Clinical Investigations

Pulmonary Function in Non-Insulin-Dependent Diabetes mellitus
Maurizio Marvisi^a, Lino Bartolini^a, Patrizia del Borrello^a, Marco Brianti^a, Giuseppe Marani^a, Achille Guariglia^a, Angelo Cuomo<sup>b

a</sup>Department of Internal Medicine, Cortemaggiore Hospital, Piacenza, and
^bDepartment of Respiratory Diseases, University of Parma, Italy

Address of Corresponding Author

Respiration 2001;68:268-272 (DOI: 10.1159/000050509)

 Outline

• Key Words
• Abstract
• Introduction
• Materials and Methods
• Statistical Methods
• Results
• Discussion
• References

• Author Contacts
• Article Information
• Publication Details
• Drug Dosage / Copyright

  Key Words

• Microangiopathy, diabetic renal
• Non-insulin-dependent diabetes mellitus
• Pulmonary function
• Pulmonary diffusion capacity

  Abstract

Background: In type I diabetes mellitus, lung function has been investigated in several clinical studies, but there are few data concerning pulmonary function abnormalities in patients with non-insulin-dependent diabetes mellitus (NIDDM). Objectives: The aim of this study was to assess the presence of pulmonary function abnormalities in patients with NIDDM and to verify the possible associations between diabetic renal microangiopathy, retinopathy and diabetes control. Method and Patients: Thirty patients with NIDDM were collected and divided into two similar groups: subjects with retinopathy and/or diabetic glomerulopathy (group 1, n = 15) and patients without any complications (group 2, n = 15). 17 were males and 13 females, aged from 45 to 81 years. They had had diabetes for 3-23 years and were studied at the Division of Internal Medicine, with an outpatient service for diabetic patients. All patients were non-smokers. The presence of diabetic glomerulopathy was determined by measuring the 24-hour protein excretion rate using the nephelometric method. The presence of retinopathy was determined by using ophthalmoscopy. Glycosylated hemoglobin was measured as an indicator of glycemic control. We performed a global spirometry and measured pulmonary diffusion capacity by the single-breath method corrected by alveolar volume. Results: We found a significant reduction in lung diffusion capacity for carbon monoxide (DL_CO) in the group of patients with other signs of diabetic microangiopathy (p < 0.005) and a significative correlation between DL_CO and the grade of albuminuria (r = -0.83, p < 0.001). Conclusions: Pulmonary function abnormalities, in particular a reduction in diffusion capacity, are common in patients with NIDDM and signs of diabetic microangiopathy. A possible explanation is related to an impaired pulmonary microvasculature and alveolar epithelial basal lamina.

Copyright © 2001 S. Karger AG, Basel

 introduction

Diabetes is a systemic disease that produces changes in the structure and function of several tissues, particularly connective tissues, with complications that affect the eyes, kidney, capillaries and nervous system. The pathogenesis of diabetic complications is still a matter of debate and is thought to involve both a microangiopathic process and non-enzymatic glycosylation of tissue proteins. This process results in impaired collagen and elastin cross-linkage with a reduction in strength and elasticity of connective tissue. The presence in the lung of an abundant connective tissue and an extensive microvascular circulation raises the possibility that lung may be a 'target organ' in diabetic patients [1].

In type 1 diabetes (IDDM), lung function has been investigated in several clinical studies. These studies evidenced reduced elastic recoil [2, 3], reduced lung volumes [2, 3, 4, 5], diminished respiratory muscle performance [6], a reduction in the transfer coefficient (KCO) [7, 8], an association between a reduction in total lung capacity and higher KCO in young patients (less than 35 years) [4] and above all a decrease in pulmonary diffusion capacity for carbon monoxide (DL_CO) [2, 4, 5, 8, 9]. Autopsy findings in human diabetics have demonstrated the presence of a thickened alveolar epithelial and pulmonary capillary basal lamina [10, 11, 12]. On the other hand, Minette et al. [13] found a normal transfer factor, transfer coefficient, oxygen consumption and arterial blood gases in 10 insulin-dependent patients. The data were collected at rest and during two levels of submaximal exercises [13]. In the English literature, there are very few data concerning pulmonary function abnormalities in patients with type 2 diabetes mellitus (NIDDM). In a recent article, Isotani et al. [14] investigated the change in pulmonary diffusion capacity in 54 Japanese NIDDM patients. The authors found a significative reduction in DL_CO in patients with proliferative retinopathy [14]. The aim of this study was to assess the presence of pulmonary complications in patients with NIDDM and the possible correlations between diabetic renal microangiopathy, retinopathy, age and diabetes control.

 materials and methods

We studied 30 patients with NIDDM (17 males and 13 females), aged from 45 to 81 years, mean age 64.10 ± 9.50 (±SD), who had had diabetes between 3 and 23 years (mean 11.27 ± 5.21). There was no evidence of connective tissue diseases and previous lung diseases. All patients were non-smokers, were treated with sulfonylureas, metformin, antihypertensive drugs, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors and had a body mass index <30 kg/m² (table 1).

Table 1. Characteristics of the study groups

All subjects had an insignificant occupational history. We excluded the presence of pulmonary, cardiac and renal diseases performing a chest X-ray, flow-volume spirometry, transthoracic Doppler echocardiography (SIM 7000, Challenger, Esaote Biomedica, Florence, Italy) and an evaluation of creatinine clearance. Glycosylated hemoglobin (HbA1c) was measured as an indicator of glycemic control, using high-performance liquid chromatography. We measured the level of hemoglobin in all patients because of its influence on the DL_CO/alveolar volume (VA) value. The presence of retinopathy was determined by using ophthalmoscopy, performed by the same expert ophthalmologist; the disease was graded as follows: 0 = none; 1 = increased capillary permeability, capillary closure and dilatation, microaneurysms; 2 = dilatated veins, arteriovenous shunts; 3 = hemorrhages (dot and blot), hard exudates; 4 = new vessels, scars; 5 = vitreohemorrhage and retinal detachment. The presence of diabetic glomerulopathy was determined by measuring the 24-hour protein excretion rate (microalbuminuria) and using the nephelometric method; an albumin excretion rate >30 mg/24 h was considered abnormal [15]. We performed a global spirometry in all patients using a dry wedge spirometer (Vitalograph); lung volumes were determined by a closed circuit helium dilution technique, DL_CO was measured by a single-breath method and corrected by alveolar volume (VA), using a Morgan Transfert machine model C [16]. We divided the patients into two equal groups: group 1 (n = 15), subjects with diabetic microangiopathy (diabetic glomerulopathy with or without retinopathy; table 2) and group 2 (n = 15), subjects without complications; the groups were matched for age and duration of diabetes (table 1). All patients gave written informed consent after the purpose of the study had been explained.

Table 2. Characteristics of the patients (group 1, n = 15)

 statistical methods

All data are expressed as means ± SD. Statistical comparisons were made using Student's t test and the Mann-Whitney U test for non-parametric data. The correlations between spirometric data and microalbuminuria, grade of retinopathy, HbA1c and age were made with Spearman's rank sum test. p < 0.05 was chosen as the value indicating significance. (GraphPad Software, San Diego, Calif., USA).

 results

We found a significant reduction of DL_CO in patients with microalbuminuria and/or retinopathy (T = 309.0; Z = 3.153; p = 0.002), but we found no variation between the two groups in other spirometric parameters like total lung capacity (Z = 1.037; p = 0.300), forced vital capacity (Z = 0.809; p = 0.419), forced expiratory volume at the 1st second (Z = 0.851; p = 0.395), residual volume (Z = 0.290; p = 0.771) and DL_CO/VA (Z = 0.581; p = 0.561; table 1). There was a significative correlation between DL_CO and the grade of albuminuria (R = -0.83, p < 0.001; fig. 1) and a weak but nonsignificant correlation between DL_CO and the grade of retinopathy (p = 0.067). We found no correlation between DL_CO, age and diabetic control expressed as glycosylated hemoglobin (table 3).

Table 3. Correlations with DLCO in group 1 patients

Fig. 1. Correlation between DLCO and albuminuria in group 1. n = 15, r = -0.83, p < 0.001.

 discussion

Diabetes is a systemic disease that involves the lung as well as the kidney, eyes and nerves. In fact, the presence of an extensive pulmonary microvascular circulation and abundant connective tissue raises the possibility that the lung may be a target organ of the pathologic processes induced by chronic hyperglycemia. Many authors described a thickening of alveolar epithelial and pulmonary capillary basal lamina in human subjects with IDDM; others found ultrastructural changes in pneumocytes, bronchiolar epithelium and connective tissue proteins in rats with streptozotocin-induced diabetes [17]. Recently, Fuso et al. [18] demonstrated, measuring postural variation of DL_CO and capillary blood volume, that in IDDM patients there is no significant increase in DL_CO in supine position; Ljubic et al. [19] found a significative correlation between DL_CO/VA reduction and the grade of proteinuria. To our knowledge, recently, the only report regarding NIDDM has been published by Isotani et al. [14]. The authors found a significant reduction in DL_CO/VA (p < 0.05) in diabetic patients. The percentage of reduction was significantly (p < 0.05 ) lower in subjects with proliferative retinopathy than in patients with simple diabetic retinopathy [14]. Our study confirms the data obtained by Isotani [14] and other authors studying patients with IDDM: abnormalities of lung functions are common in NIDDM. In our small patient cohort, the only alteration was a reduction in DL_CO, with normal DL_CO/VA and total lung capacity that was common in subjects with other signs of diabetic microangiopathy, in particular albuminuria and was not correlated with age and diabetic control. We found a correlation between DL_CO reduction and the grade of albuminuria, but there was no significant correlation between DL_CO (and DL_CO/VA) and the grade of retinopathy; which may be ascribed to the low incidence of retinopathy in our patient cohort (only 1 patient had grade 5 and 4 patients had no sign of retinopathy). On the other hand, Isotani et al. [14] studied Japanese patients, and the incidence of complications is influenced by the genetic background. The normality of DL_CO/VA seems to exclude that a reduction in pulmonary capillary blood volume is the cause of the reduction in diffusion capacity. A possible explanation may be the impaired pulmonary microvasculature and/or alveolar epithelial basal lamina, but other causes such as a modification of surfactant and its actions and an altered affinity of glycosylated hemoglobin for carbon monoxide may play a relevant role [4, 20]. Some authors postulated that the thickened alveolar interstitium may be a reflection of the increase in lysyl oxidase activity, an enzyme that plays a major role in connective tissue formation and whose activity has been shown to have increased in rats with experimentally induced diabetes 2. It might be possible that further histological studies on pulmonary microvasculature and compliance measurements of the lung would give more informations about the reasons for reduced DL_CO values. At this point the following questions still need to be addressed. What is the significance of subclinical pulmonary dysfunctions in terms of the development of pulmonary disease? Can this mild reduction in diffusion capacity at rest impair exercise tolerance?

  References

1.

Sandler M: Is the lung a target organ in diabetes mellitus? Arch Intern Med 1990;150:1385-1388. 

2.

Sandler M, Bunn AE, Stewart RI: Cross-section study of pulmonary function in patients with insulin dependent diabetes mellitus. Am Rev Respir Dis 1987;135:223-229. 

3.

Schuyler MR, Niewoehner DE, Inkley SR, et al: Abnormal lung elasticity in juvenile diabetes mellitus. Am Rev Respir Dis 1976;113:37-41. 

4.

Cooper BG, Taylor R, Alberti GMM, et al: Lung function in patients with diabetes mellitus. Respir Med 1990;84:235-239. 

5.

Maccioni FJ, Colebatch HJH: Lung volume and distensibility in insulin dependent diabetes mellitus. Am Rev Respir Dis 1991;143:1253-1256. 

6.

Wanke T, Formanek D, Auinger M, et al: Inspiratory muscle performance and pulmonary function changes in IDDM. Am Rev Respir Dis 1991;143:97-100. 

7.

Oulhen P, Barthelemy L, Bellet-Barthas M, et al: Respiratory function study on insulin dependent diabetics. Rev Fr Mal Respir 1982;10:213-224. 

8.

Weir DC, Jennings PE, Hendy MS, et al: Transfer factor for carbon monoxide in patients with diabetes with and without microangiopathy. Thorax 1988;43:725-726. 

9.

Strojek K, Ziora D, Sroczynski JW, et al: Pulmonary complications of type 1 diabetic patients. Diabetologia 1992,35:1173-1176.

10.

Vracko R, Thorning D, Huang TW: Basal lamina of alveolar epithelial and capillaries. Quantitative changes with aging and diabetes mellitus. Am Rev Respir Dis 1979;120:973-983. 

11.

Kodolova IM, Lysenco LV, Saltykov BB: Changes in the lung in diabetes mellitus. Arkh Patol 1982;44:35-40.

12.

Weynand B, Jonckheere A, Frans A, et al: Diabetes mellitus induces a thickening of the pulmonary basal lamina. Respiration 1999;66:14-19. 

13.

Minette Ph, Buysschaert M, Rahier J, et al: Pulmonary gas exchange in life-long nonsmoking patients with diabetes mellitus. Respiration 1999;66:20-24. 

14.

Isotani H, Nakamura Y, Kameoka K, Tanaka K, Furukawa K, Kitaoka H, Ohsawa N: Pulmonary diffusion capacity, serum angiotensin-converting enzyme activity and the angiotensin-converting enzyme gene in Japanese non-insulin dependent diabetes mellitus patients. Diabetes Res Clin Pract 1999;43:173-177. 

15.

Chukwuna C: Type 2 diabetes nephropathy in perspective. J Diabetes Complications 1995;9:55-67. 

16.

American Thoracic Society: Single breath carbon monoxide diffusing capacity (transfer factor). Recommendation for a standard technique. Am Rev Respir Dis 1987;136:1299-1307. 

17.

Ofulue F, Thurlbeck MW: Experimental diabetes and the lung. Am Rev Respir Dis 1988;138:284-289. 

18.

Fuso L, Cotroneo P, Basso S, et al: Postural variations of pulmonary diffusion capacity in insulin dependent diabetes mellitus. Chest 1996; 110:1009-1013. 

19.

Ljubic S, Metelko Z, Car N, et al:. Reduction of diffusion capacity for carbon monoxide in diabetic patients. Chest 1998;114:1033-1035. 

20.

Lipscomb DJ, Patel K, Hughes JMB: Interpretation of increase in the transfer factor coefficient for carbon monoxide (DL_CO/VA or KCO). Thorax 1978;33:728-733. 

  Author Contacts

M. Marvisi
Cortemaggiore Hospital, Via Libertà 6
I-29100 Piacenza (Italy)
Tel. +39 0523 832811, Fax +39 0523 832860, E-Mail mmarvis@tin.it

  Article Information

Presented in part at the Annual Congress of the European Respiratory Society, Barcelona (Spain), 1995.

Received: Received: December 20, 1999
Accepted: September 30, 2000
Number of Print Pages : 5
Number of Figures : 1, Number of Tables : 3, Number of References : 20

  Publication Details

Respiration (International Review of Thoracic Diseases)
Founded 1944 as 'Schweizerische Zeitschrift für Tuberkulose und Pneumonologie' by E. Bachmann, M. Gilbert, F. Häberlin, W. Löffler, P. Steiner and E. Uehlinger, continued 1962-1967 as 'Medicina Thoracalis'

Vol. 68, No. 3, Year 2001 (Cover Date: May-June 2001)

Journal Editor: C.T. Bolliger, Cape Town
ISSN: 0025-7931 (print), 1423-0356 (Online)

For additional information: http://www.karger.com/journals/res

  Drug Dosage / Copyright

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