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Glucose is the key metabolic substrate for tissue energy production. In the perinatal period the mother supplies glucose to the fetus and for most of the gestational period the normal lower limit of fetal glucose concentration is around 3 mmol/L. Just after birth, for the first few hours of life in a normal term neonate appropriate for gestational age, blood glucose levels can range between 1.4 mmol/L and 6.2 mmol/L but by about 72 h of age fasting blood glucose levels reach normal infant, child and adult values (3.5–5.5 mmol/L). Normal blood glucose levels are maintained within this narrow range by factors which control glucose production and glucose utilisation. The key hormones which regulate glucose homoeostasis include insulin, glucagon, epinephrine, norepinephrine, cortisol and growth hormone. Pathological states that affect either glucose production or utilisation will lead to hypoglycaemia. Although hypoglycaemia is a common biochemical finding in children (especially in the newborn) it is not possible to define by a single (or a range of) blood glucose value/s. It can be defined as the concentration of glucose in the blood or plasma at which the individual demonstrates a unique response to the abnormal milieu caused by the inadequate delivery of glucose to a target organ (eg, the brain). Hypoglycaemia should therefore be considered as a continuum and the blood glucose level should be interpreted within the clinical scenario and with respect to the counter-regulatory hormonal responses and intermediate metabolites.
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What is a normal blood glucose?
Maria Güemes,
1,2
Soa A Rahman,
1,2
Khalid Hussain
1,2
1
Genetics and Genomic
Medicine Programme, UCL
Institute of Child Health,
London, UK
2
Department of Paediatric
Endocrinology, Great Ormond
Street Hospital for Children
NHS, London, UK
Correspondence to
Professor Khalid Hussain,
Genetics and Genomic
Medicine Programme,
UCL Institute of Child Health,
30 Guilford Street, London
WC1N 1EH, UK;
Khalid.Hussain@ucl.ac.uk
Received 29 June 2015
Revised 24 August 2015
Accepted 27 August 2015
To cite: Güemes M,
Rahman SA, Hussain K. Arch
Dis Child Published Online
First: [please include Day
Month Year] doi:10.1136/
archdischild-2015-308336
ABSTRACT
Glucose is the key metabolic substrate for tissue energy
production. In the perinatal period the mother supplies
glucose to the fetus and for most of the gestational
period the normal lower limit of fetal glucose
concentration is around 3 mmol/L. Just after birth, for
the rst few hours of life in a normal term neonate
appropriate for gestational age, blood glucose levels can
range between 1.4 mmol/L and 6.2 mmol/L but by
about 72 h of age fasting blood glucose levels reach
normal infant, child and adult values (3.55.5 mmol/L).
Normal blood glucose levels are maintained within this
narrow range by factors which control glucose
production and glucose utilisation. The key hormones
which regulate glucose homoeostasis include insulin,
glucagon, epinephrine, norepinephrine, cortisol and
growth hormone. Pathological states that affect either
glucose production or utilisation will lead to
hypoglycaemia. Although hypoglycaemia is a common
biochemical nding in children (especially in the
newborn) it is not possible to dene by a single (or a
range of) blood glucose value/s. It can be dened as the
concentration of glucose in the blood or plasma at
which the individual demonstrates a unique response to
the abnormal milieu caused by the inadequate delivery
of glucose to a target organ (eg, the brain).
Hypoglycaemia should therefore be considered as a
continuum and the blood glucose level should be
interpreted within the clinical scenario and with respect
to the counter-regulatory hormonal responses and
intermediate metabolites.
INTRODUCTION
Blood glucose is the key substrate for energy pro-
duction during the perinatal, neonatal and post-
natal periods. Apart from the rst few days of
life, normal fasting blood glucose concentrations
are kept within a narrow physiological range of
3.55.5 mmol/L. Continuous blood glucose moni-
toring shows that blood glucose concentrations
may ickeron either side of these two values
(especially post meal) but then rapidly and spon-
taneously revert to within this normal range.
1
Fasting and postprandial normal blood glucose
levels are maintained within this narrow range by
a complex interplay of hormones which control
glucose production and glucose utilisation. The
liver produces glucose through glycogenolysis
(breakdown of stored glycogen) and gluconeogen-
esis (formation of glucose from non-carbohydrate
sources such as lactate, alanine and glycerol).
Apart from the liver, there is now evidence to
show that the kidney also plays an important role
as a gluconeogenic organ.
2
The key hormones
which regulate glucose homoeostasis include
insulin, glucagon, epinephrine, norepinephrine,
cortisol and growth hormone (GH). Insulin typic-
ally regulates glucose homoeostasis in the post-
prandial state whereas the other hormones
control blood glucose levels during the fasting
state. Glucagon and epinephrine are the main line
of defence against hypoglycaemia whereas cortisol
and GH have a permissive role in regulating
blood glucose levels.
During the perinatal period, the continuous fetal
supply of glucose comes from the mother.
3
In a
normal fetus there is no endogenous glucose pro-
duction, however under conditions where there is
reduced glucose supply, the fetus has the capability
to generate glucose endogenously.
4
The rate at
which the fetus undertakes glucose utilisation and
oxidation is determined by the maternal arterial
blood glucose concentration.
5
After birth, the continuous glucose delivery to
the fetus is disrupted and for the rst few hours
after birth, there is a transitional phase of physiolo-
gically low normal blood glucose levels (transitional
neonatal hypoglycaemia) which normalise around
72 h after birth. It is during these rst few hours
after birth that blood glucose concentrations show
marked physiological variability and this represents
a normal transition phase of glucose physiology.
Any pathological states which affect glucose pro-
duction or utilisation will lead to hypoglycaemia. In
the neonatal, infancy and childhood periods, the
nding of biochemical hypoglycaemia is common.
However, despite the commonality of hypogly-
caemia, in our current state of knowledge about
glucose physiology, it is not possible to dene hypo-
glycaemia by a particular blood glucose value/s. The
brain is the key organ for glucose utilisation and
there is no doubt that low blood glucose levels can
lead to neuronal energy deciency and hence lead to
brain injury.
6
There are no evidence-based studies
that dene a particular blood glucose which leads to
irreparable brain damage.
Having an understanding of the physiological
and biochemical mechanisms that regulate normal
blood glucose levels will help in the diagnostic
approach to a child with hypoglycaemia. A low
blood glucose level has to be interpreted within the
clinical scenario, the presence or absence of alterna-
tive substrates, the method used to measure blood
glucose and in the neonatal period in relation to
feeds.
7
As hypoglycaemia is a common biochemical
nding, making the correct diagnosis is extremely
important as this will guide the clinician in patient
management. Any child presenting with unex-
plained hypoglycaemia will need a full biochemical
diagnostic workup searching for the underlying
cause of the hypoglycaemia.
The aims of this review are to highlight the dif-
culty in dening hypoglycaemia, to describe the
physiological and biochemical mechanisms that
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regulate blood glucose levels during the perinatal, neonatal and
infancy periods and to review what normalblood glucose
levels are during these periods.
WHY IS IT DIFFICULT TO DEFINE HYPOGLYCAEMIA?
Hypoglycaemia cannot be dened by a particular blood glucose
value especially in the newborn period. The majority of appro-
priate for age term newborns show transient low blood glucose
concentrations (transitional neonatal hypoglycaemia, discussed
below) and this is a normal physiological adaptation process.
Several different methods have been used to dene hypogly-
caemia but none of these are satisfactory.
8
A single low blood
glucose value cannot be applied unanimously to all the patients.
In the newborn and infancy periods, hypoglycaemia cannot
be dened by the onset of signs and symptoms as these tend to
be non-specic and are not easy to recognise in this age group
(unlike older children and adults). Hypoglycaemic symptoms
can be non-specic, like lethargy, poor feeding and irritability,
to more specic ones, such as apnoea, seizures or coma. Hence,
the relevance of a carefully detailed clinical assessment is of the
utmost importance. The responses of the brain to hypogly-
caemia (neuroglycopaenic symptoms arise when insufcient
glucose is available to fuel the brain) occur over a range of
blood glucose levels and these responses can be modied by pre-
vious episodes (antecedent) of hypoglycaemia and by the pres-
ence of alternative brain fuels (like ketone bodies and lactate). It
is impossible to establish a single blood glucose value which
leads to brain damage as this will depend on the severity, fre-
quency and duration of hypoglycaemia.
In adults, clinical hypoglycaemia is dened as a blood glucose
level which is sufciently low to induce symptoms and signs of
impaired brain function.
9
Guidelines in adults emphasise the
value of Whipples triad for conrming hypoglycaemia, that is,
signs and/or symptoms consistent with hypoglycaemia, a docu-
mented low blood glucose concentration, and relief of signs/
symptoms when blood glucose level is restored to normal. The
same approach has been recommended for older children who
are able to describe their symptoms.
10
However, this cannot be
applied to the younger infants and of course neonates, as they
cannot convey their symptoms.
When interpreting a blood glucose result, the method of col-
lection of the blood sample will be important as some methods
(especially bedside test strips) may be inaccurate. Whole blood
glucose values are about 15% less compared with those in the
serum and plasma. On the other hand, venous blood glucose
concentrations are 10% lower than arterial. To measure the
plasma glucose, the sample of blood should be collected into a
tube containing uoride so as to inhibit glycolysis.
7
A single number cannot be applied unanimously to all the
individuals to dene signicant hypoglycaemia. Preferably, there
is a value(s) unique to each person, which varies with the state
of physiological maturity and the presence of pathology.
Therefore, signicant hypoglycaemia would be the blood or
plasma level of glucose at which the individual displays a unique
response to the anomalous circumstances caused by the reduced
supply of glucose to a target organ (for instance, the brain). The
uniqueresponse refers to the biochemical changes which are
activated when the blood glucose level is lowered with/without
the accompanying clinical manifestations. This response will be
modulated by the availability of alternative fuels, the counter-
regulatory hormonal responses and any episodes of antecedent
hypoglycaemia. Hence, it is impossible to establish a blood
glucose concentration that requires intervention in all newborns
as there is uncertainty over the duration and level of
hypoglycaemia that can lead to brain damage. Also, there is not
much known regarding whether the brain of infants at different
gestational ages, is vulnerable, or not, to such harm. It is thus
clear that hypoglycaemia is a continuum and the blood glucose
level should be interpreted within the clinical scenario and with
respect to the presence of alternative fuels (counter-regulatory
hormones and intermediate metabolites (fatty acids and ketone
bodies)) and in relation to feeds.
7
PERINATAL GLUCOSE PHYSIOLOGY
The mother supplies glucose to the placenta and fetus with the
placenta regulating the transfer of glucose and nutrients to the
fetus. For placental glucose to be transported from the maternal
circulation to the fetus there has to be a net maternal-to-fetal
plasma glucose concentration gradient that is determined by pla-
cental as well as the fetal glucose consumption.
5
Glucose is trans-
ferred to the placenta where it is partitioned between the glucose
consumption by the placenta and that transferred to the fetus.
GLUT 1 transporter protein takes up glucose from the mater-
nal plasma transporting it to the fetus by facilitative diffusion
following concentration-dependent kinetics.
11
GLUT 1 is the
main glucose transporter protein isoform in maternal-facing
microvillus and fetal-facing syncytiotrophoblast membranes. The
increased placental glucose transport in the latter part of preg-
nancy is due to the augmented surface area and the presence of
a high GLUT 1 density.
12
Studies in sheep showed that in the
second half of pregnancy, fetal glucose demand grows much
more rapidly (about a 10-fold increase) than placental glucose
transfer capacity and this then requires a decrease in fetal
glucose levels to balance glucose supply and demand.
13
The
increased glucose transport leads to, especially in the third tri-
mester, signicant deposition of glycogen and fat stores.
BLOOD GLUCOSE VALUES IN THE NORMAL FETUS
The fetus consumes glucose as its principle metabolic fuel for
energy production. The fetal glucose concentration is a function of
the maternal glucose concentration and gestational age. At around
20 weeks of gestational age there is a linear relationship between
maternal and fetal glucose concentrations.
14
For most of the gesta-
tional period (and especially after 20 weeks) the fetus is exposed to
circulating glucose concentrations only slightly below those of
maternal plasma. With a normal maternal glucose concentration of
3.55.5 mmol/L, the mean fetal-maternal plasma glucose differ-
ence at term is only 0.5 mmol/L, thus in the term healthy fetus the
normal glucose concentration is around 3 mmol/L.
3
Glucose contributes to nearly 80% of the total energy needs of
the fetus and the remaining 20% is supplied by lactate, amino
acids and glycerol.
15
The fetus uses glucose at a higher rate than
that observed in adults (57 mg/kg/min vs 23 mg/kg/min).
Under normal conditions there is no fetal glucose production
(by glycogenolysis or gluconeogenesis), but glucose production is
stimulated in the fetus exposed to prolonged periods of low
glucose supply (eg, during fasting or placental insufciency).
Glycogenic enzymes are present in fetal liver from 8 weeks of
gestation and the hepatic glycogen content increases from
3.4 mg/g at 8 weeks of gestation to 50 mg/g at term.
Insulin is the main anabolic hormone in fetal life and islet pan-
creatic β-cells can be detected in the pancreas by the 1012th
weeks of gestation.
16
Fetal pancreatic β-cells release insulin
poorly in response to changes in the blood glucose concentration
and the response to a glucose load is blunted. Insulin becomes
detectable around 1012 weeks of gestation in the fetus and
during the perinatal period insulin is more important for regulat-
ing growth rather than regulating glucose metabolism.
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GLUCOSE PHYSIOLOGY IN THE NORMAL TERM NEONATE:
MAKING THE TRANSITION TO AN INDEPENDENT
EXISTENCE
The healthy term newborn needs to adjust to an independent
existence at birth. The transplacental glucose and nutrient deliv-
ery is discontinued and the newborn will have to initiate endo-
crine and metabolic responses to maintain appropriate blood
glucose concentrations. Appropriate glycogen stores, intact and
functional glycogenolytic, gluconeogenic, lipogenic and keto-
genic mechanisms and adequate counter-regulatory hormonal
responses are required for extrauterine adaptation. Figure 1
shows the metabolic, endocrine and physiological changes
which occur at the time of birth to allow a normal term
newborn to adapt to an independent existence.
An appropriate for gestational age normal infant will have an
instantaneous postnatal drop (physiologically normal) in blood
glucose concentrations during the rst 24 h of life. During this
transitional phase, normalblood glucose values can range from
as low as 1.4 mmol/L to as high as 6.2 mmol/L.
17 18
The lowest
mean blood glucose documented within the rst few hours of
birth can be as low as 2.3 mmol/L.
19
Studies that have documen-
ted normalblood glucose concentrations in healthy, appropri-
ate for gestational age newborns in the rst hours of life are
listed in table 1.
1724
Healthy term breastfed newborns have signicantly lower
blood glucose concentrations (mean 3.6 mmol/L; range 1.5
5.3), than those who are bottle-fed (mean 4.0 mmol/L; range
2.56.2),
7
but their ketone body concentrations are raised in
response to breast feeding.
18 24
Figure 2 shows the results of a
study
24
with the serial mean and±SD plasma glucose levels
within the rst 72 h of life in exclusively breastfed infants and
gure 3 shows the distribution of these blood glucose levels.
Blood glucose concentrations in the rst few hours of life
appear lowat the time of sampling in the absence of clinical
signs of hypoglycaemia. Nevertheless, concentrations increased
immediately after a breastfeed or after 72 h of age. This is all
suggestive of an appropriate metabolic response to satisfy the
energy needs of term, breastfed infants.
In addition to the low blood glucose levels, the serum insulin
concentrations are inappropriately high during this transitional
phase of normal glucose physiology, suggesting a transient alter-
ation in the set point for insulin secretion during this
period.
25 26
However, despite the marked variability in
the blood glucose levels and transient alteration in the set point
for insulin secretion during the rst few hours of life, after
about 72 h of age, all term healthy newborns reach
fasting blood glucose levels comparable to those of children and
adults (3.55.5 mmol/L). The above endocrine and metabolic
proles observed in appropriate for gestational age normal
infants in the rst few days of life suggest that these are rela-
tively low blood glucose levels in comparison to older babies
where the glucose set point for suppression of insulin secretion
is reduced.
26
The drop in the glucose levels noted after birth appears essen-
tial to facilitate physiological transition for neonatal survival,
which includes increased glucose production by glycogenolysis,
gluconeogenesis, stimulation of appetite, adaptation to fast/feed
cycles, and promotion of oxidative fat metabolism using lipid
from fat stores and ingested milk feeds.
27
A rise in the secretion
of catecholamines and glucagon is considered important in
glucose control, although the ultimate trigger for the endocrine
and metabolic adaptation is unknown. At birth, the plasma
insulin to glucagon ratio is reversed permitting glucagon to
activate adenylate cyclase and increase the activity of cAMP-
dependent protein kinase A, which activates phosphorylase
kinase facilitating the release of glucose into the circulation.
Figure 1 The metabolic, endocrine and the physiological changes which occur at the time of birth to allow a normal term newborn to adapt to an
independent existence.
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The catecholamine increase and a surge in thyroid stimulating
hormone stimulate lipolysis and lipid oxidation, leading to aug-
mented concentrations of free fatty acids and glycerol.
28
Delivery of free fatty acids to the liver will entail the production
of ketone bodies that are an alternative energy fuel. The
newborn can adjust to postnatal nutrition because important
modications in the function of various physiological systems
happen after birth. Healthy term neonates will successfully tol-
erate enteral feeds that stimulate the production of gut hor-
mones, which in turn trigger a cascade of developmental
changes in gut function and structure, and in the relation of
pancreatic hormone production to intermediary metabolism.
29
Consequently, full-term neonates are programmed to func-
tionally and metabolically evolve from the intrauterine depend-
ent ambience to the extrauterine habitat without requiring
metabolic vigilance or interference with the natural breastfeed-
ing. Conversely, in premature or small for gestational age infants
this complex hormonal and metabolic adaptation process is
immature and underdeveloped.
HOW TO MAINTAIN NORMAL BLOOD GLUCOSE
CONCENTRATIONS: INTEGRATING THE PHYSIOLOGICAL
CHANGES RELATED TO FASTING AND FEEDING STATES
Normal fasting blood glucose levels in infants, children and
adults are maintained within a narrow range (3.55.5 mmol/L)
despite the frequent feed and fasting cycles. Insulin plays a major
role in regulating glucose production and utilisation during
feeding and fasting states. After food ingestion, the plasma
glucose level begins to rise within 15 min.
30
This increase in the
plasma glucose level and the stimuli from neurogenic and enter-
oinsular axis (gastric inhibitory peptide and glucagon-like
peptide 1) stimulates insulin production from the pancreatic β
cells. Peak concentrations of plasma glucose are reached around
3060 min following ingestion after which it starts to decrease
Table 1 Studies that have published normal blood glucose concentrations (BM) in healthy, AGA newborns in the first hours of life
Publication,
author, year,
(reference)
Study size
(n)
Age
(hours of
life)
BM in mmol/L,
Mean±SD*
(range)*
Feeding mode
when sampled Subjectscharacteristics
Study design
Method of analysis
Acharya and
Payne, 1965
20
14 0 4.0±0.9 (2.55.3) Not specified Term, AGA, no maternal or neonatal
complications
Not specified
Nelson-Somogyi
photometric assay, (assay also
measures other reducing
sugars)
14 1 3.5±1.1 (1.75.9)
14 2 3.3±1.0 (1.75.2)
14 3 3.5±1.1 (2.26.2)
14 5 3.5±1.2 (2.25.4)
14 7 3.3±1.1 (1.94.9)
14 9 3.3±0.8 (1.84.9)
14 11 3.6±1.5 (2.37.9)
14 18 3.5±0.9 (2.35.8)
14 24 3.2±0.8 (1.64.3)
14 36 3.1±0.9 (1.65.0)
14 48 3.3±0.7 (2.25.0)
Srinivasan et al,
1986
21
52 1 3.11±1.06 (0.96.6) Not fed Full term, AGA (2.54.0 kg), no maternal
or neonatal complications
Longitudinal
Beckman glucose oxidase
analyser
52 2 3.33±0.61 (2.175.33)
51 3 3.89±0.72 (2.25.4)
Heck and
Erenberg, 1987
22
113 1 3.33±1.00 Not fed Term (3742 weeks), no maternal or
neonatal complications
Longitudinal
Beckman glucose oxidase
analyser
107 2 3.39±0.83
Hawdon et al,
1992
18
9 NVD 0 4.3 Breast or
formula
Term (>37 weeks), AGA, white ethnicity,
born by NVD or C-section, no maternal or
neonatal complications
Cross-sectional
Cobas fast centrifugal
analyser
24 C-section 0 3.4
11 NVD 112 3.1
11 C-section 112 3.3
9 NVD 1224 3.7
10 C-section 1224 3.3
27 Day 2 3.5
27 Day 3 3.4
21 Day 4 4.1
20 Day 5 4.0
20 Day 6 4.2
Sweet et al,
1999
19
22 1 2.34±0.91 Breast Babies >37 weeks, normal Apgars, not
admitted to NICU, no maternal diabetes
Cross-sectional
HemoCue B-Glucose system24 1 2.52±0.84 Formula
29 1 2.58±0.94 Not fed
Hoseth et al,
2000
17
22 1 2.9±0.7 (1.44.0) Breast Term (3742 weeks), AGA, normal Apgars,
no maternal or neonatal complications
Cross-sectional
Glucose dehydrogenase
photometric method
27 2 3.2±0.8 (2.04.9)
Dollberg et al,
2001
23
50 24 3.97±0.76(1.85.8) Not specified Term (3841 weeks), AGA, normal Apgars,
no maternal or neonatal complications
Cross-sectional
Nova Stat
Profile M glucose oxidase
electrode
Diwakar and
Sasidhar, 2002
24
200 3 3.0±1.05 (1.48.3) Fed and not fed Term (3742 weeks), AGA, normal Apgars,
no maternal or neonatal complications
Longitudinal
Hitachi 902 Nova Biomedical
Corp
6 2.95±0.75 (1.65.4)
24 2.89±0.79 (1.37.6)
72 3.0±0.79 (1.47.1)
*When available.
Whole blood values reported using Nova Stat were adjusted to plasma glucose values using a correction factor of 1.135.
AGA, appropriate size for gestational age; NVD, normal vaginal delivery; C-section, caesarean section; NICU, neonatal intensive care unit.
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until absorption is complete, generally after 45 h, with a similar
time pattern of the plasma insulin concentrations.
Following the ingestion of a meal, the insulin and glucagon
responses will determine the magnitude of the suppression of
endogenous liver glucose production.
31
Endogenous glucose
production may be suppressed up to 5060% with about 25
grams less glucose being secreted into the bloodstream.
32
Postprandially, blood glucose concentrations are determined
by a balance between the rates of glucose removal from the sys-
temic circulation and the rate of glucose being delivered into it.
7
Also, postprandially the processes of glycogenolysis, gluconeo-
genesis, lipolysis and ketogenesis are all suppressed. The main
tissues that account for the removal of glucose from the blood-
stream include the liver, brain, muscle, small intestine and
adipose tissue. Except for the brain, it is the plasma insulin con-
centration that largely determines the magnitude of glucose
uptake by the tissues.
7
The uptake of glucose by the brain is
independent of the plasma insulin concentration and is deter-
mined by the plasma glucose concentration.
7
The postabsorptive state,reects the 46 h interval following
the ingestion of a meal.
7
During this interval, a steady state is
reached where plasma glucose concentrations are maintained
within a normal range since the rate of glucose production equals
that of glucose consumption.
7
During this state, it is estimated
that glucose turnover (glucose production and utilisation) is
roughly 10 mmol/kg/min.
33
In this state, 80% of glucose utilisa-
tion is non-insulin dependent, especially by the brain (which
accounts for 50% of the total), renal and gastrointestinal systems
and red blood cells. During this phase, interactions between
insulin and the counter-regulatory hormones (glucagon, cortisol,
GH, epinephrine and norepinephrine) will maintain glucose con-
centrations. The release of hepatic stored glycogen is controlled
by glucagon while insulin limits the effects of glucagon by pre-
venting lipolysis and proteolysis. Counter-regulatory hormones
such as cortisol and GH participate in setting the sensitivity of
the peripheral tissues to glucagon and insulin.
As the period of the fast is lengthened, the tissues increase the
utilisation of free fatty acids and ketone bodies while that of
glucose decreases.
34
There is a reduction in glucose output from
the liver, which is accounted for mainly by a decrease in glyco-
genolysis, with an increase in the rate of gluconeogenesis. It is
speculated that increased gluconeogenesis is explained by the
augmented secretion of counter-regulatory hormones such as
glucagon, and the reduction in insulin secretion.
7
The augmen-
ted glucagon production is associated with diminished insulin
secretion permitting fat deposits to be converted into glycerol
and fatty acids, and allowing the degradation of proteins into
amino acids for gluconeogenesis. Released free fatty acids bind
to albumin to be transported to the liver, where they participate
in mitochondrial β-oxidation or they are re-esteried to triacyl-
glycerols and phospholipids.
7
β-oxidation generates acetyl-Co
that can be turned into ketone bodies (acetoacetate and
3β-hydroxybutyrate) via the hydroxymethylglutaryl coenzyme A
pathway, or it can be oxidised in the Krebs cycle.
Following a nocturnal fast, the main gluconeogenic precursors
are lactate, glycerol and alanine. Recycling of carbon atoms
from plasma glucose generates the majority of the overnight
fasting lactate and alanine.
7
In gluconeogenesis, the rst reaction
converts pyruvate to oxaloacetate to phosphoenolpyruvate.
The second reaction is the rate-limiting step for the process of
gluconeogenesis, and implicates the conversion of fructose-1,
6-biphosphate to fructose-6-biphosphate. In the last step
glucose-6-phosphate is transformed into free glucose.
Young children differ from adults in that glycogen stores are
limited and only sufcient for approximately 12 h of starvation,
after which gluconeogenesis will be responsible for the mainten-
ance of a normal blood glucose concentration.
7
Haymond
et al
35
showed that after a 30 h fast, children had lower glucose
and alanine concentrations than adult men and women. For this
reason, children do not tolerate long fasting periods.
Childrens brain in relation to body size, is much larger than
in adults. That is why the glucose production rates are higher in
children, so as to meet the brains higher metabolic demands.
Bier et al
36
measured glucose production rates in infants and
children using 6,6-dideuteroglucose and showed that the brain
size was the principal determinant of factors that regulate
hepatic glucose output throughout life.
Sunehag et al
37
have shown that children between the ages of
8 years and 9 years have a higher rate of gluconeogenesis, on a
body weight basis, than adolescents between the ages of 14 years
and 16 years. Interestingly, the fraction of glucose produced from
gluconeogenesis was almost the same between the two groups.
The same study showed that gluconeogenesis contributed to
50% of glucose production in the childhood period. A higher
glucose utilisation rate per kilogram body weight is demonstrated
in neonates and young children when starved, compared with
adult requirements.
7
Hence for these reasons, children are more
susceptible to hypoglycaemia in comparison to adults.
Figure 2 Plasma glucose concentrations measured serially in 200
term appropriate size for gestational age and exclusively breastfed
infants, at 3 h, 6 h, 24 h and 72 h of age (adapted from Diwakar and
Sasidhar
24
).
Figure 3 Plasma glucose concentration distributions at the time of
sampling in 200 term appropriate size for gestational age and
exclusively breastfed infants, at 3 h, 6 h, 24 h and 72 h of age
(adapted from Diwakar and Sasidhar
24
).
Güemes M, et al.Arch Dis Child 2015;0:16. doi:10.1136/archdischild-2015-308336 5
Review
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As the period of fast becomes more prolonged, the ongoing
energy requirements of muscle and other tissues rely progres-
sively more on free fatty acids and ketone bodies. Hepatic fatty
acid oxidation generates ketone bodies, which are transferred to
peripheral tissues for use as an alternative fuel.
7
It is mainly the
brain that has no other substantial non-glucose-derived energy
source but ketone bodies. The brains continuous requirement
of energy allows ketone bodies to replace glucose as the pre-
dominant fuel for nervous tissue during prolonged fasting.
38
During the period of a fast there is a complex interaction of
metabolic and hormonal mechanisms, which leads to important
uctuations in the concentrations of the counter-regulatory hor-
mones and intermediary metabolites. Children differ in their
response to fasting in comparison to adults.
35
For example,
studies in adults have shown that the blood concentrations of
free fatty acids, glycerol and ketones progressively rise as the star-
vation period is prolonged.
39
Children exposed to a short fast
develop ketosis and ketonuria quickly, suggesting that children
convert more rapidly to a fuel economy based largely on fat.
Thus infants and children develop hypoglycaemia more readily.
CONCLUSIONS
Apart from the immediate neonatal period, the normal range of
fasting blood glucose concentration is 3.55.5 mmol/L. Blood
glucose concentrations are kept within this range by a complex
interplay of hormones which control glucose production and
utilisation. In term appropriate for age healthy newborns within
the rst few hours of life, normalblood glucose concentrations
can range between 1.4 mmol/L and 6.2 mmol/L, but by about
72 h of life they reach values of 3.55.5 mmol/L.
Hypoglycaemia should be considered as a continuum and the
blood glucose level should be interpreted within the clinical
scenario and with respect to the counter-regulatory hormonal
responses and intermediate metabolites.
Contributors MG wrote the section on neonatal glucose physiology and created
table 1 and gure 1. SAR wrote the section on perinatal glucose physiology and
drew gures 2 and 3. KH wrote the rest of the manuscript and checked the
completed manuscript. He completed all the references.
Competing interests None declared.
Provenance and peer review Commissioned; externally peer reviewed.
REFERENCES
1 Kaufman FR. Role of the continuous glucose monitoring system in pediatric
patients. Diabetes Technol Ther 2000;2(Suppl 1):S4952.
2 Mitrakou A. Kidney: its impact on glucose homeostasis and hormonal regulation.
Diabetes Res Clin Pract 2011;93(Suppl 1):S6672.
3 Kalhan SC, DAngelo L, Savin SM, et al. Glucose production in pregnant women at
term gestation: Sources of glucose for human fetus. J Clin Invest 1979;63:38894.
4 DiGiacomo JE, Hay WW Jr. Fetal glucose metabolism and oxygen consumption
during sustained hypoglycemia. Metabolism 1990;39:193202.
5 Hay WW Jr. Regulation of placental metabolism by glucose supply. Reprod Fertil
Dev 1995;7:36575.
6 Burns CM, Rutherford MA, Boardman JP, et al. Patterns of cerebral injury and
neurodevelopmental outcomes after symptomatic neonatal hypoglycemia. Pediatrics
2008;122:6574.
7 Hussain K, Dunne MJ. Hypoglycemia. In: Clinical Pediatric Endocrinology. 5th
edition. Eds: Brook CGD, Clayton PE, Brown RS. Oxford, UK: Blackwell Publishing,
2005:47491.
8 Cornblath M, Hawdon JM, Williams AF, et al. Controversies regarding denition of
neonatal hypoglycemia: suggested operational thresholds. Pediatrics
2000;105:11415.
9 Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of adult
hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin
Endocrinol Metab 2009;94:70928.
10 Thornton PS, Stanley CA, De Leon DD, et al. Recommendations from the Pediatric
Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in
Neonates, Infants, and Children. J Pediatr 2015;167:23845.
11 Hay WW Jr. Placental transport of nutrients to the fetus. Horm Res
1994;42:21522.
12 Jansson T, Wennergren M, Illsley NP. Glucose transporter protein expression in
human placenta throughout gestation and in intrauterine growth retardation. J Clin
Endocrinol Metab 1993;77:155462.
13 Molina RD, Meschia G, Battaglia FC, et al. Gestational maturation of
placental glucose transfer capacity in sheep. Am J Physiol 1991;261(3 Pt 2):
R697704.
14 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;37:35863.
15 Rao PN, Shashidhar A, Ashok C. In utero fuel homeostasis: lessons for a clinician.
Indian J Endocrinol Metab 2013;17:608.
16 Piper K, Brickwood S, Turnpenny LW, et al. Beta-cell differentiation during early
human pancreas development. J Endocrinol 2004;181:1123.
17 Hoseth E, Joergensen A, Ebbesen F, et al. Blood glucose levels in a population of
healthy, breast fed, term infants of appropriate size for gestational age. Arch Dis
Child Fetal Neonatal Ed 2000;83:F1179.
18 Hawdon JM, Ward-Platt MP, Aynsley-Green A. Patterns of metabolic adaptation for
preterm and term infants in the rst neonatal week. Arch Dis Child
1992;67:35765.
19 Sweet DG, Hadden D, Halliday HL. The effect of early feeding on the neonatal
blood glucose level at 1-hour of age. Early Hum Dev 1999;55:636.
20 Acharya PT, Payne WW. Blood chemistry of normal full-term infants in the rst 48
hours of life. Arch Dis Child 1965;40:4305.
21 Srinivasan G, Pildes RS, Cattamanchi G, et al. Plasma glucose values in normal
neonates: a new look. J Pediatr 1986;109:1147.
22 Heck LJ, Erenberg A. Serum glucose levels in term neonates during the rst 48
hours of life. J Pediatr. 1987;110:11922.
23 Dollberg S, Bauer R, Lubetzky R, et al. A reappraisal of neonatal blood
chemistry reference ranges using the Nova M electrodes. Am J Perinatol
2001;18:43340.
24 Diwakar KK, Sasidhar MV. Plasma glucose levels in term infants who are
appropriate size for gestation and exclusively breast fed. Arch Dis Child Fetal
Neonatal Ed 2002;87:F468.
25 Hawdon JM, Aynsley-Green A, Alberti KG, et al. The role of pancreatic insulin
secretion in neonatal glucoregulation. Healthy term and preterm infants. Arch Dis
Child 1993;68:2749.
26 Stanley CA, Anday EK, Baker L, et al. Metabolic fuel and hormone responses to
fasting in newborn infants. Pediatrics 1979;64:61319.
27 Stanley CA, Rozance PJ, Thornton PS, et al. Re-evaluating transitional neonatal
hypoglycemia": mechanism and implications for management. J Pediatr
2015;166:15201525.e1.
28 Sperling MA, Ganguli S, Leslie N, et al. Fetal-perinatal catecholamine secretion: role
in perinatal glucose homeostasis. Am J Physiol 1984;247(1 Pt 1):E6974.
29 Aynsley-Green A, Lucas A, Lawson GR, et al. Gut hormones and regulatory peptides
in relation to enteral feeding, gastroenteritis, and necrotizing enterocolitis in infancy.
J Pediatr 1990;117(1 Pt 2):S2432.
30 Mitrakou A, Kelley D, Veneman T, et al. Contribution of abnormal muscle and liver
glucose metabolism to postprandial hyperglycemia in NIDDM. Diabetes
1990;39:138190.
31 Mitrakou A, Vuorinen-Markkola H, Raptis G, et al. Simultaneous assessment of
insulin secretion and insulin sensitivity using a hyperglycemia clamp. J Clin
Endocrinol Metab 1992;75:37982.
32 Firth RG, Bell PM, Marsh HM, et al. Postprandial hyperglycemia in patients with
noninsulin-dependent diabetes mellitus. Role of hepatic and extrahepatic tissues.
J Clin Invest 1986;77:152532.
33 Bolli GB, Gottesman IS, Cryer PE, et al. Glucose counterregulation during
prolonged hypoglycemia in normal humans. Am J Physiol 1984;247(2 Pt 1):
E20614.
34 Fukao T, Mitchell G, Sass JO, et al. Ketone body metabolism and its defects.
J Inherit Metab Dis 2014;37:54151.
35 Haymond MW, Karl IE, Clarke WL, et al. Differences in circulating gluconeogenic
substrates during short-term fasting in men, women, and children. Metabolism
1982;31:3342.
36 Bier DM, Leake RD, Haymond MW, et al. Measurement of trueglucose production
rates in infancy and childhood with 6,6-dideuteroglucose. Diabetes 1977;26:101623.
37 Sunehag AL, Treuth MS, Toffolo G, et al. Glucose production, gluconeogenesis, and
insulin sensitivity in children and adolescents: an evaluation of their reproducibility.
Pediatr Res 2001;50:11523.
38 Zhang Y, Kuang Y, Xu K, et al. Ketosis proportionately spares glucose utilization in
brain. J Cereb Blood Flow Metab 2013;33:130711.
39 Cahill GF Jr. Starvation in man. Clin Endocrinol Metab 1976;5:397415.
6 Güemes M, et al.Arch Dis Child 2015;0:16. doi:10.1136/archdischild-2015-308336
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group.bmj.com on September 16, 2015 - Published by http://adc.bmj.com/Downloaded from
What is a normal blood glucose?
Maria Güemes, Sofia A Rahman and Khalid Hussain
published online September 14, 2015Arch Dis Child
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... The range of GLU in normal people ranges from 3.5 to 5.5 mmol/L. 8 We also included postprandial 2-hour glucose levels (GLU_2H). Generally, GLU_2H lower than 7.78 mmol/L is considered within the normal limit. ...
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Chapter
IntroductionBlood glucose homeostasis in the fetusMechanisms maintaining a normal blood glucose concentrationIntegration of the changes associated with feeding and fastingGlucose and the brainDifferences in blood glucose regulation between children and adults [35]Overview of the different causes of hypoglycemia in childhoodNew syndromes
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