Intermittent Hypoxia Causes Insulin Resistance in Lean Mice Independent of Autonomic Activity

Iiyori, Nao; Alonso, Laura; Li, Jianguo; Sanders, Mark H.; Garcı́a-Ocaña, Adolfo; O’Doherty, Robert M.; Polotsky, Vsevolod Y.; O’Donnell, Christopher P.

doi:10.1164/rccm.200610-1527oc

Cited by 319 publications

(264 citation statements)

References 49 publications

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“…Resolution of OSA with weight loss may contribute to weight loss-induced improvement in insulin resistance (41). Murine data indicate that intermittent hypoxia (IH) mediates the effect of OSA on insulin resistance (26,42). The impact of IH is further highlighted by our present findings, which demonstrate that insulin resistance is linked specifically to IH rather than to apnea periodicity (RDI).…”

Section: Osa Systemic Inflammation and Metabolic Dysfunction In Sevmentioning

confidence: 56%

Obstructive Sleep Apnea, Insulin Resistance, and Steatohepatitis in Severe Obesity

Polotsky

Patil

Savransky

et al. 2009

Am J Respir Crit Care Med

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191

139

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Rationale: Obstructive sleep apnea is associated with insulin resistance and liver injury. It is unknown whether apnea contributes to insulin resistance and steatohepatitis in severe obesity. Objectives: To examine whether sleep apnea and nocturnal hypoxemia predict the severity of insulin resistance, systemic inflammation, and steatohepatitis in severely obese individuals presenting for bariatric surgery. Methods: We performed sleep studies and measured fasting blood glucose, serum insulin, C-reactive protein, and liver enzymes in 90 consecutive severely obese individuals, 75 women and 15 men, without concomitant diabetes mellitus or preexistent diagnosis of sleep apnea or liver disease. Liver biopsies (n 5 20) were obtained during bariatric surgery. Measurements and Main Results: Obstructive sleep apnea with a respiratory disturbance index greater than 5 events/hour was diagnosed in 81.1% of patients. The median respiratory disturbance index was 15 6 29 events/hour and the median oxygen desaturation during apneic events was 4.6 6 1.8%. All patients exhibited high serum levels of C-reactive protein, regardless of the severity of apnea, whereas liver enzymes were normal. Oxygen desaturation greater than 4.6% was associated with a 1.5-fold increase in insulin resistance, according to the homeostasis model assessment index. Histopathology data suggested that significant nocturnal desaturation might predispose to hepatic inflammation, hepatocyte ballooning, and liver fibrosis. Fasting blood glucose levels and steatosis scores were not affected by nocturnal hypoxia. There was no relationship between the respiratory disturbance index and insulin resistance or liver histopathology. Conclusions: Hypoxic stress of sleep apnea may be implicated in the development of insulin resistance and steatohepatitis in severe obesity.Keywords: hypoxemia; fatty liver disease; metabolic syndrome; sleepdisordered breathing; liver injury Obstructive sleep apnea (OSA) is a complex disorder consisting of upper airway obstruction, chronic intermittent hypoxia (CIH), and sleep fragmentation (1). Epidemiologic studies have demonstrated that OSA is associated with insulin resistance and glucose intolerance, independent of obesity (2-4). Clinical investigations have also shown that OSA results in low-grade systemic inflammation (5, 6). Both insulin resistance and systemic inflammation may contribute to the increased cardiovascular risk in patients with OSA (7-9). Insulin resistance, systemic inflammation, and OSA are particularly prevalent in patients with severe obesity defined as a body mass index (BMI) exceeding 40 kg/m 2 (2, 10-12). While obesity causes systemic inflammation, insulin resistance, and sleep apnea (12-15), sleep apnea may further exacerbate the inflammatory and metabolic disturbances (2, 3, 6). Nevertheless, it is not known whether concomitant OSA is implicated in metabolic dysregulation and systemic inflammation in severe obesity.One of the consequences of obesity and insulin resistance is nonalcoholic fatty liver disease (N...

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Section: Osa Systemic Inflammation and Metabolic Dysfunction In Sevmentioning

confidence: 56%

Obstructive Sleep Apnea, Insulin Resistance, and Steatohepatitis in Severe Obesity

Polotsky

Patil

Savransky

et al. 2009

Am J Respir Crit Care Med

Self Cite

191

139

View full text Add to dashboard Cite

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“…Observational studies have also demonstrated that OSA is an independent risk factor for prediabetes and incident diabetes (10)(11)(12)(13). Both animal and human models of intermittent hypoxia and sleep fragmentation acutely mimicking OSA show evidence of insulin resistance and glucose intolerance (14)(15)(16)(17). Despite this strong association between OSA and alterations in glucose metabolism, there is still controversy as to whether treatment of OSA with continuous positive airway pressure (CPAP) has metabolic benefits (18,19).…”

mentioning

confidence: 99%

Eight Hours of Nightly Continuous Positive Airway Pressure Treatment of Obstructive Sleep Apnea Improves Glucose Metabolism in Patients with Prediabetes. A Randomized Controlled Trial

Pamidi

Wroblewski²,

Stępień

et al. 2015

Am J Respir Crit Care Med

160

117

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Rationale: Although obstructive sleep apnea (OSA) is associated with impaired glucose tolerance and diabetes, it remains unclear whether OSA treatment with continuous positive airway pressure (CPAP) has metabolic benefits.Objectives: To determine the effect of 8-hour nightly CPAP treatment on glucose metabolism in individuals with prediabetes and OSA.Methods: In a randomized controlled parallel group study, 39 participants were randomly assigned to receive either 8-hour nightly CPAP (n = 26) or oral placebo (n = 13). Sleep was polysomnographically recorded in the laboratory on each night. CPAP adherence was ensured by continuous supervision. Participants continued their daily routine activities outside the laboratory. Glucose metabolism was assessed at baseline and after 2 weeks of assigned treatment using both the oral and intravenous glucose tolerance tests. The primary outcome was the overall glucose response as quantified by the area under the curve for glucose during 2-hour oral glucose tolerance testing. Secondary outcomes included fasting and 2-hour glucose and insulin, the area under the curves for insulin and insulin secretion, norepinephrine, insulin sensitivity, acute insulin response to glucose, and 24-hour blood pressure.

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“…Intermittent hy poxia, a mo del of OSA, induces acute insulin resistance in healthy humans (9) and animals (10). Mice recei ving obesityinducing diets showed a greater increase of the HOMA index under intermittent hypoxia than lean mice (11).…”

Section: Introductionmentioning

confidence: 99%

Melatonin prevents hyperglycemia in a model of sleep apnea

Kaminski

Martinez

Fagundes

et al. 2015

Arch. Endocrinol. Metab.

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Objective: Obstructive sleep apnea is a common disorder associated with aging and obesity. Apneas cause repeated arousals, intermittent hypoxia, and oxidative stress. Changes in glucolipidic profile occur in apnea patients, independently of obesity. Animal models of sleep apnea induce hyperglycemia. This study aims to evaluate the effect of the antioxidants melatonin and N-acetylcysteine on glucose, triglyceride, and cholesterol levels in animals exposed to intermittent hypoxia. Materials and methods: Two groups of Balb/c mice were exposed to intermittent hypoxia (n = 36) or sham intermittent hypoxia (n = 36) for 35 days. The intermittent hypoxia group underwent a total of 480 cycles of 30 seconds reducing the inspired oxygen fraction from 21% to 7 ± 1% followed by 30 seconds of normoxia, during 8 hours daily. Melatonin or N-acetylcysteine were injected intraperitonially daily from day 21 on. Results: At day 35, glucose levels were significantly higher in the intermittent hypoxia group than in the control group. The intermittent hypoxia groups receiving N-acetylcysteine and vehicle showed higher glucose levels than the group receiving melatonin. The lipid profile was not affected by intermittent hypoxia or antioxidant administration. Conclusions:The present results suggest that melatonin prevents the well-recognized increase in glucose levels that usually follows exposure to intermittent hypoxia. Further exploration of the role of melatonin in sleep apnea is warranted. Arch Endocrinol Metab. 2015;59(1):66-70

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Intermittent Hypoxia Causes Insulin Resistance in Lean Mice Independent of Autonomic Activity

Cited by 319 publications

References 49 publications

Obstructive Sleep Apnea, Insulin Resistance, and Steatohepatitis in Severe Obesity

Obstructive Sleep Apnea, Insulin Resistance, and Steatohepatitis in Severe Obesity

Eight Hours of Nightly Continuous Positive Airway Pressure Treatment of Obstructive Sleep Apnea Improves Glucose Metabolism in Patients with Prediabetes. A Randomized Controlled Trial

Melatonin prevents hyperglycemia in a model of sleep apnea

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