The Effect of Prematurity and Intrauterine Growth Restriction on Glucose Metabolism in the Newborn

Abstract

After completing this article, readers should be able to: At birth, the transplacental supply of nutrients, especially glucose, to the newborn is interrupted abruptly. This sets into motion a complex cascade of metabolic and endocrine events that allow a healthy term newborn to adjust to his or her new environment. This cascade is triggered by a surge in the concentrations of glucagon and catecholamines and cessation of insulin secretion. Glucagon and catecholamines increase glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis. The complex enzyme machinery responsible for these processes is mature in term healthy newborns. In contrast, the metabolic and endocrine processes allowing the transition to the extrauterine environment are not developed fully in preterm infants and those who have suffered intrauterine growth restriction (IUGR), placing these newborns at significant risk of hypoglycemia. This review focuses on the regulation of glucose metabolism during the fetal period and the metabolic and endocrine changes that occur at birth and in the postnatal period, with special reference to preterm infants and infants who have experienced IUGR.Carbohydrate is transported to the fetus as glucose, which is taken up from the maternal plasma by glucose transporters. GLUT1 and GLUT3 are the primary glucose transporters involved in the transplacental movement of glucose and are present on both the microvillus and basal membranes of the syncytial barrier. Glucose is transported to the fetus by facilitative diffusion according to concentration-dependent kinetics, with placental glucose transport capacity increasing with gestational age.The placental transport of glucose to the fetus requires a net maternal-to-fetal plasma glucose concentration gradient that is determined by placental as well as fetal glucose consumption. It is the fetal plasma glucose concentration (rather than the maternal glucose concentration) that regulates the proportion of glucose that is used by the placenta for metabolism and the proportion transferred to the fetus. When placental function and fetal growth are normal, there is no net glucose production by the fetus. However, when placental growth is restricted or the fetus is subjected to reduced glucose supply, the decreased fetal glucose availability during the in utero period leads to fetal hypoglycemia and hypoinsulinemia, with initiation of endogenous fetal glucose production and, consequently, IUGR. Studies in sheep have shown that fetal glucose utilization is maintained by reduced transfer of glucose back to the placenta and by endogenous glucose production. These important early nutritional events in IUGR infants may be a trigger for the programmed development of long-term adult disorders, including insulin resistance, diabetes mellitus, and obesity.The components of the glucose-sensing and insulin-secreting pathways (glucokinase, KATP channels, and L-type Ca2+ channels) are present in the human fetus from as early as 14 to 18 weeks’ gestation, but the insulin secretory responses to glucose are attenuated at this early gestation. The reason for this attenuated response is not clear, but it may be related to insufficient adenosine triphosphate synthesis, which regulates the activity of the KATP channels located on the surface of the pancreatic beta cell. During fetal development, pancreatic beta cells mature, with the biphasic insulin release developing toward the postnatal phase. One of the most important changes during development is an increase in glucose-stimulated insulin secretion, with a reduction in the glucose-stimulated threshold.The plasma ratio of insulin to glucagon during the fetal period plays an important role in regulating the balance between glucose consumption and storage. An increased ratio of insulin to glucagon facilitates glucose deposition as glycogen, favors accretion of protein, and increases the synthesis of lipids. Hepatic glycogen content increases with gestational age; most deposition occurs toward the end of the gestational period. This glycogen store forms an important source of carbohydrate that will be used for systemic glucose needs after birth.At birth, the healthy term newborn must adapt to an independent existence. The transplacental supply of nutrients, including glucose, is interrupted, and the newborn must initiate metabolic and endocrine responses to maintain adequate circulating blood glucose concentrations. Extrauterine adaptation requires adequate glycogen stores; intact and functional glycogenolytic, gluconeogenic, and lipogenic mechanisms; and appropriate counterregulatory hormonal responses.A normal infant at term exhibits an immediate postnatal fall in blood glucose concentrations during the first 2 to 4 hours from values close to maternal levels to approximately 45 mg/dL (2.5 mmol/L). The trigger for the metabolic and endocrine adaptation with reference to glucose control is unclear, but surges in catecholamines and glucagon secretion are believed to be important. The increased plasma insulin:glucagon ratio is reversed at birth, thus allowing glucagon to activate adenylate cyclase and increase the activity of the cAMP-dependent protein kinase, PKA. This, in turn, activates phosphorylase kinase, which facilitates glucose release.The catecholamine surge activates lipolysis and lipid oxidation, resulting in increases in the levels of glycerol and free fatty acids. Free fatty acids are used to generate ketone bodies, which are used as an alternative source of fuel. Healthy term breastfed babies have significantly lower blood glucose concentrations than those who are bottle-fed, but their ketone body concentrations are elevated in response to breastfeeding. Major changes occur in the function of several physiologic systems after birth that enables the neonate to adapt to postnatal nutrition. Successful enteral feeding in healthy term newborns stimulates the secretion of gut peptides and plays a key role in triggering a cascade of developmental changes in gut structure and function and in the relationship of pancreatic endocrine secretion to intermediary metabolism. Hence, term infants are programmed functionally and metabolically to make the transition from their intrauterine-dependent environment to their extrauterine existence without the need for metabolic monitoring or interference with the natural breastfeeding process. This complex metabolic and endocrine adaptation process is incomplete and compromised when the infant is born preterm or following IUGR.Both preterm and IUGR infants have multiple risk factors for developing hypoglycemia (Table T1). Because the last trimester of pregnancy is associated with deposition of fat in adipose tissue and glycogen stores in liver, the preterm infant is born with significant reductions in the amounts of stored glycogen and fat, thereby potentially limiting substrate availability. This increases the risk of hypoglycemia for the preterm infant in the immediate newborn period.Glycogen content also is reduced markedly in IUGR infants, both in liver and skeletal muscle, because of lower fetal plasma concentrations of glucose and insulin, which are the principal regulators of glycogen synthesis. Chronic hypoxia in IUGR infants stimulates adrenaline secretion, which depletes glycogen stores by activating glycogen phosphorylase and increasing glycogenolysis. In babies who have IUGR due to placental insufficiency, the diminished glucose transport leads to hypoinsulinemia that subsequently reduces protein synthesis and storage of triglycerides.Gluconeogenic pathways appear to be activated within the first few postnatal days in preterm babies; some studies have shown that preterm infants can produce glucose at rates comparable to term newborns within 24 hours of birth. The rate-limiting factor for hepatic glucose production and gluconeogenesis in preterm infants is not a lack of gluconeogenic precursors (eg, alanine, lactate, glycerol), but more likely the rate of induction of the gluconeogenic enzymes. IUGR infants also have the ability to switch on the gluconeogenic pathway shortly after birth, but they can have hypoglycemia associated with increased levels of lactate and amino acids.Studies in growth-retarded rat pups demonstrate that despite adequate levels of the counterregulatory hormone glucagon, activation of the key gluconeogenic enzyme, phosphoenolpyruvate carboxykinase, is delayed.Plasma insulin concentrations in relation to plasma glucose concentrations are greater in preterm infants than term infants. It appears that the elevated insulin:glucose ratio and relative immaturity of ketogenesis persist for some months after birth. IUGR and preterm babies also can present with either transient or persistent hyperinsulinemic hypoglycemia that can cause significant hypoglycemia. The mechanism of the transient form of hyperinsulinemic hypoglycemia is unclear, but the persistent form may be related to defects in KATP channels of the pancreatic beta cells.The pattern of enteral feeding in term, IUGR, and preterm infants has profound effects on their metabolic and endocrine adaptation. The pattern of metabolic adaptation in the preterm baby and the infant with IUGR differs from that in the term infant. Regular bolus feeding in term babies induces postnatal surges in preprandial concentrations of gut hormones together with cyclical hormonal responses to feeding. Insulin growth factor-1 and epidermal growth factor in human milk are important for gut growth and maturation. Motilin increases gastric emptying as well as peristalsis, and enteroglucagon is trophic to the gut mucosa. Enteroglucagon, gastrin, and pancreatic polypeptide all act to increase gut and pancreatic growth and development. Gastric inhibitory polypeptide plays an important role in the enteroinsular axis by promoting meal-associated increases in pancreatic insulin secretion. This pattern of metabolic adaptation is not seen with preterm and IUGR infants receiving continuous intravenous fluids who demonstrate lower concentrations of blood alanine, glycerol, and 3-hydroxybutyrate.For adequate counterregulation to hypoglycemia, preterm and IUGR infants must have intact hormonal systems. Preterm infants are able to mount an appropriate catecholamine response to the stimulus of stress. The role of cortisol in counterregulation is not as clear because some preterm infants have cortisol levels that are inappropriately low at times of stress. Other studies have demonstrated appropriate cortisol responses in preterm neonates to stress. We have demonstrated inappropriately low serum cortisol responses in preterm babies who have severe hyperinsulinemic hypoglycemia. The underlying mechanism is not clear, but it may be related to a lack of drive from the hypothalamic-pituitary axis.The preterm infant also may be susceptible to hypoglycemia after the first few weeks of birth. In the immediate postnatal period, the regular feeding of preterm infants ensures that they receive a nearly constant supply of energy. However, as the feeding interval is increased, the infant must depend more on hepatic glucose production to maintain normoglycemia. Normoglycemia between feedings can be maintained only if adequate glucose is released from glycogenolysis or gluconeogenesis. A key enzyme that controls the terminal steps in these processes is hepatic microsomal glucose-6-phosphatase, which catalyzes the dephosphorylation of glucose-6-phosphate to glucose and regulates the final step in hepatic glucose production. Hepatic glucose-6-phosphatase activity is low before birth in preterm infants and can remain low in some preterm infants for several months after birth. This delayed postnatal appearance of hepatic glucose-6-phosphatase in preterm infants may make them vulnerable to repeated hypoglycemic episodes and resultant cerebral damage or to the risk of sudden and unexpected death. The low activity of hepatic glucose-6-phosphatase activity in preterm infants also may account for the diminished responses to intravenous and intramuscular glucagon. It has been shown that about 18% of preterm infants have problems in maintaining normoglycemia at the time of discharge if a feeding is omitted or delayed. In contrast, the activity of hepatic glucose-6-phosphatase in term infants rises rapidly to adult values after delivery, but the factors regulating the postnatal expression of this enzyme are not known.Term infants are functionally and metabolically programmed to make the transition from their intrauterine-dependent environment to their extrauterine existence without the need for metabolic monitoring. However, this complex metabolic and endocrine adaptation process is incomplete and compromised when the infant is born preterm or following IUGR. Both preterm and IUGR infants have multiple risk factors for developing hypoglycemia and require regular monitoring of their blood glucose levels even after full enteral feedings have been established.