Prediabetes is associated with restrictive pattern of lung disease in otherwise asymptomatic adults: a cross-sectional study

Background: Very few studies have been conducted to study the effects of prediabetes on lung functions. Evidence suggests that prediabetes causes mechanical changes in the periphery of lungs which may have adverse affects on the lung functions. Material and methods: In this observational cross sectional study, 800 apparently healthy adult subjects were selected who underwent spirometry, fasting plasma glucose analysis and 2-h oral glucose tolerance test. Spirometric indices such as percent predicted values of forced vital capacity, forced expiratory volume in 1 second, and forced vital capacity/forced expiratory volume in 1 second were considered. Based on fasting plasma glucose and 2 hr oral glucose tolerance test the subjects were further divided into two groups, i.e. subjects with normal glucose levels and those with prediabetics. Results: It was observed that 400 (50%) subjects had normal glucose levels, 400 (50%) had prediabetes. Furthermore it was observed that as compared to the control group, forced vital capacity (% pred.) and forced expiratory volume in 1 second (% pred.) were significantly lower but forced vital capacity/forced expiratory volume in 1 second (% pred.) was significantly higher in prediabetes group. Conclusion: Based on the results of spirometry it may be concluded that restrictive lung pattern (low lung volume) may be in prediabetes itself before the development of type 2 diabetes mellitus.


Introduction
Prediabetes is a condition, which precedes diabetes mellitus, characterized by high blood glucose levels (100-125mg/ dl) than the normal (70-99mg/dl). However these high levels of blood glucose are not sufficient enough to meet the required criteria for a diagnosis of diabetes mellitus [1]. Prediabetes may be divided into impaired glucose tolerance (IGT) characterized by fasting blood glucose <126mg/dl or 2-h blood glucose levels in between 140 mg/dl to 200mg/dl and impaired fasting glucose (IFG) characterized by a fasting blood glucose level of 110mg/ dl-125mg/dl or 2-h blood glucose level of < 140 mg/dl. Both IFG and IGT are known risk factors for diabetes mellitus and both of them increase in prevalence with age [2,3]. The prevalence of prediabetes is increasing all over the world and it is estimated that >470 million people will have prediabetes by 2030 [3].
Because IFG and IGT vary among populations with different ethnic backgrounds, prevalence of prediabetes varies [4]. Prediabetes is asymptomatic and can often go undiagnosed for many years with a yearly conversion rate of 5-10% into full fledged diabetes mellitus [5]. IFG and IGT can occur as separate entities or they can occur simultaneously [6]. Some individuals may remain with prediabetes throughout their life and in some reversion from prediabetes to normoglycaemia may occur [7]. Literature suggests that in people with prediabetes, there is progressive impairment of insulin secretion or as worsening of insulin resistance which ultimately causes a gradual increase in fasting and post-prandial plasma glucose levels [8]. Decreased level of HDL cholesterol, increased level of LDL cholesterol, triglycerides and hypertension, are present more frequently among prediabetic individuals hence they are at a heightened risk of cardiovascular diseases [9]. Microvascular and macrovascular complications start during the toxic state of pre¬diabetes and much of the cardiovascular disease burden is already evident during prediabetes [10]. It is a known fact that elevated glucose levels damage endothelial cells, which can lead to microvascular disease [10]. There is data that suggests increased presence of restrictive lung disease (RLD) in prediabetes that is usually characterized by breathlessness [11]. These changes during prediabetes suggest that there are some mechanical changes in the periphery of lungs prior to effects on the pulmonary capillary bed which lead to a decreased forced vital capacity (FVC) in patients with prediabetes [12,13].
Thus, this study was conducted with the aim to see whether there was any impact on the lung function tests in recently diagnosed cases of prediabetes or not.

Material and methods
After getting clearance from the Institutional Ethical Committee, this cross sectional observational study was carried in the Department of Physiology Government Medical College & SMHS hospital, Srinagar, J&K, India from January 2019 to January 2020. In this study a total of 800 adult subjects participated. They were further divided into healthy controls who had normal blood glucose levels (400 subjects) and those who had prediabetes (400 subjects).
Exclusion criteria ■ Subjects aged < 18 years. ■ Subjects who could not perform the spirometry correctly.
■ Subjects having history of any obstructive or restrictive lung disease.
■ Subjects with a history of smoking. ■ Subjects previously diagnosed with type 1or type 2 diabetes mellitus.
■ Subjects who were pregnant. ■ Subjects with diseases or on drugs which affect blood glucose levels and lung function.

Study protocol
Anthropometric measurements: Written consent was taken from all the participants before the commencement of study. Weight of subjects was measured by a digital weighing scale (Omron-HN 289, Japan). Height was measured using a stadiometer in all the subjects. Body mass index (BMI) was calculated by Quetlet's index expressed as kg/m². BMI of 25kg/ m² or more was considered as overweight and 30kg/m² or more was considered as obesity [14].
Blood sugar levels: Fasting blood glucose (FBG) estimation and 2-h oral glucose tolerance test (OGTT) was done in all the subjects. Analysis of blood sugar levels of the samples was done using automated analyzer (Roche Hitachi 912, USA). Based on the results of FBG and 2-h OGTT and the criteria set by American Diabetes Association [15]  Isolated IFG, Isolated IGT and combined IFG & IGT were considered as subgroups of prediabetes [15].

Statistical analysis
Statistical analysis was done using GraphPad 7 (San Diego, CA, USA). All the anthropometric and biochemical data variables were expressed in terms of Mean±SD. Normality was checked by D'Agostino-Pearson test. Chi-square test was used for nominal data (gender). For comparing the anthropometric parameters between the two groups Student's unpaired t-test was used. Indices of spirometry between the controls and various subtypes of prediabetes were compared by ANOVA test. P value <0.05 was considered as statistically significant.

Results
A total of 800 subjects were selected for this study in which 400 (50%) were healthy controls whereas 400 (50%) were cases diagnosed with prediabetes. Furthermore 455 (57%) were males and 345 (43%) were females as shown in Table 1. There was no significant difference in age between the two groups however BMI of the case group was significantly higher than the control group as shown in Table 2. In this study it was observed that FVC (% pred.) and FEV1 (% pred.) were significantly lower where as FEV1/FVC (% pred.) was significantly higher in prediabetics (IFG, IGT & combination of both) as compared to the control group as shown in Table 3.

Discussion
Literature suggests that the number of prediabetics is increasing at an alarming pace which makes it a potential health hazard [4]. Prevalence of prediabetes is in varies considerably due to the various types of diagnostic criteria, population studied and selection of tests [17]. It has been seen that prediabetes progresses to overt T2DM in approximately 25% of prediabetics over a span of 3-5 years and almost 70% of prediabetics develop T2DM within their life span [18,19]. Prediabetes has been reported to reduce lung function but the exact mechanism by which it affects lung function is yet to be ascertained although it is postulated that there may be mechanical changes in the periphery of lungs due to hyperglycemia before the development of T2DM [12]. Prediabetes has a strong association with obesity. Study conducted by Rahmanian K et al [20] in a sample of 788 subjects, 360 men and 428 women, showed that subjects with prediabetes had higher BMI, p<0.05. In a cross sectional study conducted by Fernando GR et al [21], they observed that prevalence of obesity was 45.9% in prediabetes. Findings in our study were similar. In a cross sectional study by Sanchez E et al [22] lung function tests of about 3455 subjects were done out of which 1093 (31.6%) had prediabetes and 2362 subjects were taken as healthy controls. They observed that subjects with prediabetes showed a significantly lower FVC ( [23] in a cross-sectional study of 1237 subjects demonstrated that there is a significant association of restrictive pattern of lung disease in prediabetics. In another cross sectional study Yamane T et al [24] Distribution of subjects on the basis of gender.
Anthropometric measurements of controls vs cases.
Chi-square test for gender distribution; N: total number of subjects.
BMI: body mass index; kg: kilogram; m²: meter square Data expressed as Mean ± SD ᴥ: highly significant.  demonstrated that prediabetes was significantly associated with low % FVC. They observed that IGT subtype of prediabetes was associated with restrictive pattern of lung disease. Our findings were similar but we observed that both IGT and IFG were associated with restrictive pattern of lung disease.

Conclusion
Thus it may be concluded that prediabetes, in otherwise asymptomatic subjects, is significantly associated with restrictive pattern of lung disease. Thus, frequent monitoring of blood glucose levels especially in obese people, for timely diagnosis of prediabetes, is of paramount significance so that the complications related to prediabetes could be minimized which will ultimately increase the quality of life in prediabetics.
The main lacunae of this study are the scarcity of literature because fewer studies have been conducted to assess the lung function tests in prediabetes.

Disclosures:
There is no conflict of interest for all authors.