Effects of Hyperglycemia on the Developing Brain in Newborns

Tayman, Cüneyt; Yış, Uluç; Hırfanoğlu, İbrahim Murat; Öztekin, Osman; Göktaş, Güleser; Bilgin, Bülent Çağlar

doi:10.1016/j.pediatrneurol.2014.04.015

Cited by 19 publications

(22 citation statements)

References 21 publications

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“…Additionally, there was upregulation of mRNA expression of the antiapoptotic enzyme Bcl-2. Collectively, these results suggest that unlike the diabetic brain (or mature brain as the case may be), the neonatal brain may be able to withstand hyperglycemia without sustaining injury, despite the occurrence of the oxidative stress demonstrated in a similar model (21). One potential mechanism may be the higher concentration of low molecular weight antioxidants, alpha tocopherol, ascorbate, and glutathione in the developing brain regions, relative to the mature brain, that may reduce the risk of injury (22).…”

Section: Discussionmentioning

confidence: 86%

“…This was done to mimic the intermittent hyperglycemia in ELBW infants, which often lasts for several hours each day over several days, as mentioned earlier (36,37). Furthermore, we also based our model on an earlier study that showed an intermittent hyperglycemia animal protocol was associated with evidence of oxidative stress in the brain regions (21). Hyperglycemia in human neonates is characterized by hypoinsulinemia/insulin insensitivity, whereas induction of hyperglycemia in healthy animals would stimulate insulin secretion.…”

Section: Induction Of Recurrent Hypoinsulinemic Hyperglycemiamentioning

confidence: 99%

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Recurrent hypoinsulinemic hyperglycemia in neonatal rats increases PARP-1 and NF-κB expression and leads to microglial activation in the cerebral cortex

et al. 2015

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Background: Hyperglycemia is a common metabolic problem in extremely low-birth-weight preterm infants. Neonatal hyperglycemia is associated with increased mortality and brain injury. Glucose-mediated oxidative injury may be responsible. Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme involved in DNA repair and cell survival. However, PARP-1 overactivation leads to cell death. NF-κB is coactivated with PARP-1 and regulates microglial activation. The effects of recurrent hyperglycemia on PARP-1/NF-κB expression and microglial activation are not well understood. Methods: Rat pups were subjected to recurrent hypoinsulinemic hyperglycemia of 2 h duration twice daily from postnatal (P) day 3-P12 and killed on P13. mRNA and protein expression of PARP-1/NF-κB and their downstream effectors were determined in the cerebral cortex. Microgliosis was determined using CD11 immunohistochemistry. results: Recurrent hyperglycemia increased PARP-1 expression confined to the nucleus and without causing PARP-1 overactivation and cell death. NF-κB mRNA expression was increased, while IκB mRNA expression was decreased. inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), and neuronal nitric oxide synthase (nNOS) mRNA expressions were decreased. Hyperglycemia significantly increased the number of microglia. conclusion: Recurrent hyperglycemia in neonatal rats is associated with upregulation of PARP-1 and NF-κB expression and subsequent microgliosis but not neuronal cell death in the cerebral cortex.

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Section: Discussionmentioning

confidence: 86%

Section: Induction Of Recurrent Hypoinsulinemic Hyperglycemiamentioning

confidence: 99%

Recurrent hypoinsulinemic hyperglycemia in neonatal rats increases PARP-1 and NF-κB expression and leads to microglial activation in the cerebral cortex

et al. 2015

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“…However, there is a wide variation among clinicians in the criteria used for insulin therapy and the target blood glucose ranges, leading to continuous hyperglycemia in many infants. Published and unpublished studies from our laboratory and other laboratories demonstrate that the two hyperglycemia models have similar adverse effects (oxidative stress and inflammation) on the brain regions.…”

Section: Methodsmentioning

confidence: 99%

“…Pups assigned to the hyperglycemia groups were subjected to hyperglycemia twice a day at 08:00 and 16:00 for 10 consecutive days (20 hyperglycemia episodes in total) from P3 to P12 using a previously described method. 14,15 These postnatal ages were chosen because of their similarity to the stage of hippocampal development in the ELGAN (P3) and full-term (P12) human infant, respectively. 9,27 Pups were separated from the dams, weighed and subcutaneously injected with 30% dextrose (3 mg/g body weight; moderate-HG group) or 50% dextrose (5 mg/g body weight; severe-HG group).…”

Section: Induction Of Recurrent Hyperglycemiamentioning

confidence: 99%

“…10,12,13 Previous studies from our laboratory and other laboratories have demonstrated that recurrent hyperglycemia during the first two postnatal weeks causes oxidative stress, DNA damage, inflammation and microgliosis in the cerebral cortex and hippocampus of rats. 14,15 Oxidative stress and inflammation may negatively influence hippocampal dendritogenesis and function. Furthermore, in adult rats, hyperglycemia alters glycogen and lactate metabolism in the hippocampus.…”

Section: Introductionmentioning

confidence: 99%

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Neonatal hyperglycemia alters the neurochemical profile, dendritic arborization and gene expression in the developing rat hippocampus

et al. 2018

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Hyperglycemia (blood glucose concentration >150 mg/dL) is common in extremely low gestational age newborns (ELGANs; birth at <28 week gestation). Hyperglycemia increases the risk of brain injury in the neonatal period. The long-term effects are not well understood. In adult rats, hyperglycemia alters hippocampal energy metabolism. The effects of hyperglycemia on the developing hippocampus were studied in rat pups. In Experiment 1, recurrent hyperglycemia of graded severity (moderate hyperglycemia (moderate-HG), mean blood glucose 214.6 ± 11.6 mg/dL; severe hyperglycemia (severe-HG), 338.9 ± 21.7 mg/dL; control, 137.7 ± 2.6 mg/dL) was induced from postnatal day (P) 3 to P12. On P30, the hippocampal neurochemical profile was determined using in vivo H MR spectroscopy. Dendritic arborization in the hippocampal CA1 region was determined using microtubule-associated protein (MAP)-2 immunohistochemistry. In Experiment 2, continuous hyperglycemia (mean blood glucose 275.3 ± 25.8 mg/dL; control, 142.3 ± 2.6 mg/dL) was induced from P2 to P6 by injecting streptozotocin (STZ) on P2. The mRNA expression of glycogen synthase 1 (Gys1), lactate dehydrogenase (Ldh), glucose transporters 1 (Glut1) and 3 (Glut3) and monocarboxylate transporters 1 (Mct1), 2 (Mct2) and 4 (Mct4) in the hippocampus was determined on P6. In Experiment 1, MRS demonstrated lower lactate concentration and glutamate/glutamine (Glu/Gln) ratio in the severe-HG group, compared with the control group (p< 0.05). Phosphocreatine/creatine ratio was higher in both hyperglycemia groups (p < 0.05). MAP-2 histochemistry demonstrated longer apical segment length, indicating abnormal synaptic efficacy in both hyperglycemia groups (p < 0.05). Experiment 2 showed lower Glut1, Gys1 and Mct4 expression and higher Mct1 expression in the hyperglycemia group, relative to the control group (p < 0.05). These results suggest that hyperglycemia alters substrate transport, lactate homeostasis, dendritogenesis and Glu-Gln cycling in the developing hippocampus. Abnormal neurochemical profile and dendritic structure due to hyperglycemia may partially explain the long-term hippocampus-mediated cognitive deficits in human ELGANs.

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Early Enhanced Parenteral Nutrition, Hyperglycemia, and Death Among Extremely Low-Birth-Weight Infants

et al. 2015

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IMPORTANCE Efforts to optimize early parenteral nutrition (PN) in extremely low-birth-weight (ELBW) infants to promote growth and development may increase hyperglycemia risk. Recent studies have identified an association between early hyperglycemia and adverse outcomes in ELBW infants. OBJECTIVES To examine the prevalence of early hyperglycemia and clinical outcomes among ELBW infants before (2002-2005) and after (2006-2011) the implementation of an early enhanced PN protocol and to assess the independent effects of early enhanced PN and early hyperglycemia on mortality. DESIGN, SETTING, AND PARTICIPANTS Observational cohort study in a level III neonatal intensive care unit. Prospectively collected clinical data in the neonatal intensive care unit's medical database, nutritional information, and blood glucose levels were merged for analysis. All ELBW infants born between January 1, 2002, and December 31, 2011, without lethal malformations and still alive at 12 hours of life were eligible for inclusion in the study. MAIN OUTCOMES AND MEASURES Mortality was the main outcome measure. Severe hyperglycemia was defined as 2 consecutive blood glucose levels exceeding 216 mg/dL at least 3 hours apart. A multivariable logistic regression model was applied to determine the independent effects of early enhanced PN and hyperglycemia on mortality. RESULTS In total, 343 infants were included in the study, 129 in a historical comparison group before the enhanced PN protocol and 214 in the early enhanced PN group. Baseline characteristics were similar between the study groups. After the introduction of early enhanced PN, the prevalence of severe hyperglycemia during the first week of life was higher in the early enhanced PN group (11.6% [15 of 129] vs 41.6% [89 of 214], P < .001), as was the mortality (10.9% [14 of 129] vs 24.3% [52 of 214], P = .003). When adjusting for background characteristics, treatment, and nutritional data, early severe hyperglycemia remained a strong independent risk factor for death (odds ratio, 4.68; 95% CI, 1.82-12.03), together with gestational age (odds ratio, 0.62; 95% CI, 0.49-0.79). CONCLUSIONS AND RELEVANCE The implementation of an enhanced PN protocol was correlated with an increased prevalence of severe hyperglycemia and higher mortality. In the multivariable analysis, an enhanced PN regimen per se was not predictive of mortality, whereas early severe hyperglycemia remained strongly predictive of death. To avoid detrimental effects on outcomes in ELBW infants, the optimal composition of early PN to avoid postnatal growth failure must be carefully balanced against hyperglycemia risk.

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Effects of Hyperglycemia on the Developing Brain in Newborns

Cited by 19 publications

References 21 publications

Recurrent hypoinsulinemic hyperglycemia in neonatal rats increases PARP-1 and NF-κB expression and leads to microglial activation in the cerebral cortex

Recurrent hypoinsulinemic hyperglycemia in neonatal rats increases PARP-1 and NF-κB expression and leads to microglial activation in the cerebral cortex

Neonatal hyperglycemia alters the neurochemical profile, dendritic arborization and gene expression in the developing rat hippocampus

Early Enhanced Parenteral Nutrition, Hyperglycemia, and Death Among Extremely Low-Birth-Weight Infants

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