The diabetic lung: impact of diabetes and obesity on lung health (IDOL)

Abstract

Type 2 diabetes (T2DM) is a chronic metabolic disorder that causes systemic effects. Microvascular and macrovascular secondary complications are frequent and cause increasing mortality and morbidity. Diabetic pneumopathy, or the ˈdiabetic lungˈ, is rarely considered among the secondary complications of T2DM and primarily presents in a restrictive pattern. Restrictive lung diseases are diagnosed by a reduced forced vital capacity (<80%) and a normal forced expiratory volume in one second (FEV1)/FVC ratio (>0.7). Many chronic inflammatory lung diseases including asthma, chronic obstruction pulmonary disease (COPD) and chronic bronchitis are more frequently observed in people with T2DM compared with those who do not have diabetes. Despite this, and the proposal of several mechanisms explaining this association, lung function is not routinely monitored in T2DM. Added to this, the primary risk factor for T2DM development is obesity, which itself has been associated with pulmonary decline. Therefore, the aim of this thesis was to investigate if respiratory decline in people with T2DM is indeed being driven by hyperglycaemia or if obesity (in the form of body mass index (BMI)) within the T2DMpopulation is confounding this association.

A systematic review examining asthma and COPD risk in people with T2DM and/or obesity was undertaken. Data compiled from 109 studies showed that the pulmonary impairment in T2DMwas consistent with airways restriction but did not meet the clinical definition of restrictive lung disease. T2DM and living in the geographical continent of Asia, but not obesity, were independently associated with the risk of this lung decline. Furthermore, once COPD and asthma were established in the T2DM population, worsening glycaemia did not exacerbate the pulmonary damage in asthma and reduced only the FVC in COPD, suggesting that the impact ofT2DM on lung function is subject to limitation.

The UK Biobank is a biomedical project of 500,000 people within the UK which has been ongoing since 2006. It contains an extensive amount of clinical, medical and demographic data and therefore provides significant advantageous opportunities to examine healthcare related matters on a vast scale. In this thesis, information was extracted from the UK Biobank regarding lung function measurements, demographics, diabetes and lung disease status, BMI, smoking status and glycated haemoglobin (HbA1c) levels to examine the prevalent and incident risk of lung disease in the T2DM population and to elucidate proteomic signatures and biological pathways associated with these co-morbid conditions. Consistent with data from the systematic review, T2DM increased the odds of having a chronic inflammatory lung disease by 2-fold in some instances. Analysis of UK Biobank data suggested that obesity is a risk factor for lung decline in the absence of T2DM. However, once T2DM was established, lung function was significantly worse across all BMI categories in comparison to those who did not have T2DM. It was observed that once a diagnosis of a lung disease was present, T2DM further exacerbatedFEV1. However, T2DM exerts a finite impact on the FEV1/FVC ratio. T2DM, age, being a woman, a history of smoking, and reduced FEV1 and FEV1/FVC ratio, but not obesity, were also found to be risk factors for the development of lung disease in the UK Biobank population. Proteomic investigation revealed a protein signature of 256 proteins that were significantly different in theT2DM population with a lung disease compared to population controls and T2DM controls without an established lung disease. The protein signatures identified were subject to pathway analysis. Twenty-nine biological pathways associated with co-morbid lung disease in the T2DM population were identified.

To validate the UK Biobank findings and to isolate the direct impact of hyperglycaemia in lung cells, the IMR90 human lung fibroblast cell was grown under normal and high glucose conditions and RNA-sequencing undertaken. Differential expression analysis identified thirty-nine differentially expressed genes and subsequent pathway analysis on these genes identified three biological pathways associated with the high glucose environment. The endocytosis pathway was the only common overlapping pathway between the UK Biobank and IMR90 analyses, with dynamin (DNM1), insulin-like growth factor receptor 2 (IGF2R) and SRC Proto-Oncogene, Non Receptor Tyrosine Kinase (SRC) being the leading dysregulated genes within the endocytosis pathway. Endocytosis is a critical process in glucose metabolism. Disruption of this process may lead to reduced receptors on the cell surface and inadequate glucose uptake in the peripheral tissues.

Overall, this thesis provides insights into the risk of lung impairment and lung disease as a secondary complication of T2DM. The work has revealed a direct role for hyperglycaemia in lung decline that is independent of obesity. Recognition of this microvascular damage is vital and needs to be translated into the clinical setting, where monitoring of the lungs is likely needed for people with T2DM.

Thesis is embargoed until 28th February 2027

Date of Award	Feb 2025
Original language	English
Sponsors	Department for the Economy
Supervisor	Paula McClean (Supervisor), Catriona Kelly (Supervisor) & Priyank Shukla (Supervisor)