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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Blood glucose is the key substrate for energy production during the perinatal, neonatal and postnatal periods. Apart from the first few days of life, normal fasting blood glucose concentrations are kept within a narrow physiological range of 3.5–5.5 mmol/L. Continuous blood glucose monitoring shows that blood glucose concentrations may ‘flicker’ on either side of these two values (especially post meal) but then rapidly and spontaneously 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 gluconeogenesis (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 typically regulates glucose homoeostasis in the postprandial 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 production, 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 first few hours after birth, there is a transitional phase of physiologically low normal blood glucose levels (transitional neonatal hypoglycaemia) which normalise around 72 h after birth. It is during these first 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 production or utilisation will lead to hypoglycaemia. In the neonatal, infancy and childhood periods, the finding of biochemical hypoglycaemia is common. However, despite the commonality of hypoglycaemia, in our current state of knowledge about glucose physiology, it is not possible to define hypoglycaemia 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 deficiency and hence lead to brain injury.6 There are no evidence-based studies that define 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 alternative substrates, the method used to measure blood glucose and in the neonatal period in relation to feeds.7 As hypoglycaemia is a common biochemical finding, making the correct diagnosis is extremely important as this will guide the clinician in patient management. Any child presenting with unexplained 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 difficulty in defining hypoglycaemia, to describe the physiological and biochemical mechanisms that regulate blood glucose levels during the perinatal, neonatal and infancy periods and to review what ‘normal’ blood glucose levels are during these periods.
Why is it difficult to define hypoglycaemia?
Hypoglycaemia cannot be defined by a particular blood glucose value especially in the newborn period. The majority of appropriate 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 define hypoglycaemia 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 defined by the onset of signs and symptoms as these tend to be non-specific and are not easy to recognise in this age group (unlike older children and adults). Hypoglycaemic symptoms can be non-specific, like lethargy, poor feeding and irritability, to more specific 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 hypoglycaemia (neuroglycopaenic symptoms arise when insufficient glucose is available to fuel the brain) occur over a range of blood glucose levels and these responses can be modified by previous episodes (antecedent) of hypoglycaemia and by the presence 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, frequency and duration of hypoglycaemia.
In adults, clinical hypoglycaemia is defined as a blood glucose level which is sufficiently low to induce symptoms and signs of impaired brain function.9 Guidelines in adults emphasise the value of Whipple’s triad for confirming hypoglycaemia, that is, signs and/or symptoms consistent with hypoglycaemia, a documented 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 collection 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 fluoride so as to inhibit glycolysis.7
A single number cannot be applied unanimously to all the individuals to define significant 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, significant 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 ‘unique’ response 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 placental as well as the fetal glucose consumption.5 Glucose is transferred 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 maternal 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 pregnancy 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 trimester, significant 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 gestational 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 3.5–5.5 mmol/L, the mean fetal-maternal plasma glucose difference 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 (5–7 mg/kg/min vs 2–3 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 insufficiency). 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 pancreatic β-cells can be detected in the pancreas by the 10–12th 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 10–12 weeks of gestation in the fetus and during the perinatal period insulin is more important for regulating growth rather than regulating glucose metabolism.
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 delivery is discontinued and the newborn will have to initiate endocrine and metabolic responses to maintain appropriate blood glucose concentrations. Appropriate glycogen stores, intact and functional glycogenolytic, gluconeogenic, lipogenic and ketogenic 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 first 2–4 h of life. During this transitional phase, ‘normal’ blood 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 first few hours of birth can be as low as 2.3 mmol/L.19 Studies that have documented ‘normal’ blood glucose concentrations in healthy, appropriate for gestational age newborns in the first hours of life are listed in table 1.17–24
Healthy term breastfed newborns have significantly 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 2.5–6.2), 7 but their ketone body concentrations are raised in response to breast feeding.18 ,24 Figure 2 shows the results of a study24 with the serial mean and±SD plasma glucose levels within the first 72 h of life in exclusively breastfed infants and figure 3 shows the distribution of these blood glucose levels. Blood glucose concentrations in the first few hours of life appear ‘low’ at 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 alteration 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 first 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 (3.5–5.5 mmol/L). The above endocrine and metabolic profiles observed in appropriate for gestational age normal infants in the first few days of life suggest that these are relatively 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 essential 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.
The catecholamine increase and a surge in thyroid stimulating hormone stimulate lipolysis and lipid oxidation, leading to augmented 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 modifications in the function of various physiological systems happen after birth. Healthy term neonates will successfully tolerate enteral feeds that stimulate the production of gut hormones, 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 functionally and metabolically evolve from the intrauterine dependent ambience to the extrauterine habitat without requiring metabolic vigilance or interference with the natural breastfeeding. 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 (3.5–5.5 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 enteroinsular 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 30–60 min following ingestion after which it starts to decrease until absorption is complete, generally after 4–5 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 50–60% 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 systemic circulation and the rate of glucose being delivered into it.7 Also, postprandially the processes of glycogenolysis, gluconeogenesis, lipolysis and ketogenesis are all suppressed. The main tissues that account for the removal of glucose from the bloodstream include the liver, brain, muscle, small intestine and adipose tissue. Except for the brain, it is the plasma insulin concentration 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 determined by the plasma glucose concentration.7
The ‘postabsorptive state’, reflects the 4–6 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 µmol/kg/min.33 In this state, 80% of glucose utilisation 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 concentrations. The release of hepatic stored glycogen is controlled by glucagon while insulin limits the effects of glucagon by preventing 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 glycogenolysis, 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 augmented 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-esterified to triacylglycerols 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 first 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 sufficient for approximately 12 h of starvation, after which gluconeogenesis will be responsible for the maintenance of a normal blood glucose concentration.7 Haymond et al35 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.
Children’s 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 brain’s higher metabolic demands. Bier et al36 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 al37 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.
As the period of fast becomes more prolonged, the ongoing energy requirements of muscle and other tissues rely progressively 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 brain’s continuous requirement of energy allows ketone bodies to replace glucose as the predominant 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 fluctuations in the concentrations of the counter-regulatory hormones 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 starvation 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.
Apart from the immediate neonatal period, the normal range of fasting blood glucose concentration is 3.5–5.5 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 first few hours of life, ‘normal’ blood 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 3.5–5.5 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 figure 1. SAR wrote the section on perinatal glucose physiology and drew figures 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.
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