Glucose dynamics during ozone exposure measured using radiotelemetry: Stress drivers and human concordance

Background. Stress-related neurobehavioral and metabolic disorders are associated with altered circulating adrenal-derived hormones and hyperglycemia. Temporal assessment of glucose and these hormones is critical for insights on an individuals health. Objectives. Here we use implantable-telemetry in rats to assess real-time changes in circulating glucose during and after exposure to the air pollutant ozone, and link responses to circulating neuroendocrine stress and metabolic hormones. We also proposed to compare rodent glucose and corticosterone (cortisol in humans) responses to humans exposed to ozone. Methods. First, using a cross-over design, we monitored glucose levels during single or repeated ozone exposures (0.0, 0.2, 0.4 and 0.8-ppm) and non-exposure periods in male Wistar-Kyoto-rats implanted with glucose-telemeters. A second cohort of un-implanted rats was exposed to ozone (0.0, 0.4 or 0.8-ppm) for 30-min, 1-hour, 2-hour, or 4-hour with hormones measured immediately after exposure. Then we assessed glucose metabolism in sham and adrenalectomized rats with or without pharmacological interventions of adrenergic and glucocorticoid receptors. Finally, we assessed glucose and cortisol in serum samples form a clinical study involving exposure of human volunteers to air or 0.3 ppm ozone. Results. Ozone (0.8-ppm) caused hyperglycemia and hypothermia beginning 90-min into exposure, with reversal of effects 4-6 hours post-exposure. Glucose monitoring during four daily 4-hour ozone exposures revealed duration of hyperglycemia, adaptation, and diurnal variations. Ozone-induced hyperglycemia was preceded by increased adrenocorticotropic hormone, corticosterone, and epinephrine, but depletion of thyroid-stimulating, prolactin, and luteinizing hormones. Hyperglycemia was inhibited in rats that are adrenalectomized and/or treated with glucocorticoid inhibitor. There was coherence among rats and humans in ozone-induced corticosterone/cortisol increases. Discussion. We demonstrate for the first time the temporality of neuroendocrine-stress-mediated biological sequalae responsible for ozone-induced metabolic dysfunction as exposure occurs. Real-time glucose monitoring with stress hormones assessment may be useful in identifying interactions among pollutants and stress-related illnesses.

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Neuroendocrine Regulation of Air Pollution Health Effects: Emerging Insights

Toxicological Sciences ◽

10.1093/toxsci/kfy129 ◽

2018 ◽

Vol 164 (1) ◽

pp. 9-20 ◽

Cited By ~ 19

Author(s):

Samantha J Snow ◽

Andres R Henriquez ◽

Daniel L Costa ◽

Urmila P Kodavanti

Keyword(s):

Air Pollution ◽

Lung Injury ◽

Air Pollutants ◽

Allostatic Load ◽

Glucocorticoid Receptors ◽

Stress Hormones ◽

Air Pollutant ◽

Ozone Exposure ◽

Metabolic Effects

Abstract Air pollutant exposures are linked to cardiopulmonary diseases, diabetes, metabolic syndrome, neurobehavioral conditions, and reproductive abnormalities. Significant effort is invested in understanding how pollutants encountered by the lung might induce effects in distant organs. The role of circulating mediators has been predicted; however, their origin and identity have not been confirmed. New evidence has emerged which implicates the role of neuroendocrine sympathetic-adrenal-medullary (SAM) and hypothalamic-pituitary-adrenal (HPA) stress axes in mediating a wide array of systemic and pulmonary effects. Our recent studies using ozone exposure as a prototypical air pollutant demonstrate that increases in circulating adrenal-derived stress hormones (epinephrine and cortisol/corticosterone) contribute to lung injury/inflammation and metabolic effects in the liver, pancreas, adipose, and muscle tissues. When stress hormones are depleted by adrenalectomy in rats, most ozone effects including lung injury/inflammation are diminished. Animals treated with antagonists for adrenergic and glucocorticoid receptors show inhibition of the pulmonary and systemic effects of ozone, whereas treatment with agonists restore and exacerbate the ozone-induced injury/inflammation phenotype, implying the role of neuroendocrine activation. The neuroendocrine system is critical for normal homeostasis and allostatic activation; however, chronic exposure to stressors may lead to increases in allostatic load. The emerging mechanisms by which circulating mediators are released and are responsible for producing multiorgan effects of air pollutants insists upon a paradigm shift in the field of air pollution and health. Moreover, since these neuroendocrine responses are linked to both chemical and nonchemical stressors, the interactive influence of air pollutants, lifestyle, and environmental factors requires further study.

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Continuous Glucose Monitoring in the Management of Neonates with Persistent Hypoglycaemia and Congenital Hyperinsulinism

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab601 ◽

2021 ◽

Author(s):

Myat Win ◽

Rowan Beckett ◽

Lynn Thomson ◽

Ajay Thankamony ◽

Kathy Beardsall

Keyword(s):

Real Time ◽

Preterm Infants ◽

Continuous Glucose Monitoring ◽

Clinical Care ◽

Neurodevelopmental Outcome ◽

Glucose Monitoring ◽

Relative Difference ◽

Congenital Hyperinsulinism ◽

Glucose Levels ◽

Sensor Glucose

Abstract Background Persistent hypoglycaemia is common in the newborn and is associated with poor neurodevelopmental outcome. Adequate monitoring is critical in prevention, but is dependent on frequent, often hourly blood sampling. Continuous glucose monitoring (CGM) is increasingly being used in children with type 1 diabetes mellitus, but use in neonatology remains limited. We aimed to introduce real-time CGM to provide insights into patterns of dysglycaemia and to support the management of persistent neonatal hypoglycaemia. Methods This is a single centre retrospective study of real-time CGM use over a 4-year period in babies with persistent hypoglycaemia. Results CGMs were inserted in 14 babies: 8 term and 6 preterm infants, 9 with evidence of congenital hyperinsulinism (CHI). A total of 224 days of data were collected demonstrating marked fluctuations in glucose levels in babies with CHI, with a higher sensor glucose SD (1.52±0.79 mmol/l vs 0.77±0.22mmol/l) in infants with CHI compared to preterm infants. A total of 1254 paired glucose values (CGM and blood) were compared and gave a mean absolute relative difference (MARD) of 11%. Conclusion CGM highlighted the challenges of preventing hypoglycaemia in these babies when using intermittent blood glucose levels alone, and the potential application of CGM as an adjunct to clinical care.

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Rare case of type B insulin resistance in association with systemic lupus erythematosus: illustrating diagnostic and management challenges

BMJ Case Reports ◽

10.1136/bcr-2021-242960 ◽

2021 ◽

Vol 14 (8) ◽

pp. e242960

Author(s):

Aaisha Saqib ◽

Yik Man ◽

Rayan Ismail ◽

Dulmini Kariyawasam

Keyword(s):

Systemic Lupus Erythematosus ◽

Insulin Resistance ◽

Blood Glucose ◽

Lupus Erythematosus ◽

Glucose Monitoring ◽

Type B ◽

Systemic Lupus ◽

Serum Samples ◽

Glucose Levels ◽

Insulin Requirements

A 42 year-old Caribbean woman with, known type 2 diabetes, was admitted with worsening fatigue, arthritis and rashes. She was diagnosed with multisystem systemic lupus erythematosus and was initially treated with systemic steroids. During this admission, she had persistently elevated capillary glucose levels with insulin requirements over 8 U/kg/day that still did not control her blood glucose levels. Due to her profound hyperglycaemia, serum samples of fasting insulin, C-peptide, paired with blood glucose were analysed, which confirmed significant hyperinsulinaemia. Further analysis confirmed the presence of insulin receptor antibodies consistent with type B insulin resistance.She was started on intravenous cyclophosphamide (Euro-Lupus regimen) along with continuous glucose monitoring system. After completing her six cycles of cyclophosphamide, she no longer required insulin treatment. The goal of therapy for our patient with confirmed type B insulin resistance was to manage hyperglycaemia with high doses of insulin until autoantibodies were eliminated with immunosuppressive therapy.

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Ozone-Induced Dysregulation of Neuroendocrine Axes Requires Adrenal-Derived Stress Hormones

Toxicological Sciences ◽

10.1093/toxsci/kfz182 ◽

2019 ◽

Vol 172 (1) ◽

pp. 38-50 ◽

Cited By ~ 11

Author(s):

Andres R Henriquez ◽

John S House ◽

Samantha J Snow ◽

Colette N Miller ◽

Mette C Schladweiler ◽

...

Keyword(s):

Gene Expression ◽

Hedgehog Signaling ◽

Stress Hormones ◽

Transcriptional Response ◽

Global Gene Expression ◽

Thyroid Stimulating Hormone ◽

Ozone Exposure ◽

Short Term ◽

Sham Surgery ◽

Wistar Kyoto

Abstract Acute ozone inhalation increases circulating stress hormones through activation of the sympathetic-adrenal-medullary and hypothalamic-pituitary-adrenal axes. Rats with adrenalectomy (AD) have attenuated ozone-induced lung responses. We hypothesized that ozone exposure will induce changes in circulating pituitary-derived hormones and global gene expression in the brainstem and hypothalamus, and that AD will ameliorate these effects. Male Wistar-Kyoto rats (13 weeks) that underwent sham surgery (SHAM) or AD were exposed to ozone (0.8 ppm) or filtered-air for 4 h. In SHAM rats, ozone exposure decreased circulating thyroid-stimulating hormone (TSH), prolactin (PRL), and luteinizing hormone (LH). AD prevented reductions in TSH and PRL, but not LH. AD increased adrenocorticotropic hormone approximately 5-fold in both air- and ozone-exposed rats. AD in air-exposed rats resulted in few significant transcriptional differences in the brainstem and hypothalamus (approximately 20 genes per tissue). In contrast, ozone-exposure in SHAM rats resulted in either increases or decreases in expression of hundreds of genes in the brainstem and hypothalamus relative to air-exposed SHAM rats (303 and 568 genes, respectively). Differentially expressed genes from ozone exposure were enriched for pathways involving hedgehog signaling, responses to alpha-interferon, hypoxia, and mTORC1, among others. Gene changes in both brain areas were analogous to those altered by corticosteroids and L-3,4-dihydroxyphenylalanine, suggesting a role for endogenous glucocorticoids and catecholamines. AD completely prevented this ozone-induced transcriptional response. These findings show that short-term ozone inhalation promotes a shift in brainstem and hypothalamic gene expression that is dependent upon the presence of circulating adrenal-derived stress hormones. This is likely to have profound downstream influence on systemic effects of ozone.

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Beta-2 Adrenergic and Glucocorticoid Receptor Agonists Modulate Ozone-Induced Pulmonary Protein Leakage and Inflammation in Healthy and Adrenalectomized Rats

Toxicological Sciences ◽

10.1093/toxsci/kfy198 ◽

2018 ◽

Vol 166 (2) ◽

pp. 288-305 ◽

Cited By ~ 10

Author(s):

Andres R Henriquez ◽

Samantha J Snow ◽

Mette C Schladweiler ◽

Colette N Miller ◽

Janice A Dye ◽

...

Keyword(s):

Corn Oil ◽

Stress Hormones ◽

Lavage Fluid ◽

Ozone Exposure ◽

Cell Trafficking ◽

Receptor Agonists ◽

Protein Leakage ◽

Chronic Pulmonary Diseases ◽

Circulating Lymphocytes ◽

Wistar Kyoto

Abstract We have shown that acute ozone inhalation activates sympathetic-adrenal-medullary and hypothalamus-pituitary-adrenal stress axes, and adrenalectomy (AD) inhibits ozone-induced lung injury and inflammation. Therefore, we hypothesized that stress hormone receptor agonists (β2 adrenergic-β2AR and glucocorticoid-GR) will restore the ozone injury phenotype in AD, while exacerbating effects in sham-surgery (SH) rats. Male Wistar Kyoto rats that underwent SH or AD were treated with vehicles (saline + corn oil) or β2AR agonist clenbuterol (CLEN, 0.2 mg/kg, i.p.) + GR agonist dexamethasone (DEX, 2 mg/kg, s.c.) for 1 day and immediately prior to each day of exposure to filtered air or ozone (0.8 ppm, 4 h/day for 1 or 2 days). Ozone-induced increases in PenH and peak-expiratory flow were exacerbated in CLEN+DEX-treated SH and AD rats. CLEN+DEX affected breath waveform in all rats. Ozone exposure in vehicle-treated SH rats increased bronchoalveolar lavage fluid (BALF) protein, N-acetyl glucosaminidase activity (macrophage activation), neutrophils, and lung cytokine expression while reducing circulating lymphocyte subpopulations. AD reduced these ozone effects in vehicle-treated rats. At the doses used herein, CLEN+DEX treatment reversed the protection offered by AD and exacerbated most ozone-induced lung effects while diminishing circulating lymphocytes. CLEN+DEX in air-exposed SH rats also induced marked protein leakage and reduced circulating lymphocytes but did not increase BALF neutrophils. In conclusion, circulating stress hormones and their receptors mediate ozone-induced vascular leakage and inflammatory cell trafficking to the lung. Those receiving β2AR and GR agonists for chronic pulmonary diseases, or with increased circulating stress hormones due to psychosocial stresses, might have altered sensitivity to air pollution.

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Exacerbation of ozone-induced pulmonary and systemic effects by β2-adrenergic and/or glucocorticoid receptor agonist/s

Scientific Reports ◽

10.1038/s41598-019-54269-w ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Andres R. Henriquez ◽

Samantha J. Snow ◽

Mette C. Schladweiler ◽

Colette N. Miller ◽

Janice A. Dye ◽

...

Keyword(s):

Glucose Intolerance ◽

Glucocorticoid Receptors ◽

Dual Therapy ◽

Lavage Fluid ◽

Ozone Exposure ◽

Systemic Effects ◽

Dependent Manner ◽

Pollution Effects ◽

Circulating Lymphocytes ◽

Wistar Kyoto

AbstractAgonists of β2 adrenergic receptors (β2AR) and glucocorticoid receptors (GR) are prescribed to treat pulmonary diseases. Since ozone effects are mediated through the activation of AR and GR, we hypothesized that the treatment of rats with relevant therapeutic doses of long acting β2AR agonist (LABA; clenbuterol; CLEN) and/or GR agonist (dexamethasone; DEX) would exacerbate ozone-induced pulmonary and systemic changes. In the first study, male 12-week-old Wistar-Kyoto rats were injected intraperitoneally with vehicle (saline), CLEN (0.004 or 0.02 mg/kg), or DEX (0.02 or 0.1 mg/kg). Since dual therapy is commonly used, in the second study, rats received either saline or combined CLEN + DEX (each at 0.005 or 0.02 mg/kg) one day prior to and on both days of exposure (air or 0.8ppm ozone, 4 hr/day x 2-days). In air-exposed rats CLEN, DEX or CLEN + DEX did not induce lung injury or inflammation, however DEX and CLEN + DEX decreased circulating lymphocytes, spleen and thymus weights, increased free fatty acids (FFA) and produced hyperglycemia and glucose intolerance. Ozone exposure of vehicle-treated rats increased bronchoalveolar lavage fluid protein, albumin, neutrophils, IL-6 and TNF-α. Ozone decreased circulating lymphocytes, increased FFA, and induced hypeerglycemia and glucose intolerance. Drug treatment did not reverse ozone-induced ventillatory changes, however, lung effects (protein and albumin leakage, inflammation, and IL-6 increase) were exacerbated by CLEN and CLEN + DEX pre-treatment in a dose-dependent manner (CLEN > CLEN + DEX). Systemic effects induced by DEX and CLEN + DEX but not CLEN in air-exposed rats were analogous to and more pronounced than those induced by ozone. These data suggest that adverse air pollution effects might be exacerbated in people receiving LABA or LABA plus glucocorticoids.

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