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In normal children, including newborns after the first 3 days of life, plasma glucose concentrations range from 70 to 100 mg/dL, even during periods of fasting. Coordinated metabolic and endocrine responses to fasting maintain a normal supply of glucose for brain metabolism because the brain can neither synthesize nor efficiently store glucose. Congenital or acquired defects in these fasting systems result in hypoglycemia disorders, which often present in the neonatal period or during transitions to longer feeding intervals in infancy. To promote timely diagnosis and effective treatment of hypoglycemia by the primary care physician and endocrinologist, this chapter integrates current molecular and clinical knowledge.


Maintenance of a normal plasma glucose concentration requires the integrated function of three fasting systems that regulate the response to fasting: (1) hepatic glycogenolysis, (2) hepatic gluconeogenesis, and (3) hepatic ketogenesis. These three fasting systems are regulated by the endocrine system, specifically, by insulin and the counter-regulatory hormones—glucagon, epinephrine, growth hormone (GH), and cortisol. During fasting, insulin secretion is turned off when the plasma glucose concentration decreases below the threshold for glucose-stimulated insulin secretion (∼85 mg/dL). Suppression of insulin secretion allows the activation of the fasting systems. The second hormonal defense against hypoglycemia is activation of glucagon secretion and a sympathoadrenal discharge when the plasma glucose concentration falls to 65 to 70 mg/dL, which increases glucose release from liver glycogen stores (glycogenolysis) to increase the plasma glucose concentration. At plasma glucose concentrations below 65 mg/dL, secretion of cortisol and GH increases as well. Glycogenolysis provides glucose for brain and other tissues for up to 8 to 10 hours in older children, but for much shorter periods of time in infants. Liver gluconeogenesis, that is, the conversion of non-glucose precursors, such as lactate, pyruvate, and the carbon skeleton of glucogenic amino acids (eg, alanine) into glucose (activated by glucagon and cortisol), also contributes to the maintenance of plasma glucose concentrations during fasting. After longer periods of fasting, adipose tissue lipolysis (activated by GH and epinephrine) releases glycerol (another gluconeogenic substrate) and free fatty acids (FFAs) that, in the liver, are converted through β-oxidation to β-hydroxybutyrate and acetoacetate, which can partly support the energy needs of the brain when appropriately elevated, thereby limiting glucose utilization. Liberation and utilization of fat as an energy source limits catabolism of lean body mass. Over periods of prolonged fasting, fatty acid oxidation and ketogenesis account for almost 80% of the body’s energy sources.

Abnormalities in these fasting systems or the counter-regulatory hormonal response to fasting result in hypoglycemia.

The Fetus and Neonate

Throughout gestation, glucose is transported from the maternal circulation across the placenta via insulin-independent glucose transporter proteins (GLUTs) and provides nearly all the energy needs of the fetus. Fetal glucose concentrations are only slightly lower than maternal levels in utero, but fall following birth to ...

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