In this population-based national cohort study, we identified associations between various degrees of hyperglycemia and specific respiratory symptoms, lung function, and all-cause mortality. Furthermore, we observed that factors such as gender, age, obesity, and hypertension did not significantly interact with the development of RLD in individuals with diabetes. Notably, this study stands as the largest and most comprehensive investigation of the relationship between lung health and the extent of hyperglycemia exposure, distinguishing itself from prior studies that primarily focused on the presence of diabetes with lung function.
Most studies investigating glycemia and lung function have overlooked the potential impact of MetS. It is well-established that impaired lung function is significantly linked with MetS, particularly factors like abdominal obesity, hypertension, high TG, and LDL-C(9). Furthermore, only a limited number of studies have explored the connection between blood glucose levels and aspects of lung health beyond spirometry-measured lung function, including pulmonary symptoms and long-term mortality. As such, this analysis, employing data from the Nhanes Large Sample Cohort Study, aimed to investigate the association between glycaemic status and overall lung health. This included an assessment of lung symptoms, lung function, and long-term prognosis, with a comprehensive adjustment for confounding factors, offering fresh insights into this domain.
In recent years, with the expanding body of research on the potential impact of glucose on lung health, there has been a divergence of findings concerning the influence of glycaemic control on lung function. A meta-analysis of 93 studies revealed that inadequate glycemic control was linked to diminished lung function in diabetic patients [17]. Intriguingly, Zhang et al [12]. recently identified an L-shaped association between glucose levels and lung function in an analysis of 8,584 subjects. This study showed a negative correlation between HbA1c and FEV1 in diabetic patients with good glycemic control but not in those with poor glycemic control [12]. Consequently, there remains uncertainty surrounding the relationship between glycemic control and lung function. An L-shaped correlation between glycated hemoglobin and exertional dyspnea, FEV1, and FVC is affirmed by our findings. The observation aligns with Zhang et al.'s research, emphasizing a non-linear relationship between glucose levels and quantitative lung function indices. The potential factors contributing to this observation include: Hyperglycemia-induced microvascular and macrovascular damage in diabetes mellitus can heighten patients' vulnerability to the onset and progression of pulmonary hypertension, potentially impacting their long-term prognosis and survival [18]. Furthermore, the accumulation of Advanced Glycation End products (AGE) in the lungs due to hyperglycemia can elevate oxidative stress levels in the pulmonary system, potentially resulting in pulmonary fibrosis [19], which manifests itself clinically in the onset of symptoms of Exertional dyspnea and restrictive ventilatory dysfunction. Deteriorations in quantitative lung function indices, such as FEV1 and FVC, serve as early indicators of lung injury. These changes are particularly sensitive to the effects of hyperglycemia, insulin resistance, low-grade inflammatory response, and obesity [12]. However, with the long-term harmful effects of hyperglycemia, the further deterioration of lung function tends to progress toward ventilatory dysfunction. At this stage, the decline in quantitative lung function indices becomes more gradual. Nevertheless, contrary to the findings of Zhang et al, our study demonstrates that blood glucose maintains a weak negative correlation with lung function parameters in poorly controlled diabetic patients. This discrepancy may be attributed to the more extensive adjustment for confounding factors related to the Mets in our study.
It is noteworthy that the results suggest for patients' long-term lung health, a higher risk of developing RLD in patients as glycemia worsens, particularly evident among diabetic patients with poor glycemic control. This aligns with prior research indicating an association between restrictive lung phenotypes and glucose metabolism in both diabetic and non-diabetic patients [6, 20]. This association can be mechanistically explained in several ways. Firstly, hyperglycemia might lead to RLD by reducing parenchymal compliance, as evidenced by decreased DLCO (diffusing capacity of the lungs for carbon monoxide) and DLCO/VA (DLCO corrected for alveolar volume) in spirometry [21]. This reduction could be attributed to factors such as insulin resistance, leptin resistance, leptin-induced inflammation, chronic low-grade inflammation, microvascular damage, pulmonary microangiopathy, non-enzymatic protein glycosylation in the extracellular matrix, and localized oxidative stress in lung endothelium [22, 23]. Secondly, diabetic patients often experience sympathetic dysfunction in bronchial innervation, leading to abnormal ventilatory responses to central and peripheral stimuli, thereby impairing autonomic ventilatory control [24, 25]. Additionally, recent studies have indicated that respiratory muscle disorders due to defective muscle metabolism or phrenic neuropathy can diminish lung capacity and hasten pulmonary restrictive complications in diabetic patients [26]. We divided the study population into groups based on patient demographics and medical histories to more thoroughly investigate the relationship between blood glucose levels and RLD. The connection between greater blood glucose levels and an increased risk of study outcomes persisted when possible confounders were taken into account, and it was unaffected by age, gender, weight, or hypertension. In addition, conventional risk factors combined with blood glucose improved predictive efficiency. Together, these findings imply that blood glucose levels might serve as both a prognostic indicator and a possible target for therapeutic interventions in the future.
Diabetes mellitus is associated with higher mortality from a variety of diseases. Some studies have shown an association between diabetes and the risk of death from respiratory diseases such as chronic obstructive pulmonary disease (COPD), pneumonia, and acute respiratory distress syndrome (ARDS) [27, 28]. However, these studies did not stratify the status of glycemic control in diabetes, and in our results, we found that for individuals affected by RLD, having diabetes with inadequate glycemic control alone led to a notable 2.08-fold rise in all-cause mortality when compared to individuals with normal glucose metabolism. Sustained high blood glucose levels may alter inflammatory pathways associated with impaired lung function. Oxidative stress and non-enzymatic basing of proteins are recognized in the etiology of diabetic lung injury [29]. Therefore, patients with diabetes should pay more attention to the long-term prognostic impact of good long-term glycaemic control on respiratory disease in clinical and public health practice.
Furthermore, our study encompasses a comprehensive array of confounding variables, and the results obtained using the glycaemic classification group find support in the continuous model. Several limitations exist in this study. Firstly, these findings are observational and do not establish causality. Secondly, since the NHANES study stands for the National Health and Nutrition Examination Survey, the number of patients with diabetes mellitus combined with RLD observed to have experienced a mortality outcome during the follow-up period was limited, which may need to be validated in a larger population-based study in the future. Although a large number of covariates were included in the multivariate adjustment in the study, unknown confounders from unmeasured factors could not be completely excluded.