Paul J. Rozance

Hypoglycemia in Newborn Infants: Features Associated with Adverse Outcomes

The purpose of this review article is to document from the literature values of blood/plasma glucose concentration and associated clinical signs and conditions in newborn infants (both term and preterm) that indicate a reasonable clinical probability that hypoglycemia is a proximate cause of acute and/or sustained neurological injury and to review the physiological and pathophysiological responses to hypoglycemia that may influence the ultimate outcome of newborns with low blood glucose. Our overall conclusion is that there is inadequate information in the literature to define any one value of glucose below which irreparable hypoglycemic injury to the central nervous system occurs, at any one time or for any defined period of time, in a population of infants or in any given infant. Clinical signs of prolonged and severe neurological disturbance (coma, seizures), extremely and persistently low plasma/blood glucose concentrations (0 to <1.0 mmol/l [0 to <18–20 mg/dl] for more than 1–2 h), and the absence of other obvious central nervous system (CNS) pathology (hypoxia-ischemia, intracranial hemorrhage, infection, etc.) are important for the diagnosis of injury due to glucose deficiency. Specific conditions, such as persistent hyperinsulinemia with severe hypoglycemic episodes that include seizures, also contribute to the diagnosis of hypoglycemic injury. Such lack of definitive measures of injury specific to glucose deficiency indicates that clinicians should be on the alert for infants at risk of hypoglycemia and for clinical signs and conditions that might herald severe hypoglycemia; they should have a low threshold for investigating and diagnosing ‘hypoglycemia’ with frequent measurements of plasma/blood glucose concentration; and they should treat low glucose concentrations promptly and maintain them in a safe range. Because there is no conclusive evidence or consensus in the literature that defines an absolute value or duration of ‘hypoglycemia’ that must occur, with our without related clinical complications, to produce neurological injury, clinicians should consider the information currently available, determine a ‘target’ plasma or blood glucose concentration that is acceptable, and treat infants with glucose concentrations below this value accordingly. Our intent in this review article is to highlight the studies relevant to this issue and help clinicians formulate a safe and, hopefully, effective strategy for the diagnosis and treatment of hypoglycemia.

Intrauterine Growth Restriction Increases Fetal Hepatic Gluconeogenic Capacity and Reduces Messenger Ribonucleic Acid Translation Initiation and Nutrient Sensing in Fetal Liver and Skeletal Muscle

Expression of key metabolic genes and proteins involved in mRNA translation, energy sensing, and glucose metabolism in liver and skeletal muscle were investigated in a late-gestation fetal sheep model of placental insufficiency intrauterine growth restriction (PI-IUGR). PI-IUGR fetuses weighed 55% less; had reduced oxygen, glucose, isoleucine, insulin, and IGF-I levels; and had 40% reduction in net branched chain amino acid uptake. In PI-IUGR skeletal muscle, levels of insulin receptor were increased 80%, whereas phosphoinositide-3 kinase (p85) and protein kinase B (AKT2) were reduced by 40%. Expression of eukaryotic initiation factor-4e was reduced 45% in liver, suggesting a unique mechanism limiting translation initiation in PI-IUGR liver. There was either no change (AMP activated kinase, mammalian target of rapamycin) or a paradoxical decrease (protein phosphatase 2A, eukaryotic initiation factor-2 alpha) in activation of major energy and cell stress sensors in PI-IUGR liver and skeletal muscle. A 13- to 20-fold increase in phosphoenolpyruvate carboxykinase and glucose 6 phosphatase mRNA expression in the PI-IUGR liver was-associated with a 3-fold increase in peroxisome proliferator-activated receptor-gamma coactivator-1 alpha mRNA and increased phosphorylation of cAMP response element binding protein. Thus PI-IUGR is-associated with reduced branched chain amino acid uptake and growth factors, yet up-regulation of proximal insulin signaling and a marked increase in the gluconeogenic pathway. Lack of activation of several energy and stress sensors in fetal liver and skeletal muscle, despite hypoxia and low energy status, suggests a novel strategy for survival in the PI-IUGR fetus but with potential maladaptive consequences for reduced nutrient sensing and insulin sensitivity in postnatal life.

Intrauterine growth restriction decreases pulmonary alveolar and vessel growth and causes pulmonary artery endothelial cell dysfunction in vitro in fetal sheep.

Intrauterine growth restriction (IUGR) increases the risk for bronchopulmonary dysplasia (BPD). Abnormal lung structure has been noted in animal models of IUGR, but whether IUGR adversely impacts fetal pulmonary vascular development and pulmonary artery endothelial cell (PAEC) function is unknown. We hypothesized that IUGR would decrease fetal pulmonary alveolarization, vascular growth, and in vitro PAEC function. Studies were performed in an established model of severe placental insufficiency and IUGR induced by exposing pregnant sheep to elevated temperatures. Alveolarization, quantified by radial alveolar counts, was decreased 20% (P < 0.005) in IUGR fetuses. Pulmonary vessel density was decreased 44% (P < 0.01) in IUGR fetuses. In vitro, insulin increased control PAEC migration, tube formation, and nitric oxide (NO) production. This response was absent in IUGR PAECs. VEGFA stimulated tube formation, and NO production also was absent. In control PAECs, insulin increased cell growth by 68% (P < 0.0001). Cell growth was reduced in IUGR PAECs by 29% at baseline (P < 0.01), and the response to insulin was attenuated (P < 0.005). Despite increased basal and insulin-stimulated Akt phosphorylation in IUGR PAECs, endothelial NO synthase (eNOS) protein expression as well as basal and insulin-stimulated eNOS phosphorylation were decreased in IUGR PAECs. Both VEGFA and VEGFR2 also were decreased in IUGR PAECs. We conclude that fetuses with IUGR are characterized by decreased alveolar and vascular growth and PAEC dysfunction in vitro. This may contribute to the increased risk for adverse respiratory outcomes and BPD in infants with IUGR.

Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children

Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children Paul S. Thornton, MB, BCh, Charles A. Stanley, MD, Diva D. De Leon, MD, MSCE, Deborah Harris, PhD, Morey W. Haymond, MD, Khalid Hussain, MD, MPH, Lynne L. Levitsky, MD, Mohammad H. Murad, MD, MPH, Paul J. Rozance, MD, Rebecca A. Simmons, MD, Mark A. Sperling, MBBS, David A. Weinstein, MD, MMSc, Neil H. White, MD, and Joseph I. Wolfsdorf, MB, BCh

Consequences of a compromised intrauterine environment on islet function

Low birth weight is an important risk factor for impaired glucose tolerance and diabetes later in life. One hypothesis is that fetal beta-cells inherit a persistent defect as a developmental response to fetal malnutrition, a primary cause of intrauterine growth restriction (IUGR). Our understanding of fetal programing events in the human endocrine pancreas is limited, but several animal models of IUGR extend our knowledge of developmental programing in beta-cells. Pathological outcomes such as beta-cell dysfunction, impaired glucose tolerance, and diabetes are often observed in adult offspring from these animal models, similar to the associations of low birth weight and metabolic diseases in humans. However, the identified mechanisms underlying beta-cell dysfunction across models and species are varied, likely resulting from the different methodologies used to induce experimental IUGR, as well as from intraspecies differences in pancreas development. In this review, we first present the evidence for human beta-cell dysfunction being associated with low birth weight or IUGR. We then evaluate relevant animal models of IUGR, focusing on the strengths of each, in order to define critical periods and types of nutrient deficiencies that can lead to impaired beta-cell function. These findings frame our current knowledge of beta-cell developmental programing and highlight future research directions to clarify the mechanisms of beta-cell dysfunction for human IUGR.

Describing hypoglycemia — Definition or operational threshold?

Severe glucose deficiency leads to cerebral energy failure, impaired cardiac performance, muscle weakness, glycogen depletion, and diminished glucose production. Thus, maintenance of glucose delivery to all organs is an essential physiological function. Normal term infants have sufficient alternate energy stores and capacity for glucose production from glycogenolysis and gluconeogenesis to ensure normal glucose metabolism during the transition to extrauterine life and early neonatal period. Milk feedings particularly enhance glucose homeostasis. Energy sources often are low in preterm and growth restricted infants, who are especially vulnerable to glucose deficiency. Plasma glucose concentration is the only practical measure of glucose sufficiency, but by itself is a very limited guide. Key to preventing complications from glucose deficiency is to identify infants at risk, promote early and frequent feedings, normalize glucose homeostasis, measure glucose concentrations early and frequently in infants at risk, and treat promptly when glucose deficiency is marked and symptomatic.

The Intrauterine Growth Restriction Phenotype: Fetal Adaptations and Potential Implications for Later Life Insulin Resistance and Diabetes

The intrauterine growth restricted (IUGR) fetus develops unique metabolic adaptations in response to exposure to reduced nutrient supply. These adaptations provide survival value for the fetus by enhancing the capacity of the fetus to take up and use nutrients, thereby reducing the need for nutrient supply. Each organ and tissue in the fetus adapts differently, with the brain showing the greatest capacity for maintaining nutrient supply and growth. Such adaptations, if persistent, also have the potential in later life to promote nutrient uptake and storage, which directly lead to complications of obesity, insulin resistance, reduced insulin production, and type 2 diabetes.

Re-Evaluating "Transitional Neonatal Hypoglycemia": Mechanism and Implications for Management

A Committee of the Pediatric Endocrine Society was recently asked by xxx to develop guidelines for evaluation and management of hypoglycemia in neonates, infants, and children. To aid in formulating recommendations for neonates, in this review, we analyzed available data on the brief period of hypoglycemia which commonly is observed in normal newborns during the transition from fetal to extrauterine life, hereafter referred to as transitional neonatal hypoglycemia in normal newborns. The goal was to better understand the mechanism underlying this phenomenon in order to formulate recommendations for recognizing neonates requiring diagnosis and treatment during the first days of life for disorders causing severe and persistent hypoglycemia. It has long been known that plasma glucose concentrations are lower in the first 1–3 days of life in normal newborn infants than at later ages. Not until the 1960s was it appreciated that hypoglycemia in neonates could sometimes be symptomatic and, as in older infants and children, cause seizures or permanent brain damage (1, 2). Although studies in laboratory animals have demonstrated postnatal developmental changes in specific enzymes involved in hepatic gluconeogenesis and ketogenesis (3, 4), it is unclear that such changes adequately explain transitional neonatal hypoglycemia in human newborns or if other mechanisms may be involved (5, 6). A National Institutes of Health conference outlined many of the “gaps in knowledge” about neonatal hypoglycemia and lamented the lack of a rational basis for defining hypoglycemia in neonates (7). For this re-evaluation of transitional neonatal hypoglycemia in normal newborns, we used the strategy routinely employed by pediatric endocrinologists for evaluation of hypoglycemia in older infants and children. This strategy, based on an examination of the major metabolic fuel and hormone responses to hypoglycemia, makes it possible to discover the mechanism of hypoglycemia and to make a specific diagnosis of the underlying cause (Figure; available at www.jpeds.com) (8). We reviewed published data in normal newborns on metabolic fuel and hormone responses during the period of transitional neonatal hypoglycemia. We focused on mean responses as being most likely representative of normal newborns, recognizing the possibility of heterogeneity, particularly with regard to peri-partum stresses and feeding practices. We found that transitional neonatal hypoglycemia most closely resembles known genetic forms of congenital hyperinsulinism, which cause a lowering of the plasma glucose threshold for suppression of insulin secretion. This conclusion is based on strong evidence supported by two or more independent reports and provides a novel perspective on both the diagnosis and management of hypoglycemia in the first several days after birth. Figure Hypoglycemia diagnosis based on plasma metabolic fuel responses. Measurement of major fuels (lactate as a gluconeogenic substrate, FFA from adipose tissue lipolysis, and beta-hydroxybutyrate as the major ketone from hepatic ketogenesis) at a time of hypoglycemia ...

An animal model of placental insufficiency-induced intrauterine growth restriction.

Intrauterine growth restriction (IUGR), often associated with functional placental insufficiency, results in increased perinatal mortality and morbidity. For obvious reasons, many questions regarding the progression of IUGR pregnancies cannot be addressed experimentally in humans, predicating the use of animal models. Although no animal model fully recapitulates human pregnancy, the pregnant sheep has been used extensively to investigate maternal-fetal interactions. In sheep, surgical placement of catheters in both the maternal and fetal vasculature allows repeated sampling from nonanesthetized pregnancies. Considerable insight has been gained on placental oxygen and nutrient transfer and utilization from use of pregnant sheep, often confirmed in the human once appropriate technologies became available. This review will focus on one sheep model, used to examine the impact of placental insufficiency-induced IUGR on oxygen and nutrient transport and utilization.

Reductions in insulin concentrations and β-cell mass precede growth restriction in sheep fetuses with placental insufficiency

In pregnancy complicated by placental insufficiency (PI) and intrauterine growth restriction (IUGR), the fetus near term has reduced basal and glucose-stimulated insulin concentrations and reduced β-cell mass. To determine whether suppression of insulin concentrations and β-cell mass precedes reductions in fetal weight, which would implicate insulin deficiency as a cause of subsequent IUGR, we measured basal and glucose-stimulated insulin concentrations and pancreatic histology at 0.7 gestation in PI fetuses. Placental weights in the PI pregnancies were 40% lower than controls (265 ± 26 vs. 442 ± 41 g, P < 0.05), but fetal weights were not different. At basal conditions blood oxygen content, plasma glucose concentrations, and plasma insulin concentrations were lower in PI fetuses compared with controls (2.5 ± 0.3 vs. 3.5 ± 0.3 mmol/l oxygen, P < 0.05; 1.11 ± 0.09 vs. 1.44 ± 0.12 mmol/l glucose; 0.12 ± 0.01 vs. 0.27 ± 0.02 ng/ml insulin; P < 0.05). During a steady-state hyperglycemic clamp (~2.5 ± 0.1 mmol/l), glucose-stimulated insulin concentrations were lower in PI fetuses than controls (0.28 ± 0.02 vs. 0.55 ± 0.04 ng/ml; P < 0.01). Plasma norepinephrine concentrations were 3.3-fold higher (P < 0.05) in PI fetuses (635 ± 104 vs. 191 ± 91 pg/ml). Histological examination revealed less insulin area and lower β-cell mass and rates of mitosis. The pancreatic parenchyma was also less dense (P < 0.01) in PI fetuses, but no differences were found for pancreatic progenitor cells or other endocrine cell types. These findings show that hypoglycemia, hypoxemia, and hypercatecholaminemia are present and potentially contribute to lower insulin concentrations and β-cell mass due to slower proliferation rates in early third-trimester PI fetuses before discernible reductions in fetal weight.