE AFFINITY
TRANSPORTER PRIMARY TISSUE FUNCTION FOR GLUCOSE
GLUT-1 All tissue; particularly important Basal glucose uptake 111
in central nervous system
(CNS) (glial cells) and testes
GLUT-2 Liver and pancreas Hepatic glucose uptake and 1
release
Component of B-cell
glucose sensor together
with glucokinase
GLUT-3 Most tissues; particularly Basal glucose uptake 1111
important in CNS (neurons)
GLUT-4 Muscle and fat Insulin-sensitive transporter 11
GLUT-5 Intestine and liver Fructose uptake 1
GLUT-6 (pseudogene)
GLUT-7 Liver Microsomal transporter ?
Adapted from Lane R, Simmons R. Semin Neonatal Nutrit Metab. 1997;4:4.

hepatic glucose production and pro- enhancing cellular glucose uptake. Complications
moting peripheral glucose utiliza- In the newborn rat, GLUT-4 does Neonatal hyperglycemia has been
tion. LBW infants often require not reach adult levels until day 14 associated with a wide spectrum of
exogenous insulin to resolve hyper- or 15. Decreased skeletal muscle sequelae, ranging from the clinically
glycemia despite an almost twofold expression of GLUT-4 also may manageable (dehydration) to the
rise in endogenous plasma insulin contribute to the insulin resistance devastating (death). Although rare
concentration. In most preterm and hyperglycemia seen in ELBW/ today, previous reports of intracra-
infants, endogenous glucose produc- LBW infants. Similarly, deceased nial hemorrhage and death among
tion cannot be inhibited completely cardiac expression of GLUT-4 has preterm infants who were markedly
(no more than 50% to 60%) by any been seen in experimental conditions hyperglycemic and other reports
level of insulinemia, and only very in the fetus in response to chronic documenting abnormal neurodevel-
high concentrations of insulin (more hyperglycemia, perhaps providing a opmental outcome in such infants
than 10-fold above normal) enhance mechanism to limit excessive glu- indicated a much worse severity of
peripheral glucose utilization. Post- cose uptake. illness and much more ominous
insulin receptor defects are consid- Enzyme regulation also is an prognosis than occurs today. For
ered most likely to be responsible. important component for establish- example, among selected groups of
Studies of multiple species in the ing neonatal glucose homeostasis. preterm infants ranging from 24 to
early newborn period demonstrate Preterm neonates may have imma- 34 weeks’ gestational age who had
severe and protracted hyperglycemia
that hepatocytes express a relatively ture biochemical pathways that
in earlier reports, more than 50%
high amount of GLUT-1 but rela- metabolize glucose incompletely.
subsequently died. The predominant
tively low levels of GLUT-2. The The fetal liver produces noninsulin-
cause of death was intracranial hem-
decreased GLUT-2 expression may dependent hexokinase in preference orrhage. Hyperglycemia causes a
limit hepatocyte sensitivity and to glucokinase. In response to insu- rise in serum osmolarity; each incre-
responsivity to an increase in insulin lin, only a small amount of glucoki- ment of 1 mmol/L (18 mg/dL) in
concentration that accompanies nase is available for glucose trans- blood glucose concentration
hyperglycemia, resulting in an port. The enzymes necessary for accounts for a rise of 1 mOsm/L in
inability to decrease hepatic glucose converting glucose to glycogen, serum osmolarity. If serum osmolar-
production. which increase in activity with ity exceeds 300 mOsm/L (roughly, a
GLUT-4 is found in insulin- increasing gestational age, may be serum glucose value of 22.2 mmol/L
sensitive tissues, primarily skeletal deficient in the immature neonate. [400 mg/dL]), rapidly shifting water
muscle, heart, and adipose tissue. These enzymes include phosphoglu- may cause cerebral hemorrhage.
When translocated by insulin to the comutase, uridine diphosphoglucose Cellular damage from such an insult
cell membrane, GLUT-4 helps to (UDPG) pyrophosphorylase, and apparently is augmented by pre-
decrease glucose concentration by UDPG glycogen synthetase. existing hyperglycemia. Observa-

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ENDOCRINOLOGY
Hyperglycemia

tions in neonatal rats have shown studied five clinically stable neo- that 40 to 60 kcal/kg per day is nec-
that moderate hyperglycemia signifi- nates of less than 28 weeks’ gesta- essary to spare protein for subse-
cantly increases morphologic dam- tion. Each received glucose infu- quent somatic growth.
age throughout the forebrain with sions of 6 mg/kg per minute, It is appropriate to feed infants
induced ischemic events. The patho- followed by infusions of 9 mg/kg who have hyperglycemia unless
physiology of increased ischemic per minute, during which time the other clinical problems are consid-
damage during hyperglycemia is investigators traced the appearance ered severe enough to prevent feed-
unclear; hypotheses include hyperos- of leucine and phenylalanine in the ing. Early introduction of IV amino
molarity, excessive lactic acidosis, blood as markers of proteolysis. acids by parenteral infusion has
and decreased regional cerebral They reported that proteolysis was been associated with decreased inci-
blood flow. not suppressed during glucose infu- dence and severity of hyperglycemia
Hyperosmolarity also can lead to sion, even with near-complete sup- and hyperkalemia. There is consider-
a potential osmotic diuresis that pression of glucose production. It is able theoretical rationale for this
results in polyuria and dehydration. unclear if the continuation of prote- approach; certain amino acids, such
The increase in serum osmolarity olysis in the infant who has hyper- as leucine, valine, isoleucine, glu-
associated with hyperglycemia theo- glycemia is a benefit or a detriment; tamine, and arginine, are known
retically puts the tiny infant at risk high rates of proteolysis and protein insulin secretagogues. Furthermore,
for osmotic diuresis and dehydra- turnover may be part of the normal such amino acids probably are nec-
tion. Most short-term studies have growth process, which is desirable, essary for the normal growth and
failed to observe such an effort in particularly in the LBW neonate. development of the pancreas and the
LBW infants who have hyperglyce- Suppression of proteolysis does not pancreatic islet and beta cells. At
mia; hyperglycemic periods of appear to be associated with hyper-
least glutamine and perhaps leucine
greater than 5 hours may be neces- glycemia, but further studies are
also may promote insulin action and
sary to detect a diuretic effect. required to evaluate the implications
the disposal of glucose in skeletal
Another potential effect of of these data.
aggressive glucose administration is muscle.
steatosis and associated impairment Enteral feeding has been shown
in secretion of hepatic triglycerides. Treatment to promote pancreatic function and
Although steatosis rarely causes The treatment of neonatal hypergly- the secretion of insulin. Even mini-
clinical signs in the neonate, it can cemia must be based on the diagno- mal amounts, such as in “minimal
be detected by modest elevations of sis and suspected etiology of the enteral feeding” regimens, induces
liver transaminases. condition in each case. Hyperglyce- the gut production of “enteroinsular
Hyperglycemia also might jeopar- mia detected by reagent strips read hormones,” also known as “incre-
dize respiratory function by raising visually should be confirmed by tins,” including gastric inhibitory
the respiratory quotient (RQ), the laboratory methods. The exogenous polypeptide and pancreatic polypep-
ratio between CO2 generated and O2 glucose infusion rate and medica- tide. These hormones increase insu-
consumed. Carbohydrate oxidation tions being administered should be lin secretion by direct actions on the
results in an RQ of 1.0. Because noted. Urine output, urine glucose pancreatic beta cells. Such observa-
lipogenesis produces CO2 without concentration, and plasma glucose tions warrant efforts to feed preterm
consuming CO2, the resulting concentration should be measured to infants who have hyperglycemia,
increase in CO2 production requires assess the potential for dehydration even if full enteral feedings cannot
an increase in minute ventilation and osmotic diuresis. Serum electro- or should not be attempted.
that may compromise the fragile lytes should be determined to calcu- If severe hyperglycemia persists,
ELBW/LBW infant. Studies in late fluid replacement therapy. exogenous insulin administration
infants have demonstrated this Weight should be measured to deter- may be warranted. Guidelines about
increase in CO2 production, but the mine hydration status. when to use insulin treatment and
clinical significance remains unclear. When the blood glucose concen- how to provide this form of therapy
Another complication of hyper- tration is in the range of 6.9 to remain highly controversial and vary
glycemia is electrolyte imbalance. 19.43 mmol/L (125 to 350 mg/dL), widely among clinicians and institu-
A significant finding in neonates reducing exogenous glucose admin- tions. Many consider insulin treat-
who have glycosuria is an increase istration should be sufficient to ame- ment unnecessary, others use it spar-
in sodium excretion due to increased liorate the hyperglycemia. The rate ingly if at all, and many use it
filtered sodium load, even with min- of infusion should be decreased according to fairly liberal guidelines,
imal glycosuria. Creatinine clearance gradually, by 1 to 2 mg/kg per considering that it also might pro-
is altered significantly during the minute every 2 to 4 hours, with fre- vide a positive protein balance,
infusion. Hyperglycemia theoreti- quent monitoring of plasma or blood improve nutrition, and control glu-
cally can trigger partial suppression glucose concentrations until normo- cose concentration. Reasonable
of endogenous glucose production, glycemia is achieved or until the guidelines indicate that insulin treat-
which is accompanied in adults by glucose infusion rate reaches 3 to ment should be reserved until
suppression of whole-body proteoly- 4 mg/dL and hyperglycemia remains plasma glucose concentrations
sis. In neonates, however, this does severe (.19.43 mmol/L [.350 mg/ exceed 16.7 to 22.2 mmol/L (300 to
not appear to be the case. Hertz et al dL]). It is important to remember 400 mg/dL) despite reducing the

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ENDOCRINOLOGY
Hyperglycemia

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Neonatal Hyperglycemia
Anusha H. Hemachandra and Richard M. Cowett
Pediatr. Rev. 1999;20;e16-e24
DOI: 10.1542/pir.20-7-e16

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