In the Newborn (Chapter 101)

Under nonstressed conditions, fetal glucose is derived entirely from the mother through placental transfer. Therefore, fetal glucose concentration usually reflects but is slightly lower than maternal glucose levels. Catecholamine release, which occurs with fetal stress such as hypoxia, mobilizes fetal glucose and free fatty acids (FFAs) through β-adrenergic mechanisms, reflecting β-adrenergic activity in fetal liver and adipose tissue. Catecholamines may also inhibit fetal insulin and stimulate glucagon release.

The acute interruption of maternal glucose transfer to the fetus at delivery imposes an immediate need to mobilize endogenous glucose. Three related events facilitate this transition: changes in hormones, changes in their receptors, and changes in key enzyme activity. There is a 3- to 5-fold abrupt increase in glucagon concentration within minutes to hours of birth. The level of insulin usually falls initially and remains in the basal range for several days without demonstrating the usual brisk response to physiologic stimuli such as glucose. A dramatic surge in spontaneous catecholamine secretion is also characteristic. Epinephrine can also augment growth hormone secretion by α-adrenergic mechanisms; growth hormone levels are elevated at birth. Acting in concert, these hormonal changes at birth mobilize glucose via glycogenolysis and gluconeogenesis, activate lipolysis, and promote ketogenesis. As a result of these processes, plasma glucose concentration stabilizes after a transient decrease immediately after birth, liver glycogen stores become rapidly depleted within hours of birth, and gluconeogenesis from alanine, a major gluconeogenic amino acid, can account for about 10% of glucose turnover in the human newborn infant by several hours of age. FFA concentrations also increase sharply in concert with the surges in glucagon and epinephrine and are followed by rises in ketone bodies. Glucose is thus partially spared for brain utilization while FFAs and ketones provide alternative fuel sources for muscle as well as essential gluconeogenic factors such as acetyl coenzyme A (CoA) and the reduced form of nicotinamide-adenine dinucleotide (NADH) from hepatic fatty acid oxidation, which is required to drive gluconeogenesis.

In the early postnatal period, responses of the endocrine pancreas favor glucagon secretion so that blood glucose concentration can be maintained. These adaptive changes in hormone secretion are paralleled by similarly striking adaptive changes in hormone receptors. Key enzymes involved in glucose production also change dramatically in the perinatal period. Thus, there is a rapid fall in glycogen synthase activity and a sharp rise in phosphorylase after delivery. Similarly, the amount of rate-limiting enzyme for gluconeogenesis, phosphoenolpyruvate carboxykinase, rises dramatically after birth, activated in part by the surge in glucagon and the fall in insulin. This framework can explain several causes of neonatal hypoglycemia based on inappropriate changes in hormone secretion and unavailability of adequate reserves of substrates in the form of hepatic glycogen, muscle as a source of amino acids for gluconeogenesis, and lipid stores for the release of fatty acids. In addition, appropriate activities of key enzymes governing glucose homeostasis are required (see Fig. 81-1).

In Older Infants and Children

Hypoglycemia in older infants and children is analogous to that of adults, in whom glucose homeostasis is maintained by glycogenolysis in the immediate postfeeding period and by gluconeogenesis several hours after meals. The liver of a 10 kg child contains 20-25 g of glycogen, which is sufficient to meet normal glucose requirements of 4-6 mg/kg/min for only 6-12 hr. Beyond this period, hepatic gluconeogenesis must be activated. Both glycogenolysis and gluconeogenesis depend on the metabolic pathway summarized in Figure 81-1. Defects in glycogenolysis or gluconeogenesis may not be manifested in infants until the frequent feeding at 3-4 hr intervals ceases and infants sleep through the night, a situation usually present by 3-6 mo of age. The source of gluconeogenic precursors is derived primarily from muscle protein. The muscle bulk of infants and small children is substantially smaller relative to body mass than that of adults, whereas glucose requirements/unit of body mass are greater in children, so the ability to compensate for glucose deprivation by gluconeogenesis is more limited in infants and young children, as is the ability to withstand fasting for prolonged periods. The ability of muscle to generate alanine, the principal gluconeogenic amino acid, may also be limited. Thus, in normal young children, the blood glucose level falls after 24 hr of fasting, insulin concentrations fall appropriately to levels of <5-10 µU/mL, lipolysis and ketogenesis are activated, and ketones may appear in the urine.

The switch from glycogen synthesis during and immediately after meals to glycogen breakdown and later gluconeogenesis is governed by hormones, of which insulin is of central importance. Plasma insulin concentrations increase to peak levels of 50-100 µU/mL after meals, which serve to lower the blood glucose concentration through the activation of glycogen synthesis, enhancement of peripheral glucose uptake, and inhibition of glucose production. In addition, lipogenesis is stimulated, whereas lipolysis and ketogenesis are curtailed. During fasting, plasma insulin concentrations fall to ≤5-10 µU/mL, and together with other hormonal changes, this fall results in activation of gluconeogenic pathways (see Fig. 81-1). Fasting glucose concentrations are maintained through the activation of glycogenolysis and gluconeogenesis, inhibition of glycogen synthesis, and activation of lipolysis and ketogenesis. It should be emphasized that a plasma insulin concentration of >5 µU/mL, in association with a blood glucose concentration of ≤40 mg/dL (2.2 mM), is abnormal, indicating a hyperinsulinemic state and failure of the mechanisms that normally result in suppression of insulin secretion during fasting or hypoglycemia.

The hypoglycemic effects of insulin are opposed by the actions of several hormones whose concentration in plasma increases as blood glucose falls. These counter-regulatory hormones, glucagon, growth hormone, cortisol, and epinephrine, act in concert by increasing blood glucose concentrations via activating glycogenolytic enzymes (glucagon, epinephrine); inducing gluconeogenic enzymes (glucagon, cortisol); inhibiting glucose uptake by muscle (epinephrine, growth hormone, cortisol); mobilizing amino acids from muscle for gluconeogenesis (cortisol); activating lipolysis and thereby providing glycerol for gluconeogenesis and fatty acids for ketogenesis (epinephrine, cortisol, growth hormone, glucagon); and inhibiting insulin release and promoting growth hormone and glucagon secretion (epinephrine).

Congenital or acquired deficiency of any one of these hormones is uncommon but will result in hypoglycemia, which occurs when endogenous glucose production cannot be mobilized to meet energy needs in the postabsorptive state, that is, 8-12 hr after meals or during fasting. Concurrent deficiency of several hormones (hypopituitarism) may result in hypoglycemia that is more severe or appears earlier during fasting than that seen with isolated hormone deficiencies. Most of the causes of hypoglycemia in infancy and childhood reflect inappropriate adaptation to fasting.

Neonatal, Transient, Small for Gestational Age, and Premature Infants (Chapter 101)

The estimated incidence of symptomatic hypoglycemia in newborns is 1-3/1,000 live births. This incidence is increased severalfold in certain high-risk neonatal groups (see Table 86-2 and Fig. 86-1). The premature and small for gestational age (SGA) infants are vulnerable to the development of hypoglycemia. The factors responsible for the high frequency of hypoglycemia in this group, as well as in other groups outlined in Table 86-2, are related to the inadequate stores of liver glycogen, muscle protein, and body fat needed to sustain the substrates required to meet energy needs. These infants are small by virtue of prematurity or impaired placental transfer of nutrients. Their enzyme systems for gluconeogenesis may not be fully developed. Transient hyperinsulinism responsive to diazoxide has also been reported as contributing to hypoglycemia in asphyxiated, SGA, and premature newborn infants. This form of hyperinsulinism associated with perinatal asphyxia, intrauterine growth restriction (IUGR), maternal toxemia and other perinatal stressors, is probably the most common cause of hyperinsulinemic hypoglycemia in neonates and may be quite severe. In most cases, the condition resolves quickly, but it may persist to 7 mo of life or more. A genetic cause of this form of dysregulated insulin secretion has not been established.

In contrast to deficiency of substrates or enzymes, the hormonal system appears to be functioning normally at birth in most low-risk neonates. Despite hypoglycemia, plasma concentrations of alanine, lactate, and pyruvate are higher, implying their diminished rate of utilization as substrates for gluconeogenesis. Infusion of alanine elicits further glucagon secretion but causes no significant rise in glucose. During the initial 24 hr of life, plasma concentrations of acetoacetate and β-hydroxybutyrate are lower in SGA infants than in full-term infants, implying diminished lipid stores, diminished fatty acid mobilization, impaired ketogenesis, or a combination of these conditions. Diminished lipid stores are most likely because fat (triglyceride) feeding of newborns results in a rise in the plasma levels of glucose, FFAs, and ketones. For infants with perinatal asphyxia and some SGA newborns who have transient hyperinsulinemia, hypoglycemia and diminished concentrations of FFAs are the hallmark of hyperinsulinemia.

The role of FFAs and their oxidation in stimulating neonatal gluconeogenesis is essential. The provision of FFAs as triglyceride feedings from formula or human milk together with gluconeogenic precursors may prevent the hypoglycemia that usually ensues after neonatal fasting. For these and other reasons, milk feedings are introduced early (at birth or within 2-4 hr) after delivery. In the hospital setting, when feeding is precluded by virtue of respiratory distress or when feedings alone cannot maintain blood glucose concentrations at levels >50 mg/dL, intravenous glucose at a rate that supplies 4-8 mg/kg/min should be started. Infants with transient neonatal hypoglycemia can usually maintain the blood glucose level spontaneously after 2-3 days of life, but some require longer periods of support. In these latter infants, insulin values >5 µU/ml at the time of hypoglycemia should be treated with diazoxide.

Infants Born to Diabetic Mothers (Chapter 101)

Of the transient hyperinsulinemic states, infants born to diabetic mothers are the most common. Gestational diabetes affects some 2% of pregnant women, and ≈1/1,000 pregnant women have insulin-dependent diabetes. At birth, infants born to these mothers may be large and plethoric, and their body stores of glycogen, protein, and fat are replete.

Hypoglycemia in infants of diabetic mothers is mostly related to hyperinsulinemia and partly related to diminished glucagon secretion. Hypertrophy and hyperplasia of the islets is present, as is a brisk, biphasic, and typically mature insulin response to glucose; this insulin response is absent in normal infants. Infants born to diabetic mothers also have a subnormal surge in plasma glucagon immediately after birth, subnormal glucagon secretion in response to stimuli, and, initially, excessive sympathetic activity that may lead to adrenomedullary exhaustion as reflected by decreased urinary excretion of epinephrine. The normal plasma hormonal pattern of low insulin, high glucagon, and high catecholamines is reversed to a pattern of high insulin, low glucagon, and low epinephrine. As a consequence of this abnormal hormonal profile, the endogenous glucose production is significantly inhibited compared with that in normal infants, thus predisposing them to hypoglycemia.

Mothers whose diabetes has been well controlled during pregnancy, labor, and delivery generally have infants near normal size who are less likely to develop neonatal hypoglycemia and other complications formerly considered typical of such infants (Chapter 101). In supplying exogenous glucose to these hypoglycemic infants, it is important to avoid hyperglycemia that evokes a prompt exuberant insulin release, which may result in rebound hypoglycemia. When needed, glucose should be provided at continuous infusion rates of 4-8 mg/kg/min, but the appropriate dose for each patient should be individually adjusted. During labor and delivery, maternal hyperglycemia should be avoided because it results in fetal hyperglycemia, which predisposes to hypoglycemia when the glucose supply is interrupted at birth. Hypoglycemia persisting or occurring after 1 wk of life requires an evaluation for the causes listed in Table 86-2.

Infants born with erythroblastosis fetalis may also have hyperinsulinemia and share many physical features, such as large body size, with infants born to diabetic mothers. The cause of the hyperinsulinemia in infants with erythroblastosis is not clear.

Hyperinsulinism

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