Airways disease, obesity, and the metabolic syndrome

Introduction Obesity and insulin resistance are common problems and are associated with reductions in lung function, although the mechanisms remain poorly understood. These conditions may also be linked to the development of asthma and chronic obstructive pulmonary disease (COPD); however, the effect of obesity on spirometry can make it difficult to diagnose coexisting airways disease. Some evidence suggests that the impairment of lung function associated with insulin resistance may be partly reversible with treatment. Aims 1. To compare the goodness of fit of weight-inclusive versus standard (non weight-inclusive) spirometric predictive equations in a healthy reference sample. 2. To examine the accuracy of standard and weight-inclusive spirometric equations in the diagnosis of airflow obstruction among symptomatic obese subjects. 3. To explore the associations between airflow obstruction, obesity, insulin resistance and metabolic syndrome in non-smokers with COPD. 4. To prospectively evaluate the effect of an insulin-sensitising medication (metformin) on respiratory function in patients with COPD and insulin resistance. Methods Data from a reference sample of healthy nonsmoking participants in the Third National Health and Nutrition Examination were used to develop weight-inclusive spirometric predictive equations. These equations were externally validated using a similar healthy reference sample from the Diabetes, Heart and Health Study (DHAH). The goodness of fit of these equations was compared with other published spirometric equations. Spriometry from a subset of healthy Polynesian participants in DHAH was used to develop Polynesian-specific spirometric reference equations. Pulmonary function test and computed tomography results were obtained from 94 obese adults referred to a tertiary pulmonary function laboratory for respiratory symptoms. The diagnostic accuracy of several weight-inclusive and non-weight-inclusive spirometric equations was assessed in the setting of obesity. 45 smokers and 48 nonsmokers with COPD were recruited from specialist outpatient clinics and primary care. Participants completed a questionnaire and interview and underwent venesection, exhaled nitric oxide measurement, skinprick testing, lung function testing, and computed tomography. Results were compared between groups. Nonsmokers with asthma were also compared with a third group of adults with asthma and normal lung function, recruited from primary care. 19 overweight adults with COPD and abnormal glucose homoeostasis were recruited from specialist clinics. Subjects took oral metformin for 6 months. At the beginning and end of the study, subjects underwent lung function testing and incremental shuttle walk testing, and completed questionnaires on quality of life, symptom severity and physical activity. Results In NHANES III, weight and BMI correlated negatively with both FEV1 and FVC. Spirometric equations were derived that included weight or indices of central obesity. However, neither they nor other published weight-inclusive equation sets exhibited better superior goodness of fit than standard equations. All the European-derived equation sets overestimated FVC among healthy Polynesian adults. A new set of Polynesian-specific reference equations was derived, which included body weight as an input variable. These equations exhibited superior goodness of fit compared to European-derived equations. In the examination of lung function laboratory data, prevalence of airflow obstruction among obese subjects was unrelated to weight. All spirometric models performed better than static lung volumes or subjective CT scores in diagnosing gold-standard-defined AFO. Weight-inclusive spirometric models were neither more likely to diagnose AFO, nor more accurate in diagnosing AFO, than weight-exclusive models. Asthma was very common among nonsmokers and was the commonest identificable cause of COPD in that group. Nonsmokers reported a similar respiratory symptom burden to smokers despite less severe obstruction. Nonsmokers’ HRCT results showed functional small airways disease, with no significant emphysema. Previously undiagnosed bronchiectasis was common in both groups (31% and 42%). Asthmatic nonsmokers with COPD exhibited greater evidence of systemic inflammation, abnormal glucose homoeostasis, and central obesity compared to subjects without COPD. Metabolic syndrome prevalence was similar between groups. Six months of regular metformin use among overweight subjects with COPD and glucose intolerance was associated with an increase in inspiratory muscle strength, and improvements in dyspnoea and quality of life. Conclusions Metabolic syndrome prevalence did not emerge as a risk factor for COPD. However, among asthmatic nonsmokers, those with COPD showed greater evidence of abnormal glucose homoeostasis and central obesity. “Metabolic syndrome” may be insufficiently specific as a marker of insulin resistance. There was no evidence that inclusion of body weight improved the goodness of fit or diagnostic accuracy of spirometric equations among Europeans. While body weight influenced spirometric lung volumes, its influence was much weaker than the effects of height, age or sex. ii In contrast, body weight improved goodness of fit of predictive equations among Polynesians. The fit of existing European-derived equations was poor in this group. The equations presented here should be externally validated and considered for clinical use. Metformin use was associated with improvements in some physiological and clinical parameters, though lung volumes were unaffected. Insulin sensitisation in COPD needs to be examined in a larger randomised trial.