Hyperglycemia accentuates and ketonemia attenuates hypoglycemia-induced neuronal injury in the developing rat brain

Ennis, Kathleen; Dotterman, Hannah; Stein, Ariel; Rao, Raghavendra

doi:10.1038/pr.2014.146

Cited by 35 publications

(29 citation statements)

References 40 publications

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“…Finally, the description of hypoglycaemic management and treatment targets was generally poor. This may be important, as there is emerging evidence both in animals and humans that glucose reperfusion injury may exacerbate oxidative stress associated with hypoglycaemia if the correction is too rapid or too high, even within the normal glucose range [3, 45, 46]. …”

Section: Discussionmentioning

confidence: 99%

Neonatal Glycaemia and Neurodevelopmental Outcomes: A Systematic Review and Meta-Analysis

et al. 2018

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Background: Hypoglycaemia is the most common metabolic problem in neonates but there is no universally accepted threshold for safe blood glucose concentrations due to uncertainty regarding effects on neurodevelopment. Objective: To systematically assess the association between neonatal hypoglycaemia on neurodevelopment outcomes in childhood and adolescence. Methods: We searched MEDLINE, EMBASE, CINAHL, and PsycINFO from inception until February 2018. We included studies that reported one or more prespecified outcomes and compared children exposed to neonatal hypoglycaemia with children not exposed. Studies of neonates with congenital malformations, inherited metabolic disorders and congenital hyperinsulinism were excluded. Two authors independently extracted data using a customized form. We used ROBINS-I to assess risk of bias, GRADE for quality of evidence, and REVMAN for meta-analysis (inverse variance, fixed effects). Results: 1,665 studies were screened, 61 reviewed in full, and 11 included (12 publications). In early childhood, exposure to neonatal hypoglycaemia was not associated with neurodevelopmental impairment (n = 1,657 infants; OR = 1.16, 95% CI = 0.86–1.57) but was associated with visual-motor impairment (n = 508; OR = 3.46, 95% CI = 1.13–10.57) and executive dysfunction (n = 463; OR = 2.50, 95% CI = 1.20–5.22). In mid-childhood, neonatal hypoglycaemia was associated with neurodevelopmental impairment (n = 54; OR = 3.62, 95% CI = 1.05–12.42) and low literacy (n = 1,395; OR = 2.04, 95% CI = 1.20–3.47) and numeracy (n = 1,395; OR = 2.04, 95% CI = 1.21–3.44). No data were available for adolescents. Conclusions: Neonatal hypoglycaemia may have important long-lasting adverse effects on neurodevelopment that may become apparent at later ages. Carefully designed randomized trials are required to determine the optimal management of neonates at risk of hypoglycaemia with long-term follow-up at least to school age.

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Section: Discussionmentioning

confidence: 99%

Neonatal Glycaemia and Neurodevelopmental Outcomes: A Systematic Review and Meta-Analysis

et al. 2018

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“…The transcript expression of BDNF ( Bdnf ; variants II, IV and VI), TrkB ( Ntrk2 ), p75 NTR ( Ngfr ), and the downstream targets of BDNF/TrkB signaling, early growth response-1 and -2 ( Egr1 and Egr2 ), 3-hydroxy-3-methylglutaryl-CoA reductase ( Hmgcr ) and profilin-1 and -2 ( Pfn1 and Pfn2 ) that regulate brain development and plasticity [36–38] was determined using previously described methods [8,14] (n=6–10 on P29 and P65).. Each sample was assayed in duplicate and normalized against ribosomal protein S18.…”

Section: Methodsmentioning

confidence: 99%

“…Rats of this age are used to model the effects of hypoglycemia in young children due to similarities in the stage of brain development and substrate utilization [7,9,11,14,15]. BDNF plays a critical role in the normal development of PFC [16–18].…”

Section: Introductionmentioning

confidence: 99%

“…Conversely, binding of BDNF to the pan-neurotropin p75 (p75 NTR ) receptor leads to cell cycle arrest, reduced neurite growth and apoptosis [20]. We have recently demonstrated that an acute episode of moderate hypoglycemia does not alter BDNF, TrkB and p75 NTR expression in the PFC of three-week-old rats [14]. The effects of recurrent moderate hypoglycemia are not known.…”

Section: Introductionmentioning

confidence: 99%

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Recurrent Moderate Hypoglycemia Suppresses Brain-Derived Neurotrophic Factor Expression in the Prefrontal Cortex and Impairs Sensorimotor Gating in the Posthypoglycemic Period in Young Rats

Rao

Ennis

Mitchell³

et al. 2016

Dev Neurosci

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Recurrent hypoglycemia is common in infants and children. In developing rat models, recurrent moderate hypoglycemia leads to neuronal injury in the medial prefrontal cortex. To understand the effects beyond neuronal injury, 3-week-old male rats were subjected to 5 episodes of moderate hypoglycemia (blood glucose concentration, approx. 30 mg/dl for 90 min) once daily from postnatal day 24 to 28. Neuronal injury was determined using Fluoro-Jade B histochemistry on postnatal day 29. The effects on brain-derived neurotrophic factor (BDNF) and its cognate receptor, tyrosine kinase receptor B (TrkB) expression, which is critical for prefrontal cortex development, were determined on postnatal day 29 and at adulthood. The effects on prefrontal cortex-mediated function were determined by assessing the prepulse inhibition of the acoustic startle reflex on postnatal day 29 and 2 weeks later, and by testing for fear-potentiated startle at adulthood. Recurrent hypoglycemia led to neuronal injury confined primarily to the medial prefrontal cortex. BDNF/TrkB expression in the prefrontal cortex was suppressed on postnatal day 29 and was accompanied by lower prepulse inhibition, suggesting impaired sensorimotor gating. Following the cessation of recurrent hypoglycemia, the prepulse inhibition had recovered at 2 weeks. BDNF/TrkB expression in the prefrontal cortex had normalized and fear-potentiated startle was intact at adulthood. Recurrent moderate hypoglycemia during development has significant adverse effects on the prefrontal cortex in the posthypoglycemic period.

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“…Third, we cannot exclude the possibility that screening and treatment may themselves have adverse effects. The observations that pain-induced stress in neonates (eg, that caused by repeated heel lancing) may impair brain development 13 and that higher blood glucose concentrations during recovery from hypoglycemia can worsen neurological damage in the developing brain 14 indicate the real potential for long-term iatrogenic harm. Therefore, in the absence of evidence from randomized clinical trials (RCTs), clinicians should follow published guidelines such as those of the American Academy of Pediatrics, which recommend glucose screening only in at-risk infants.…”

mentioning

confidence: 99%

Revisiting Transitional Hypoglycemia

McKinlay

Harding

2015

JAMA Pediatr

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Hyperglycemia accentuates and ketonemia attenuates hypoglycemia-induced neuronal injury in the developing rat brain

Cited by 35 publications

References 40 publications

Neonatal Glycaemia and Neurodevelopmental Outcomes: A Systematic Review and Meta-Analysis

Neonatal Glycaemia and Neurodevelopmental Outcomes: A Systematic Review and Meta-Analysis

Recurrent Moderate Hypoglycemia Suppresses Brain-Derived Neurotrophic Factor Expression in the Prefrontal Cortex and Impairs Sensorimotor Gating in the Posthypoglycemic Period in Young Rats

Revisiting Transitional Hypoglycemia

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