Pulmonary Insulin Resistance – The Lung as a Metabolic Organ: Investigating the Correlation between Insulin Resistance and Sleep Apnea

doi:10.21203/rs.3.rs-5176879/v1

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Pulmonary Insulin Resistance – The Lung as a Metabolic Organ: Investigating the Correlation between Insulin Resistance and Sleep Apnea

https://doi.org/10.21203/rs.3.rs-5176879/v1

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Introduction: The relationship between insulin resistance (IR) and sleep apnea has been increasingly investigated. This study aimed to examine the correlation between IR and the severity of sleep apnea, as well as the potential impact of IR on pulmonary function.

Methods: A cross-sectional analysis was conducted on 72 individuals diagnosed with sleep apnea. Demographic data, fasting blood glucose, triglycerides, and glycated hemoglobin were collected. IR was assessed using the triglyceride glucose index (TyG index). Polysomnography and spirometry were performed. Logistic regression analysis was employed to evaluate the association between IR, sleep apnea severity, and pulmonary function.

Results: The study population consisted of 37 females and 35 males with a mean age of 45.31 years. IR was present in 66% of participants. The mean Epworth sleepiness score was 8.89 ± 4.54. The apnea-hypopnea index (AHI) revealed 19.40% normal, 30.60% mild, 27.80% moderate, and 22.20% severe. A significant association was found between IR and both Epworth score (PR 60.50%, OR 1.243, P = 0.0001) and AHI (PR 65.50%, OR 4.750, P = 0.014). However, no significant association was observed between IR and mild AHI.

Conclusion: This study demonstrates a significant association between IR and the severity of sleep apnea, particularly moderate and severe AHI. These results underscore the importance of considering IR as a potential risk factor for sleep apnea and suggest the possibility of pulmonary IR in situ.

Endocrinology & Metabolism

Pulmonology

Insulin resistance

Sleep apnea

Pulmonary function

TyG index

Pulmonary insulin resistance (IR) refers to the decreased responsiveness of lung tissues to insulin's effects, has emerged as a focal point of respiratory research. While the presence of insulin receptors within the lungs underscores the direct influence of insulin on pulmonary function, IR compromises these effects, leading to impaired lung performance.¹ The mechanisms underlying pulmonary IR remain an active area of investigation, although several factors have been implicated in its pathogenesis. Chronic inflammation, a hallmark of numerous diseases, has been consistently linked to IR in various organs, including the lungs. Inflammatory mediators, released in response to chronic inflammation, can disrupt insulin signaling pathways, thereby promoting resistance.² Oxidative stress, another potential contributor to pulmonary IR, arise from an imbalance between the production of reactive oxygen species and the body's antioxidant defenses. This oxidative stress can interfere with insulin signaling and impair lung function. Environmental factors such as exposure to pollutants and smoking, both of which are known to elevate the risk of respiratory diseases, can contribute to oxidative stress and, consequently, pulmonary IR.³

The expression of insulin receptors within pulmonary tissue suggests a direct link between insulin signaling and lung health. Impaired IR has been implicated as an independent risk factor for the development of respiratory morbidities.⁴

Sleep apnea, a sleep-related disorder characterized by recurrent episodes of upper airway obstruction leading to intermittent hypoxia, has been increasingly recognized as a risk factor for a multitude of comorbidities, including cardiovascular disease, cerebrovascular disease, dementia, and metabolic syndrome. IR has been implicated as a key pathogenic mechanism linking sleep apnea to its associated comorbidities.⁵ Consequently, there has been a concerted effort to identify accurate and accessible methods for assessing IR. Among the various indices employed, the triglyceride glucose (TyG) index has emerged as a convenient and cost-effective surrogate marker for IR. Its diagnostic and prognostic value has been shown to be comparable to more established methods such as the homeostasis model assessment of IR (HOMA-IR) and the hyperinsulinemic-euglycemic clamp, which is considered the gold standard for IR assessment.⁶

The systemic nature of IR can manifest in the respiratory system, leading to a heightened susceptibility to respiratory diseases. Pulmonary IR can exacerbate disease severity and may limit the effectiveness of usual therapeutic approaches. This study aims to explore the relationship between the lung and IR. By investigating the correlation between pulmonary IR and sleep apnea, we seek to elucidate the role of the lung as a metabolic organ.

Study Design and Participants:

This study included a cross-sectional analysis of 72 participants with a clinical diagnosis of sleep apnea. The study protocol was approved by the Ethics Committee.

Clinical and Laboratory Assessments:

Baseline demographic information, including age, gender, and body mass index, was collected. Fasting blood samples were obtained from each participant for comprehensive laboratory evaluation. Serum levels of fasting glucose, triglycerides, and glycated hemoglobin were measured using standardized laboratory methods.

Assessment of Insulin Resistance

The IR was evaluated using the TyG index and, representing a reliable threshold for predicting the onset of diabetes mellitus and aligning with the hyperglycemic-hyperinsulinemic clamp method (gold standard).

The TyG index, calculated as the natural logarithm of the product of fasting triglycerides (mg/dL) and fasting glucose (mg/dL) divided by 2: Ln[fasting triglycerides (mg/dL) fasting glucose (mg/dL)/2]. A TyG index value of 4.49 serves as a benchmark for identifying IR.⁷

Overnight Polysomnography Assessment

A multidisciplinary LAMARCK SC810 polysomnograph was employed, featuring 24 amplifier channels, a 16-bit analog-to-digital converter resolution, and a sampling rate of 1024 samples per second per channel. This device concurrently assessed the following parameters: electroencephalography, electrooculography, electromyography, electrocardiogram, respiratory channels, straps, position sensors, and pulse oximetry.

Spirometry

A Koko PFT System nSpire Health 2010 spirometer was utilized, employing disposable nSpire filters. Patients were instructed to perform a forced vital capacity (FVC) maneuver. This involves a maximal inspiration followed by a maximal forced expiration. The following parameters were assessed: FVC, forced expiratory volume in one second (FEV1), and the FEV1/FVC ratio, all expressed in liters or as a percentage.

After the initial three FVC maneuvers, patients were administered 400 micrograms of salbutamol via inhaler and allowed to rest for 20 minutes before repeating the procedure. This test allows for the detection of obstructive diseases (such as asthma and chronic obstructive broncho-pulmonary disease) and restrictive diseases (such as interstitial lung diseases, chest wall restrictions, or obesity-induced restrictions). The bronchodilator challenge reveals bronchoreversibility, a characteristic feature of obstructive diseases, particularly asthma.

Statistical Analysis

Descriptive statistics were summarized as mean ± standard deviation (SD) or median (interquartile range) for continuous variables and as percentages for categorical variables. The relationship among IR, pulmonary function, and sleep apnea severity was evaluated using logistic regression analysis, adjusting for potential confounding factors. Statistical significance was considered at a P-value threshold of less than 0.05.

Ethical Considerations

This study adhered to the ethical principles outlined in the Declaration of Helsinki. The study protocol was approved by the National Commission for Research Ethics (CONEP) in Brazil, and informed consent was obtained from all participants prior to their involvement in the study. Strict confidentiality of personal information was maintained throughout the study, and all data were analyzed and reported in an aggregated and anonymized format.

A sample of 72 individuals underwent a comprehensive assessment. The group was evenly divided between females (n = 37) and males (n = 35), with a mean age of 45.31 years. Fasting glucose and triglyceride concentrations were measured, revealing mean values of 106.90 mg/dL and 124.84 mg/dL, respectively. The prevalence of IR, as determined by the TyG index, was substantial, affecting 66% of the cohort (Table 1).

The mean absolute Epworth Sleepiness Scale (ESS) was 12.89 ± 4.54 (probability of dozing 1–24) (Graph 1). The apnea-hypopnea index (AHI) revealed 19.40% (14/72) normal, 30.60% (22/72) mild, 27.80% (20/72) moderate, and 22.20% (16/72) severe AHI (Graph 2).

Graph 1. Absolute Epworth Graph 2. Apnea-hypopnea index.

A prevalence ratio (PR) of 60.50% (OR 1.243, 95% CI: 0.479–3.225) was found between excessive daytime sleepiness, EES and IR. This association was statistically significant (P = 0.0001).

There was a significant correlation between absolute AHI and IR (P = 0.013). Similarly, a significant association was observed between AHI ≥ 5 and IR (P = 0.014), with a PR of 65.50% (OR 4.750, 95% CI: 1.321–17.079). Although a PR of 54.50% (OR 0.800, 95% CI: 0.291–2.201) was found between mild AHI and IR, this association was not statistically significant. Moderate AHI was significantly associated with IR (P = 0.020), with a PR of 70.00% (OR 2.000, 95% CI: 0.665–6.013). A similar significant association was found between severe AHI and IR (P = 0.020), with a PR of 75.00% (OR 2.600, 95% CI: 0.747–9.052) (Table 3).

Table 3

Association between AHI and IR
Association	Prevalence ratio (%)	Estimated risk (OR)
IAH ≥ 5 / IR	65.50	4.750 (1.321–17.070)
IAH Leve / IR	54.50	0.800 (0.291–2.201)
IAH Moderada / IR	70.00	2.000 (0.665–6.013)
IAH Severa / IR	75.00	2.600 (0.747–9.052)

Oxygen Desaturation Index (ODI) showed that oxygen desaturation ≤ 90% was significantly associated with IR (P = 0.001).

A logistic regression analysis was conducted to investigate whether IR was a risk factor for AHI. After adjusting for gender and age, the TyG index was significantly associated with AHI (OR 5.75, 95% CI 2.9–15.00, P = 0.021).

This study provides evidence supporting the association between IR and sleep apnea severity. Our results highlight the potential for pulmonary IR to play a important role in the development and progression of sleep apnea. The pulmonary IR has garnered significant attention in respiratory research due to its impact on lung function. The presence of insulin receptors in the lungs highlights the direct influence of insulin, but IR hampers this response, leading to compromised pulmonary performance. This study establishes a link between IR and the severity of sleep apnea, especially in cases of moderate and severe AHI. Thus, these results emphasize the importance of recognizing IR as a potential contributing factor to sleep apnea risk and suggest the plausibility of localized pulmonary IR.

TyG index can serve as a practical alternative of IR measurement, and previous studies showed that a higher TyG index showed a higher risk of obstructive sleep apnea.⁸ Chronic intermittent hypoxia, a hallmark pathophysiological consequence of sleep apnea, is a primary mechanism underlying the development of IR.⁹ Additionally, sleep fragmentation and deprivation may also contribute to the pathogenesis of IR in this context.¹⁰ Moreover, genetic and epigenetic factors play a significant role in modulating the relationship between the TyG index and sleep apnea.¹¹ Our study evaluated the correlation between IR, using the TyG index, and sleep apnea. We employed logistic regression analysis to investigate whether IR was a risk factor for sleep apnea, adjusted for age and gender. Our findings revealed a significant association between the TyG index and sleep apnea.

The ESS, a self-reported questionnaire designed to gauge the propensity for napping during routine activities, has become the gold standard for quantifying daytime sleepiness in clinical and research settings.¹² The ESS is a concise, self-administered questionnaire comprising eight items, designed to quantify daytime somnolence across various levels of arousal. With a total score ranging from 0 to 24, a score of 10 or greater is indicative of excessive daytime sleepiness, a clinical hallmark of numerous sleep disorders.¹³ Our study demonstrated a significant association between the ESS and IR, independent of gender and age. The ESS has been widely employed to assess subjective daytime sleepiness in other studies.¹⁴

The AHI, calculated as the sum of hypopneas and apneas per hour of sleep, is the gold standard for quantifying the severity of sleep apnea. AHI values categorize sleep apnea into mild (5–14 events/h), moderate (15–29 events/h), and severe (> 30 events/h) categories.¹⁵ Hypertriglyceridemia is strongly linked to IR and can mask the underlying impact of AHI on insulin sensitivity. The lipolytic action of insulin, coupled with increased sympathetic tone induced by arousals and intermittent hypoxia associated with sleep apnea, contributes to the development of dyslipidemia and further exacerbates IR.¹⁶ Our findings align with a growing body of literature that underscores the strong association between sleep apnea, as quantified by the AHI and IR. Consistent with previous studies,^17,18 we observed a correlation between increasing AHI severity and the frequency of IR. The significant positive association between moderate and severe AHI and IR, in particular, highlights the potential clinical implications of this relationship.

The ODI is calculated as the number of oxygen desaturations of ≥ 3% (over the last 120 seconds) that lasts for at least 10 seconds per hour of sleep, is a commonly used metric in sleep medicine. However, the ODI has several limitations, including its reliance on an arbitrary desaturation threshold and its inability to accurately reflect the severity or frequency of hypoxic events. Furthermore, the ODI may be influenced by factors such as arousal thresholds and the presence of underlying medical conditions.¹⁹ Our study demonstrated a clinically significant link between an ODI of 10 or more events per hour and IR.

Thus, our study underscore the relationship between IR and sleep apnea, reinforcing the notion that pulmonary IR may play a pivotal role in the development and progression of this disorder. The presence of insulin receptors within the lung tissue highlights the organ's direct susceptibility to insulin's influence. However, impaired insulin sensitivity within the lungs can lead to compromised pulmonary function, ultimately contributing to the severity of sleep apnea. The significant association observed between IR, as assessed by the TyG index, and sleep apnea severity, particularly in cases of moderate and severe AHI, further supports this hypothesis. These results emphasize the importance of considering IR as a potential risk factor for sleep apnea and suggest the need for a more comprehensive approach to managing this condition, encompassing both respiratory and metabolic aspects.

This study demonstrates a significant association between IR and the severity of sleep apnea, particularly moderate and severe AHI. These results emphasize the importance of considering IR as a potential risk factor for sleep apnea and underscore the need for a more comprehensive approach to managing this condition, encompassing both respiratory and metabolic aspects. Thus our results highlight the importance of considering IR as a potential risk factor for sleep apnea and suggest the possibility of pulmonary IR in situ.

CONFLICTS OF INTEREST

None declared.

AUTHOR CONTRIBUTIONS

LJOA: conceptualization; investigation; methodology; and writing - original draft. GCMO: conceptualization; investigation; methodology; writing - review and editing. AMVB: formal analysis; and writing - review and editing. GMB: conceptualization; methodology; supervision; writing - review and editing. LMO: conceptualization; investigation; methodology; and writing - original draft.

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Table 1 is available in the Supplementary Files section.

Graphs 1 and 2 are available in the Supplementary Files section

The authors declare no competing interests.

Table1.png
GRAPH1.png
Graph 1. Absolute Epworth
GRAPH2.png
Graph 2. Apnea-hypopnea index.

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Pulmonary Insulin Resistance – The Lung as a Metabolic Organ: Investigating the Correlation between Insulin Resistance and Sleep Apnea

Status:

Version 1

Abstract

INTRODUCTION

MATERIALS AND METHODS

Study Design and Participants:

Clinical and Laboratory Assessments:

Assessment of Insulin Resistance

Overnight Polysomnography Assessment

Spirometry

Statistical Analysis

Ethical Considerations

RESULTS

DISCUSSION

CONCLUSION

Declarations

CONFLICTS OF INTEREST

AUTHOR CONTRIBUTIONS

References

Tables

Graphs

Additional Declarations

Supplementary Files

Status:

Version 1