Effects of age on ACTH, corticosterone, glucose, insulin, and mRNA levels during intermittent hypoxia in the neonatal rat

Chintamaneni, Kathan; Bruder, Eric D.; Raff, Hershel

doi:10.1152/ajpregu.00073.2013

Cited by 28 publications

(42 citation statements)

References 26 publications

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“…The IH protocol was based on a previously published model (9). Six cycles of IH were performed daily over approximately 60 minutes.…”

Section: Animal Treatment and Neonatal Ih Protocolmentioning

confidence: 99%

“…All analytic techniques have been previously published (9). Plasma ACTH and corticosterone were measured via RIA (MP Biomedicals).…”

Section: Hormone and Glucose Assaysmentioning

confidence: 99%

“…We have previously shown acute (neonatal) effects of neonatal IH including bradycardia, a decrease in body temperature, and a profound stress response of the neonatal hypothalamicpituitary-adrenal (HPA) axis (9). We have also shown that continuous perinatal hypoxia leads to an augmented HPA axis response to stress in adult rats and increased adult hypothalamic Crh mRNA expression (10).…”

mentioning

confidence: 99%

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Programming of the Hypothalamic-Pituitary-Adrenal Axis by Neonatal Intermittent Hypoxia: Effects on Adult Male ACTH and Corticosterone Responses Are Stress Specific

2014

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Intermittent hypoxia (IH) is an animal model of apnea-induced hypoxia, a common stressor in the premature neonate. Neonatal stressors may have long-term programming effects in the adult. We hypothesized that neonatal exposure to IH leads to significant changes in basal and stress-induced hypothalamic-pituitary-adrenal (HPA) axis function in the adult male rat. Rat pups were exposed to normoxia (control) or 6 approximately 30-second cycles of IH (5% or 10% inspired O₂) daily on postnatal days 2-6. At approximately 100 days of age, we assessed the diurnal rhythm of plasma corticosterone and stress-induced plasma ACTH and corticosterone responses, as well as mRNA expression of pertinent genes within the HPA axis. Basal diurnal rhythm of plasma corticosterone concentrations in the adult rat were not affected by prior exposure to neonatal IH. Adults exposed to 10% IH as neonates exhibited an augmented peak ACTH response and a prolonged corticosterone response to restraint stress; however, HPA axis responses to insulin-induced hypoglycemia were not augmented in adults exposed to neonatal IH. Pituitary Pomc, Crhr1, Nr3c1, Nr3c2, Avpr1b, and Hif1a mRNA expression was decreased in adults exposed to neonatal 10% IH. Expression of pertinent hypothalamic and adrenal mRNAs was not affected by neonatal IH. We conclude that exposure to neonatal 10% IH programs the adult HPA axis to hyperrespond to acute stimuli in a stressor-specific manner.

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“…The IH protocol was based on a previously published model (9). Six cycles of IH were performed daily over approximately 60 minutes.…”

Section: Animal Treatment and Neonatal Ih Protocolmentioning

confidence: 99%

“…All analytic techniques have been previously published (9). Plasma ACTH and corticosterone were measured via RIA (MP Biomedicals).…”

Section: Hormone and Glucose Assaysmentioning

confidence: 99%

mentioning

confidence: 99%

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Programming of the Hypothalamic-Pituitary-Adrenal Axis by Neonatal Intermittent Hypoxia: Effects on Adult Male ACTH and Corticosterone Responses Are Stress Specific

2014

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“…Moreover, since the railway began service, .10 million travelers have visited the Tibet region in 2012, of whom 31% developed AMS despite traveling with an oxygen supply on the train (3). Increasing evidence in both humans and animals suggests that exposure to either high-altitude or hypobaric hypoxia influences plasma insulin levels and glucose homeostasis, depending on the oxygen level and duration of exposure (4)(5)(6)(7)(8)(9). We previously showed that subacute hypoxia at an altitude of 5,000 m for 5 days reduces plasma insulin in rats, and this effect is blocked by a corticotropin-releasing hormone (CRH) receptor 1 (CRHR1) antagonist in vivo (10).…”

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confidence: 99%

Inactivation of Corticotropin-Releasing Hormone–Induced Insulinotropic Role by High-Altitude Hypoxia

et al. 2014

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We have shown that hypoxia reduces plasma insulin, which correlates with corticotropin-releasing hormone (CRH) receptor 1 (CRHR1) in rats, but the mechanism remains unclear. Here, we report that hypobaric hypoxia at an altitude of 5,000 m for 8 h enhances rat plasma CRH, corticosterone, and glucose levels, whereas the plasma insulin and pancreatic ATP/ADP ratio is reduced. In islets cultured under normoxia, CRH stimulated insulin release in a glucose-and CRH-level-dependent manner by activating CRHR1 and thus the cAMP-dependent protein kinase pathway and calcium influx through L-type channels. In islets cultured under hypoxia, however, the insulinotropic effect of CRH was inactivated due to reduced ATP and cAMP and coincident loss of intracellular calcium oscillations. Serum and glucocorticoid-inducible kinase 1 (SGK1) also played an inhibitory role. In human volunteers rapidly ascended to 3,860 m, plasma CRH and glucose levels increased without a detectable change in plasma insulin. By contrast, volunteers with acute mountain sickness (AMS) exhibited a marked decrease in HOMA insulin sensitivity (HOMA-IS) and enhanced plasma CRH. In conclusion, hypoxia may attenuate the CRH-insulinotropic effect by reducing cellular ATP/ADP ratio, cAMP and calcium influx, and upregulated SGK1. Hypoxia may not affect HOMA-IS in healthy volunteers but reduces it in AMS volunteers.To enjoy social activities, millions of people travel to high altitudes every year. High-altitude hypoxia often induces dysfunction and illness, particularly acute mountain sickness (AMS) (1). During the construction of the QinghaiTibet railway (at altitudes of 3,000-5,000 m) in China, .100,000 construction workers were involved, and 51% of them developed AMS (2). Moreover, since the railway began service, .10 million travelers have visited the Tibet region in 2012, of whom 31% developed AMS despite traveling with an oxygen supply on the train (3). Increasing evidence in both humans and animals suggests that exposure to either high-altitude or hypobaric hypoxia influences plasma insulin levels and glucose homeostasis, depending on the oxygen level and duration of exposure (4-9). We previously showed that subacute hypoxia at an altitude of 5,000 m for 5 days reduces plasma insulin in rats, and this effect is blocked by a corticotropin-releasing hormone (CRH) receptor 1 (CRHR1) antagonist in vivo (10). However, the underlying mechanisms have not been clearly addressed.Insulin, the unique hypoglycemic hormone, plays a crucial role in maintaining glucose sensing in pancreatic b-cells and regulating glucose uptake in a variety of tissues and cells during health and disease (11,12). Apart from glucose, many neural and endocrine hormones regulate pancreatic insulin release (13). In particular, CRH is the key regulator of the hypothalamic-pituitary-adrenal (HPA) axis; is activated by a variety of stressors, including hypoxia; and mediates a variety of neural and endocrine

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“…Conditions that cause stress to the infant increase the risk of hyperglycemia due to increased secretion of counter-regulatory hormones [19]. Among many stress factors, intermittent hypoxia is known to elicit an important adrenal response and significantly alters glucose homeostasis [20]. In our patient, fetal suffering during premature delivery due to placental abruption and respiratory distress requiring mechanical ventilation could have induced a stress response sufficient to increase insulin needs above the threshold met by β-cells with the HNF4A variant.…”

Section: Discussionmentioning

confidence: 99%

Gene Variants Associated with Transient Neonatal Diabetes Mellitus in the Very Low Birth Weight Infant

et al. 2015

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Background: Transient and permanent neonatal diabetes mellitus (NDM), usually defined as diabetes diagnosed within the first 6 months of life, are rare conditions occurring in 1:90,000-260,000 live births. The origin of NDM is rarely related to type 1 diabetes, but rather to single gene defects. Methods: Genetic analysis was performed using targeted parallel sequencing including 323 diabetes genes. Data were filtered by a locally developed program. Results: A very low birth weight neonate born at 28 weeks postmenstrual age developed diabetes 13 days after birth. The patient was treated with continuous subcutaneous insulin infusion. After 1 month, insulin treatment could be stopped. At 18 months of age, the child was normoglycemic and developing normally. Genetic analysis revealed a novel variant (p.Pro190Leu) in HNF4A, which is located in the ligand binding domain of the transcription factor, and the p.Glu23Lys variant in KCNJ11, which is associated with type 2 diabetes. Conclusion: Here, we describe a novel HNF4A variant associated with transient NDM in a premature infant. We hypothesize that the neonatal phenotype previously described in carriers of HNF4A mutations was modified by the additional variant in KCNJ11 and prematurity.

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Effects of age on ACTH, corticosterone, glucose, insulin, and mRNA levels during intermittent hypoxia in the neonatal rat

Cited by 28 publications

References 26 publications

Programming of the Hypothalamic-Pituitary-Adrenal Axis by Neonatal Intermittent Hypoxia: Effects on Adult Male ACTH and Corticosterone Responses Are Stress Specific

Programming of the Hypothalamic-Pituitary-Adrenal Axis by Neonatal Intermittent Hypoxia: Effects on Adult Male ACTH and Corticosterone Responses Are Stress Specific

Inactivation of Corticotropin-Releasing Hormone–Induced Insulinotropic Role by High-Altitude Hypoxia

Gene Variants Associated with Transient Neonatal Diabetes Mellitus in the Very Low Birth Weight Infant

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