Chronic lung disease affects hundreds of millions of people worldwide and ranks as the third leading cause of death globally, following cardiovascular disease and cancer (1). Common lung diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and bronchiectasis, often lead to significant changes in lung function, particularly resulting in airflow obstruction (2, 3). This obstruction is typically identified through lung function testing conducted after administering a bronchodilator, characterized by a reduced ratio of forced expiratory volume in one second to forced vital capacity (FEV1/FVC). In contrast, non-obstructive lung function abnormalities, commonly referred to as restrictive lung disease, are marked by a symmetric reduction in both FEV1 and FVC (4).

However, preserved ratio impaired lung function (PRISm) is a relatively underexplored lung disease that is characterized by a decrease in FVC while the ratio of forced expiratory volume in one second to forced vital capacity FEV1/FVC remains within the normal range, with the global prevalence of PRISm estimated to be between 6.6% and 17.6% (5). Although PRISm has historically been viewed as a transitional state between normal lung function and COPD, retrospective studies have shown that only approximately 23% of individuals with PRISm progress to COPD (6). Some studies have shown that PRISm is significantly associated with increased risks of mortality, as well as adverse cardiovascular and respiratory outcomes (4), and is linked to a higher prevalence of diabetes, heart disease, and hypertension among individuals with chronic diseases (7, 8). In contrast, PRISm has been independently linked to higher cardiovascular risk and increased mortality (9). It may represent a distinct clinical phenotype with unique pathophysiological and prognostic implications, rather than merely an early stage of obstructive lung disease (10).

Insulin resistance is a condition characterized by a diminished response to insulin, which results in decreased efficiency of glucose uptake and utilization, ultimately leading to metabolic abnormalities and serving as a significant risk factor for various metabolic disorders such as type 2 diabetes, hypertension, dyslipidemia, and obesity (11, 12). Recent research has highlighted the correlation between insulin resistance and pulmonary diseases, including impaired lung function and asthma, indicating that individuals with insulin resistance often experience compromised respiratory health, which suggests that metabolic dysregulation may exert both direct and indirect effects on lung function (13–15).

The concept of estimated glucose disposal rate (eGDR) has emerged as a valuable tool for assessing insulin sensitivity, particularly in individuals with diabetes. eGDR is derived from clinical parameters such as body mass index (BMI) and blood pressure, making it a useful surrogate marker for insulin resistance (16). Compared to other insulin resistance markers such as TyG, TyG-BMI, and METS-IR, recent studies have shown that eGDR has superior predictive ability for adverse cardiometabolic outcomes, including stroke and cardiovascular disease (17, 18). While the relationship between insulin resistance and various metabolic disorders has been extensively studied, research exploring the connection between insulin resistance and PRISm remains relatively scarce. These findings suggest that eGDR may also be a more effective indicator for identifying individuals at risk of PRISm, particularly in populations with metabolic disturbances. Therefore, we utilized the national health and nutrition examination surveys (NHANES) database to explore the association between eGDR and PRISm, aiming to further elucidate their potential link in metabolic health and lung function. We hypothesized that decreased insulin sensitivity, as reflected by lower eGDR, would be negatively associated with lung function and increase the likelihood of PRISm, thereby linking metabolic and respiratory health.

Preserved ratio impaired spirometry (PRISm) is a newly defined phenotype of lung function impairment, characterized by individuals exhibiting a normal FEV1/FVC ratio, while having an FEV1 less than 0.8 times the predicted value (5). Although PRISm shares some features with both obstructive and restrictive lung patterns, it is distinct in that it does not follow the typical patterns of either (10). PRISm is associated with various adverse clinical outcomes, such as increased respiratory symptoms, elevated comorbidity rates of hypertension and diabetes, and higher mortality rates (4, 7, 8). Furthermore, PRISm is a heterogeneous condition, with only a subset of individuals progressing to COPD, suggesting that PRISm may represent a unique clinical phenotype with its own pathophysiological and prognostic implications (6, 9). This study investigates the relationship between estimated glucose disposal rate (eGDR), an indicator of insulin resistance, and PRISm. Our results show that lower eGDR is significantly associated with an increased risk of PRISm, suggesting a negative relationship between insulin resistance and PRISm.

The baseline characteristics of participants further clarified the differences between the PRISm and non-PRISm groups. Notably, the PRISm group was older, had higher cotinine levels, lower eGFR, and a higher prevalence of cardiovascular diseases and obesity. While it is widely acknowledged that smoking impairs lung function, cotinine is specifically associated with reduced lung function and airflow obstruction (22). Additionally, Obesity, a recognized risk factor for both insulin resistance and respiratory diseases, increases airway resistance while simultaneously altering breathing patterns, thereby affecting ventilation and oxygenation (23); at the same time, the accumulation of visceral adipose tissue due to obesity is closely associated with a higher incidence of respiratory diseases (24). However, in the multivariable logistic regression analysis, eGDR remained significantly negatively correlated with PRISm even after fully adjusting for confounding factors such as sex, age, race, BMI, cotinine levels, liver and kidney function, cardiovascular disease, smoking, and alcohol consumption. This suggests that higher insulin sensitivity, as reflected by higher eGDR, is associated with a lower risk of developing PRISm, independent of these potential confounders.

In the multivariable logistic regression analysis, all models demonstrated a significant negative association between eGDR and PRISm. In both unadjusted and adjusted models, each unit increase in eGDR was associated with a 15.1% reduction in the likelihood of PRISm. This relationship persisted in the fully adjusted model, where even after accounting for potential confounders such as sex, age, ethnicity, BMI, cotinine levels, renal and hepatic function, cardiovascular disease, smoking, and alcohol consumption, each unit increase in eGDR was still linked to a 7.3% decrease in the likelihood of PRISm.

These findings suggest that higher eGDR levels, indicative of better insulin sensitivity, are associated with a lower risk of PRISm. This relationship may be partly explained by the characteristics of participants with moderate or severe insulin resistance, who often present with systemic inflammation—marked by elevated levels of white blood cells, neutrophils, and plasma interleukin-6—and dyslipidemia, characterized by high triglycerides and low HDL cholesterol. Insulin resistance is typically accompanied by chronic low-grade inflammation, which promotes the release of inflammatory mediators such as tumor necrosis factor-α and interleukin-6 (25, 26). These factors not only impair systemic metabolism but also directly affect lung tissue, leading to airway inflammation and structural remodeling, which contribute to airflow limitation and reduced lung function (27–29). Additionally, insulin resistance increases oxidative stress in the body, which refers to an imbalance between the production of free radicals and antioxidant defenses. Elevated levels of free radicals can damage cells, including lung cells, causing dysfunction and structural damage (30). This damage not only compromises airway patency but may also trigger an inflammatory response in the lungs, further exacerbating lung function impairment (31). Beyond systemic effects, insulin resistance may impair lung function via adipose tissue dysfunction, which promotes pro-inflammatory adipokines like resistin and reduces anti-inflammatory adiponectin (32, 33). Resistin is linked to asthma, COPD, fibrosis, and acute lung injury, while adiponectin suppresses pulmonary inflammation by inhibiting TNF-α, IL-6, and chemokine production (34, 35). These adipokine shifts may mediate the adverse impact of insulin resistance on lung health. Moreover, chronic hyperinsulinemia may also interfere with cellular repair and regeneration pathways in the lung, limiting the ability to recover from environmental or inflammatory insults (36).

Subgroup analyses in our study revealed that this association was more pronounced among females and individuals aged over 40 years. The stronger association in women may be attributable to differences in body fat distribution and hormonal regulation (37, 38). Sex-specific patterns in insulin resistance, influenced by sex steroid hormones, may partly explain this finding. Estrogens play a protective role in metabolic regulation, and their decline after menopause contributes to increased insulin resistance and diabetes risk (39). A Evidence from both human genetics and animal models has shown that disruption of estrogen signaling—such as through aromatase or estrogen receptor α deficiency—can lead to marked metabolic dysfunction (38). Moreover, estrogen, which has anti-inflammatory effects, may play a protective role in premenopausal women; with age-related hormonal changes, metabolic dysregulation may have a more deleterious impact on lung function (40). These findings suggest that insulin resistance may have a more pronounced impact on lung function in women due to hormone-related differences in insulin sensitivity and inflammation. In older adults, age-related skeletal muscle dysfunction—characterized by mitochondrial impairment, metabolic dysregulation, inflammation, and sarcopenia—leads to reduced insulin sensitivity and is a key mechanism underlying insulin resistance in the elderly (41). The synergistic effects of sarcopenia and insulin resistance can exacerbate systemic inflammation and oxidative stress, both of which are known to impair lung function (14, 42). Additionally, age-related declines in lung elasticity, respiratory muscle strength, and ventilatory responsiveness may render older adults more vulnerable to the adverse effects of metabolic abnormalities on pulmonary function (43). In contrast, no significant interaction was observed between eGDR and race or poverty-to-income ratio; however, notable associations were found within specific racial groups. Notably, significant associations between eGDR and PRISm were observed in Non-Hispanic Black and Mexican American participants. This finding aligns with prior studies indicating that both racial groups exhibit higher levels of insulin resistance and insulin secretion compared to non-Hispanic Whites. For instance, Haffner et al. reported that both Non-Hispanic Black and Mexican American individuals showed significantly higher levels of insulin resistance than their non-Hispanic White counterparts (44). Similarly, Hasson et al. highlighted the heightened insulin resistance and upregulated beta-cell function in African Americans, potentially contributing to their elevated risk of metabolic diseases (45). These metabolic characteristics may also influence pulmonary outcomes, thereby partially explaining the higher prevalence of PRISm in these populations.

The non-linear relationship observed in the restricted cubic spline analysis indicates that while higher levels of eGDR are associated with a decreased likelihood of PRISm, this association tends to plateau once eGDR exceeds approximately 12 mg/kg/min. This suggests a potential threshold effect, beyond which further improvements in insulin sensitivity confer minimal additional benefit in reducing PRISm risk. Such a plateau is biologically plausible, as metabolic improvements may only translate to clinical benefits up to a certain point, after which risk stabilizes. Interventions targeting insulin resistance may therefore be particularly beneficial for individuals with lower baseline eGDR. Additionally, ROC curve analysis demonstrated that eGDR has a certain predictive accuracy in identifying PRISm, with an AUC of 0.626. Although the AUC indicates only limited discriminatory power, this result suggests that eGDR may be more suitable as a metabolic health risk indicator rather than a standalone diagnostic tool for PRISm. In future research or clinical practice, eGDR could be combined with other biomarkers—such as inflammatory markers, lung imaging parameters, or genetic risk scores—to enhance predictive performance and facilitate early identification of high-risk individuals.

Overall, our findings demonstrate that lower eGDR, indicating higher insulin resistance, is significantly associated with increased PRISm risk, independent of common confounders. This association is stronger in women and older adults, likely due to hormonal and age-related physiological changes. The observed threshold effect suggests that improving insulin sensitivity may be most beneficial in individuals with lower baseline eGDR. While eGDR alone has limited predictive power, it may serve as a useful metabolic marker when combined with other indicators to better identify individuals at risk for PRISm.

In conclusion, our study demonstrates a significant inverse association between estimated eGDR and PRISm among a diverse population of US adults. Participants with lower eGDR values exhibited a higher prevalence of PRISm, indicating greater insulin resistance and potential metabolic dysfunction. The findings suggest that eGDR may serve as a valuable marker for assessing the risk of PRISm, particularly among women and older adults. Given the growing recognition of the interplay between metabolic health and respiratory function, further research is warranted to elucidate the underlying mechanisms linking insulin resistance and pulmonary impairment.