Asthma and Insulin Resistance in Morbidly Obese Children and Adolescents

Al-Shawwa, Baha; Al‐Huniti, Nidal; DeMattia, Laure G; Gershan, William M.

doi:10.1080/02770900701423597

Cited by 75 publications

(70 citation statements)

References 32 publications

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“…Retention of large molecules in the airway may contribute to the thickened airway smooth muscles, render the airway hyper-responsive, and lead to asthma. That may be why subjects with obesity have increased prevalence and severity of asthma (16,48).…”

Section: Discussionmentioning

confidence: 99%

“…Insulin resistance is either a precursor or a key component of numerous diseases including obesity, metabolic syndrome, T2DM, cardiovascular disorders (including strokes), Alzheimer disease, depression, asthma, chronic inflammatory diseases, cancers, and aging (11)(12)(13)(14)(15)(16)(17)(18)(19). Insulin resistance is primarily caused by the positive energy imbalance between the intake and expenditure of calories.…”

mentioning

confidence: 99%

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Hepatic Autophagy Is Suppressed in the Presence of Insulin Resistance and Hyperinsulinemia

Liu

Han

Cao

et al. 2009

Journal of Biological Chemistry

343

260

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Autophagy is essential for maintaining both survival and health of cells. Autophagy is normally suppressed by amino acids and insulin. It is unclear what happens to the autophagy activity in the presence of insulin resistance and hyperinsulinemia. In this study, we examined the autophagy activity in the presence of insulin resistance and hyperinsulinemia and the associated mechanism. Insulin resistance and hyperinsulinemia were induced in mice by a high fat diet, followed by measurements of autophagy markers. Our results show that autophagy was suppressed in the livers of mice with insulin resistance and hyperinsulinemia. Transcript levels of some key autophagy genes were also suppressed in the presence of insulin resistance and hyperinsulinemia. Conversely, autophagy activity was increased in the livers of mice with streptozotocin-induced insulin deficiency. Levels of vps34, atg12, and gabarapl1 transcripts were elevated in the livers of mice with insulin deficiency. To study the mechanism, autophagy was induced by nutrient deprivation or glucagon in cultured hepatocytes in the presence or absence of insulin. Autophagy activity and transcript levels of vps34, atg12, and gabarapl1 genes were reduced by insulin. The effect of insulin was largely prevented by overexpression of the constitutive nuclear form of FoxO1. Importantly, autophagy of mitochondria (mitophagy) in cultured cells was suppressed by insulin in the presence of insulin resistance. Together, our results show that autophagy activity and expression of some key autophagy genes were suppressed in the presence of insulin resistance and hyperinsulinemia. Insulin suppression of autophagy involves FoxO1-mediated transcription of key autophagy genes.Macroautophagy (autophagy) is a catabolic process whereby long lived large molecules and cellular organelles, such as mitochondria and endoplasmic reticulum (ER), 3 are degraded by lysosomes for an alternative energy source during starvation (1, 2). Autophagy is normally activated by glucagon or deprivation of amino acids during starvation (1) but inhibited by amino acids and/or insulin through the mTOR-or/and Akt-dependent pathways after food intake (3, 4). Thus, autophagy activity fluctuates with food intakes and fasts. Importantly, autophagy is also essential for maintaining cellular health by removing misfolded large molecules and aged/dysfunctional cellular organelles, such as mitochondria and ER (1, 5). In other words, decreased autophagy will inevitably slow the removal of misfolded large molecules and aged/dysfunctional cellular organelles. Accumulation of these molecules and dysfunctional cellular organelles may not only contribute to the development of cancers (1) but also contribute to the development of metabolic diseases, such as insulin resistance. For example, the accumulation of dysfunctional mitochondria will most likely cause increased mitochondrion-derived oxidative stress, which is known to contribute to the development of insulin resistance (6 -10).Insulin resistance is either a precursor or...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Hepatic Autophagy Is Suppressed in the Presence of Insulin Resistance and Hyperinsulinemia

Liu

Han

Cao

et al. 2009

Journal of Biological Chemistry

343

260

View full text Add to dashboard Cite

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“…122 Our review of the recent literature highlights that metabolic dysregulation plays a role in pediatric obesity-related asthma (Table 3). Higher prevalence 124 and degree of insulin resistance 22 and higher prevalence of its surrogate marker, acanthosis nigricans, 23 and metabolic syndrome, 25 have been reported among children with asthma compared with their nonasthmatic counterparts. Insulin resistance correlates with the proinflammatory markers leptin and IL-6 124 and is found to be a predictor of both lower airway obstruction and reduced lung volumes, 2 distinct measures of lung function deficits, independent of general and truncal adiposity.…”

Section: Association With Insulin Resistancementioning

confidence: 99%

“…Recently, asthma has been associated with insulin resistance, 22 dyslipidemia, 23,24 and metabolic syndrome, 25 measures of metabolic dysregulation that develop in some but not all obese children. 26,27 Moreover, genetic and epigenetic differences in molecules involved in metabolic dysregulation and its associated inflammation have been found in the context of obesityrelated asthma.…”

Section: Mechanisms Linking Obesity and Asthmamentioning

confidence: 99%

Pediatric Obesity-Related Asthma: The Role of Metabolic Dysregulation

2016

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The burden of obesity-related asthma among children, particularly among ethnic minorities, necessitates an improved understanding of the underlying disease mechanisms. Although obesity is an independent risk factor for asthma, not all obese children develop asthma. Several recent studies have elucidated mechanisms, including the role of diet, sedentary lifestyle, mechanical fat load, and adiposity-mediated inflammation that may underlie the obese asthma pathophysiology. Here, we review these recent studies and emerging scientific evidence that suggest metabolic dysregulation may play a role in pediatric obesity-related asthma. We also review the genetic and epigenetic factors that may underlie susceptibility to metabolic dysregulation and associated pulmonary morbidity among children. Lastly, we identify knowledge gaps that need further exploration to better define pathways that will allow development of primary preventive strategies for obesity-related asthma in children.

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“…However, insulin resistance may also predispose to asthma independent of body mass index (5,(8)(9)(10)(11)(12). The frequency of asthma increases with increasing insulin resistance (as reflected by acanthosis nigricans [10] or by homeostatic model assessment of insulin resistance [11,12]) in children independent of body mass. Thus, insulin resistance and compensatory hyperinsulinemia may be one of the mechanisms that increase asthmatic symptoms in obese individuals.…”

mentioning

confidence: 99%

Hyperinsulinemia Potentiates Airway Responsiveness to Parasympathetic Nerve Stimulation in Obese Rats

Nie

Jacoby

Fryer

2014

Am J Respir Cell Mol Biol

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Obesity is a substantial risk factor for developing asthma, but the molecular mechanisms underlying this relationship are unclear. We tested the role of insulin in airway responsiveness to nerve stimulation using rats genetically prone or resistant to diet-induced obesity. Airway response to vagus nerve stimulation and airway M 2 and M 3 muscarinic receptor function were measured in obeseprone and -resistant rats with high or low circulating insulin. The effects of insulin on nerve-mediated human airway smooth muscle contraction and human M 2 muscarinic receptor function were tested in vitro. Our data show that increased vagally mediated bronchoconstriction in obesity is associated with hyperinsulinemia and loss of inhibitory M 2 muscarinic receptor function on parasympathetic nerves. Obesity did not induce airway inflammation or increase airway wall thickness. Smooth muscle contraction to acetylcholine was not increased, indicating that hyperresponsiveness is mediated at the level of airway nerves. Reducing serum insulin with streptozotocin protected neuronal M 2 receptor function and prevented airway hyperresponsiveness to vagus nerve stimulation in obese rats. Replacing insulin restored dysfunction of neuronal M 2 receptors and airway hyperresponsiveness to vagus nerve stimulation in streptozotocintreated obese rats. Treatment with insulin caused loss of M 2 receptor function, resulting in airway hyperresponsiveness to vagus nerve stimulation in obese-resistant rats, and inhibited human neuronal M 2 receptor function in vitro. This study shows that it is not obesity per se but hyperinsulinemia accompanying obesity that potentiates vagally induced bronchoconstriction by inhibiting neuronal M 2 muscarinic receptors and increasing acetylcholine release from airway parasympathetic nerves.Keywords: hyperinsulinemia; obesity; asthma; airway responsiveness; neural M 2 muscarinic receptor Clinical RelevanceObesity-induced asthma does not respond well to traditional anti-inflammatory therapies, suggesting that it is a unique asthma phenotype. Here we show that hyperinsulinemia causes airway hyperresponsiveness to vagus nerve stimulation in obese rats. In human trachea and in rats, we demonstrate that insulin inhibits M 2 muscarinic receptors on airway parasympathetic nerves, resulting in increased acetylcholine release and increased airway contraction. Because hyperinsulinemia is greater and more prevalent in obese individuals, these data may explain why obese individuals are prone to asthma exacerbations and suggest that anticholinergic drugs may be effective in this specific phenotype of asthma.In the United States, 31% of adults and 15% of children are obese. In obese and overweight individuals, the prevalence of asthma (1-3) and the rate of new-onset asthma have increased (4-6). Obese patients with asthma also have increased severity of illness and reduced effectiveness of steroids compared with nonobese patients with asthma (1, 6, 7). The mechanisms by which obesity predisposes to asthma are unclear, limi...

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Asthma and Insulin Resistance in Morbidly Obese Children and Adolescents

Cited by 75 publications

References 32 publications

Hepatic Autophagy Is Suppressed in the Presence of Insulin Resistance and Hyperinsulinemia

Hepatic Autophagy Is Suppressed in the Presence of Insulin Resistance and Hyperinsulinemia

Pediatric Obesity-Related Asthma: The Role of Metabolic Dysregulation

Hyperinsulinemia Potentiates Airway Responsiveness to Parasympathetic Nerve Stimulation in Obese Rats

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