Long-term effects of neonatal hypoglycemia on brain growth and psychomotor development in small-for-gestational-age preterm infants

Duvanel, Cécile Besson; Fawer, C. L.; Cotting, Jacques; Hohlfeld, P.; Matthieu, Jean‐Marie

doi:10.1016/s0022-3476(99)70209-x

Cited by 247 publications

(185 citation statements)

References 26 publications

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“…Repeated episodes of hypoglycemia during the neonatal period can cause devastating and often permanent neurological sequelae (4,(35)(36)(37). The mechanisms underlying this significant health problem remain poorly understood (38 -40).…”

Section: Discussionmentioning

confidence: 99%

Akt2 Modulates Glucose Availability and Downstream Apoptotic Pathways during Development

Jensen

Gunter

Carayannopoulos

2010

Journal of Biological Chemistry

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Glucose is the primary energy substrate for eukaryotic cells and the predominant substrate for the brain. Studies suggest that glucose serves an additional role in the regulation of cellular functions, including viability. Zebrafish is a tractable system for defining the cellular and molecular mechanisms perturbed by impaired glucose transport and metabolism. Previously, we demonstrated a critical role for the facilitative glucose transporter, Glut1, in the regulation of embryonic brain development. In this study, we aim to identify mediators in this Glut1-sensitive process by investigating the role of the antiapoptotic kinase, Akt2. Results show that abrogating expression of akt2 causes a phenotype strikingly similar to that observed when glut1 expression is inhibited. akt2-deficient embryos exhibit increased neuronal apoptosis, impaired glucose uptake, and death by 72 h postfertilization. Similar to what was observed in the glut1 morphants, inhibiting the expression of the proapoptotic protein, bad, in the context of impaired akt2 expression results in the inhibition of apoptosis and rescue of the morphant embryos. Intriguingly, overexpression of glut1 in the akt2 morphants was also able to rescue these embryos. Quantitative reverse transcription-PCR analysis revealed decreased glut1 transcript expression in akt2 morphant embryos. Taken together, these data suggest that Akt2 modulates glucose availability by regulating Glut1 expression at the transcript level. These data support a role for akt2 in an integrative pathway directly linking glucose, Glut1 expression, and activation of apoptosis and demonstrate the dependence of akt2 on glucose availability for the maintenance of cellular viability, particularly in the central nervous system.The acute metabolic transition that a neonate experiences at birth predisposes it to the development of hypoglycemia. The sudden switch from total reliance on maternal nutrients to dependence on endogenous fuel stores requires a rapid, coordinated, and integrated hormonal and enzymatic response by the neonate (1, 2). Proper homeostatic control is critical during this period because the consequences of repeated and/or prolonged episodes of hypoglycemia can result in neurodevelopmental impairment (3). Although it is clear that dysregulation of mechanisms controlling glucose homeostasis, including deficiencies in growth hormone or cortisol and hyperinsulinism, can cause hypoglycemia during this volatile period, there is virtually nothing known about the mechanisms underlying the irreversible neurologic sequelae. Although there are substantial data defining possible mechanisms underlying injury associated with hypoxia-ischemia, most of these studies have been performed in adult animals, making conclusions regarding neonates with isolated hypoglycemia indirect at best (4).Investigators studying a variety of cell systems have established glucose uptake and metabolism as pivotal mediators of cell survival. Cancer cells are dependent on glycolysis for the generation of ATP even in the ...

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Section: Discussionmentioning

confidence: 99%

Akt2 Modulates Glucose Availability and Downstream Apoptotic Pathways during Development

Jensen

Gunter

Carayannopoulos

2010

Journal of Biological Chemistry

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“…This patient group probably represents a milder clinical phenotype. It is well known already that transient neonatal hypoglycemia or rare episodes of hypoglycemia of other causes are associated with neurodevelopmental deficits (29,30). However, it is still surprising that despite early treatment in specialized units some patients with CHI develop severe mental deficits (25).…”

Section: Discussionmentioning

confidence: 99%

Long-term follow-up of 114 patients with congenital hyperinsulinism

Meißner

Wendel

Burgard

et al. 2003

European Journal of Endocrinology

180

144

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Background: The term congenital hyperinsulinism (CHI) comprises a group of different genetic disorders with the common finding of recurrent episodes of hyperinsulinemic hypoglycemia. Objective: To evaluate the clinical presentation, diagnostic criteria, treatment and long-term follow-up in a large cohort of CHI patients. Patients: The data from 114 patients from different hospitals were obtained by a detailed questionnaire. Patients presented neonatally (65%), during infancy (28%) or during childhood (7%). Results: In 20 of 74 (27%) patients with neonatal onset birth weight was greatly increased (group with standard deviation scores (SDS) .2.0) with a mean SDS of 3.2. Twenty-nine percent of neonatal-onset vs 69% of infancy/childhood-onset patients responded to diazoxide and diet or to a carbohydrate-enriched diet alone. Therefore, we observed a high rate of pancreatic surgery performed in the neonatal-onset group (70%) compared with the infancy/childhood-onset group (28%). Partial (3%), subtotal (37%) or near total (15%) pancreatectomy was performed. After pancreatic surgery there appeared a high risk of persistent hypoglycemia (40%). Immediately post-surgery or with a latency of several years insulin-dependent diabetes mellitus was observed in operated patients (27%).

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“…There is evidence that hypoglycemia affects psychomotor development in SGA infants (21). Changes in energy metabolism associated with adaptation of the FGR fetus to chronic hypoxia and hypoglycemia in utero may therefore be an important determinant of susceptibility to perinatal hypoxic ischemic brain injury in FGR neonates.…”

Section: F Etal Growth Restriction (Fgr)mentioning

confidence: 99%

Carbohydrate and Energy Metabolism in the Brain of Rats With Thromboxane A2-Induced Fetal Growth Restriction

et al. 2011

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Fetal growth restriction (FGR) remains a cause of perinatal brain injury, sometimes leading to neurological and intellectual impairment. Although the mechanisms and pathophysiology of CNS injuries have not been elucidated completely, it is possible carbohydrate and energy metabolism may have an important role in the FGR brain. In this study, FGR was induced in rats by administration of synthetic thromboxane A 2 (STA 2 ). Pups were delivered by cesarean section. After killing, samples were obtained from the fetuses of both control and FGR rats for evaluation of carbohydrate and energy metabolism in brain tissue. Lactate and pyruvate levels in brain were reduced significantly in the FGR group. Glucose content in brain tissue tended to be increased in the FGR group. In contrast, glycogen content in brain tissue tended to be lower in the FGR group. However, these differences in glucose and glycogen content did not reach statistical significance. Brain high-energy reserves, including ATP, ADP, AMP, and phosphocreatine (P-Cr), were similar in the control and FGR groups. Gluconeogenesis compensated for chronic fetal hypoxia and decreased glycogen storage. Energy metabolism in the FGR brain is likely to be disrupted as a consequence of lower reserves of energy substrates. (Pediatr Res 70: 21-24, 2011) F etal growth restriction (FGR) is an important cause of perinatal morbidity and mortality. Surviving small-for-GA (SGA) infants have a higher incidence of neurological impairments including mental retardation and educational and/or behavioral problems (1-3). Several authors have reported that perinatal hypoxic ischemic brain damage may contribute to an increased prevalence of motor, cognitive, and affective disabilities in children born with FGR (4 -6). However, the mechanisms underlying these disabilities have not yet been fully elucidated.Various prenatal factors may affect fetal growth. Pregnancyinduced hypertension (PIH) is an especially important factor in FGR fetuses. In PIH, increasing umbilical vessel resistance causes limitations in uteroplacental blood flow. As a consequence, the supply of oxygen and nutrition to the fetus may decrease (7). FGR fetuses are frequently hypoxic and hypoglycemic (8). During labor, uterine contractions can further compromise placental blood flow and oxygen supply to the FGR fetus, thereby increasing the risk of an intrapartum hypoxic-ischemic event and subsequent brain injury (9). Several authors have also reported that FGR fetuses are not only at great risk of perinatal hypoxic ischemic events but also may be more susceptible to hypoxic-ischemic brain damage, compared with appropriate-for-GA (AGA) fetuses (9,10).Several studies have investigated the mechanisms of brain injuries in FGR model animals (11-13). Manipulations to induce FGR in animal models included surgical ligation of vessels supplying the uteroplacental unit (12) and maternal starvation (11). However, these models do not necessarily reflect the pathophysiology of FGR. It has been suggested that plasma levels ...

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Long-term effects of neonatal hypoglycemia on brain growth and psychomotor development in small-for-gestational-age preterm infants

Cited by 247 publications

References 26 publications

Akt2 Modulates Glucose Availability and Downstream Apoptotic Pathways during Development

Akt2 Modulates Glucose Availability and Downstream Apoptotic Pathways during Development

Long-term follow-up of 114 patients with congenital hyperinsulinism

Carbohydrate and Energy Metabolism in the Brain of Rats With Thromboxane A2-Induced Fetal Growth Restriction

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