Nasal mucociliary clearance and nasal and oral pH in patients with insulin-dependent diabetes.

From the Department of Pediatrics, Faculty of Medicine, Ataturk University, Erzurum, Turkey (Dr. Mukadder Ayse Selimoglu); the Department of Otolaryngology, Faculty of Medicine, Ataturk University, Erzurum, Turkey (Dr. Erol Selimoglu); and the Department of Internal Medicine, Faculty of Medicine, Ataturk University, Erzurum, Turkey (Dr. Kurt).

Reprint requests: Dr. Mukadder Ayse Selimoglu, Ataturk Universitesi Tip Fakultesi, Cocuk Sagligi ve Hastaliklari Anabilim Dali, 25240 Erzurum, Turkey. Phone: [phone]; fax: [phone]; e-mail: [e-mail]

Abstract

We studied 32 patients with insulin-dependent diabetes mellitus to determine how their rate of mucociliary clearance and their levels of nasal and oral pH compared with those of 10 nondiabetic controls and how these rhinologic measurements varied within different subsets of diabetic patients. Although we found very few statistically significant differences in all our comparisons, we did find that nasal mucociliary clearance and oral pH levels in the diabetic patients were significantly different from those of healthy subjects.

Introduction

Patients with diabetes mellitus are susceptible to a number of complications that can lead to serious morbidity and mortality. Major long-term complications can affect the retinal, renal, neuronal, and vascular systems. [1] Among the less serious complications of diabetes are rhinologic problems, such as mucosal erosions, septal perforations, and susceptibility to infections. [2] To the best of our knowledge, no study of nasal mucociliary clearance (NMC) and nasal and oral pH levels in patients with diabetes mellitus has been reported previously.

The nasal mucosa is the first barrier in the tracheobronchial tree that potentially noxious particles must penetrate. Early studies of NMC were based on direct observation of dyes and particles deposited on nasal mucosa. [3] Later, a more simple and noninvasive method was perfected in which a particle of saccharin is deposited on the nasal mucosa while an examiner notes the length of time that passes before the subject reports the first taste of sweetness. [4]

The aim of this study was to detect whether any changes in NMC are associated with diabetes mellitus and to analyze any such alterations as they correlate to fasting blood glucose (FBG) levels, glycosylated hemoglobin ([HbA.sub.1c]) concentrations, the duration of diabetes, and the patient's age.

Materials and methods

We studied 32 nonsmoking patients, 15 males and 17 females, aged 7 to 65 (mean: 35), who had insulin-dependent diabetes mellitus. For comparison purposes, we recruited 10 healthy controls, aged 12 to 57 (mean: 33), who did not have diabetes mellitus. In addition to classifying subjects according to the presence or absence of diabetes, we also divided the diabetic patients into groups according to their FBG levels, [HbA.sub.1C] concentrations, duration of disease, and age. None of the subjects had an abnormal rhinologic examination. Ten of the diabetic patients had retinopathy, 5 had foot ulcer, 4 had nephropathy, 4 had hearing loss, 3 had atherosclerosis, and 1 had neuropathy. The study also included 10 healthy controls.

To measure the rate of NMC, a 1-mm diameter particle of saccharin was placed on the surface of the inferior turbinate at a point 1 to 1.5 cm behind the anterior nares of each sitting subject; subjects were asked to swallow once every 30 seconds and to inform the examiner when they could taste the sweetness of the saccharin. Nasal and oral pH were detected by indicator paper (Universal-Indikatorpapier, pH 1-10, Merck). For statistical analysis, we used the student's t test.

Results

The nondiabetic controls had a significantly more rapid mean NMC rate (7.19 mm/min) and a significantly higher mean oral pH level (6.45) than the diabetic patients (5.17 mm/min and 5.42, respectively; p[less than]0.05) (table 1). There was no statistically significant difference between the two groups with regard to the mean nasal pH level (7.10 and 7.06, respectively). Although the number of control subjects was small, their mean NMC rate was consistent with those of other studies in the literature; between 1969 and 1990, many investigators reported normal mean values between 5.3 and 9.0 mm/min (mean: 6.6). [5]

When diabetic patients were classified according to their FBG values, the only statistically significant difference detected was in the mean oral pH levels between the groups with the highest ([greater than]19.4 mmol/L) and lowest ([lesser than]11.1 mmol/L) FBG values (table 2). Those with the highest FBG had the lowest mean oral pH (5.20), and those with the lowest FBG had the highest oral pH (6.00).

There were no statistically significant differences in mean NMC rates and oral and nasal pH levels when the diabetic patients were classified according to their [Hba.sub.1c] levels, duration of disease, and age (tables 3-5).

Discussion

Nasal mucociliary transport efficiency depends primarily on two factors: the ciliary beating of the epithelial cells and the physical properties of mucus secreted by serous and mucous glands. [6'7] The first studies of mucociliary function took place during the 1830s. [5] They consisted mainly of direct visualization of the rate of movement of various substances that were applied to the mucosa. Today, electron microscopy and high-power, phase-contrast microscopy have improved the accuracy of detecting ciliary abnormalities. However, these techniques are invasive in that they require a biopsy of the respiratory mucosa. Among all the methods that are used to measure nasal transit time, the saccharin test has two major advantages: it is simple to perform and it does not require any sophisticated equipment.

Ciliated cells in the upper and lower respiratory tracts are exposed to the external environment, so they often come into contact with noxious elements and can harbor infection. Moreover, changes in the axoneme, basal bodies, and ciliary rootlets are associated with dyskinesia and mucostasis. [8]

Electron microscopy led to the discovery of the 9-plus-2 arrangement of internal fibrils in the cilia and the subsidiary components of the axoneme, which lent support to the "sliding fibril" hypothesis of ciliary bending. Electron microscopy in combination with improved biochemical techniques were used to demonstrate the localization of ATPase activity in dynein arms. [9] Dynein, an ATPase protein, uses ATP energy to perform the cyclical reshaping that produces active sliding movements. [8-10] In experimental models, the primacy of the polyol pathway in initiating neuropathy was proven by showing that the inhibition of aldol reductase prevents a reduction in tissue myoinositol content and a decrease in ATPase activity. [1]

The cause of the decrease in the NMC rate in patients with insulin-dependent diabetes mellitus is not known, but there is speculation that it may be attributable to the decrease in ATPase activity.

There is evidence of neural or hormonal control over mucus secretions in mammalian epithelia. Although there are indications that an increase in mucous load stimulates ciliary activity, there is no convincing evidence of any direct neural or hormonal control of ciliary beat-frequency. [9] Nerve stimulation produces mucus secretion, which in turn mechanically stimulates ciliary beating. One study reported that nerve stimulation produced a faster beat rate and an increase in amplitude ([greater than or equal to]10 sec); stimulation was accompanied by an increase in mucus secretion, which might accelerate ciliary action. [9] Poor stimulation due to neuropathy is probably responsible for the slower rate of NMC in patients with diabetes.

The possibility of differential control of the constituents of mucus suggests that mucus transport may be altered by changes in the constitution of mucus or by the amount of mucus that is secreted. Regulation of hydration by controlling pH and ionic concentrations may also alter the marking of the mucociliary escalator. [9] In patients with diabetes, the alteration of tissue pH probably affects the property of mucus and thus impairs mucus transport and ciliary activity.

In our study, diabetic patients did not have significantly lower levels of nasal pH than nondiabetic patients, but they did have significantly lower levels of oral pH. The difference between the levels of nasal and oral pH can probably be attributed to the actions of the buffer system in the nasal cavity. Yue reported that the nasal cavities of diabetic patients were more alkalinic than those of nondiabetic patients, but their oral pH was more acidic. [2]

Osmotic diuresis, with its resultant loss of water and electrolytes, may influence hydration and is therefore a likely cause of the slower rate of NMC in diabetic patients.

Respiratory airway mucus is a complex mixture of glycoproteins, proteoglycans, lipids, lesser quantities of other proteins, and sometimes DNA. About 80% of the molecular weight of glycoproteins is made up of oligosaccharides, which surround the polypeptide core and protect much of it from proteolysis. [9] As diabetes mellitus interferes with carbohydrate metabolism, alterations in the composition of the mucus may influence mucus transport. This may also result in the slower rate of NMC in diabetic patients. When we evaluated the relationship between pH levels and FBG concentrations, [HbA.sub.1c] levels, and the duration of the disease, we found that only oral pH levels were altered by diabetes. Oral pH levels were significantly lower in patients with high FBG levels. Oral pH was also lower (but not significantly so) in patients with high [HbA.sub.1c] concentrations and in patients who had had diabetes for more than 15 years. Nasal pH levels were independent of these parameters, possibly because of the protection offered by the nasal cavity's buffer system.

Conclusion

To determine whether the inhibition of NMC in diabetics is due to the short- or long-term effects of their disease, we compared NMC rates in patients whose duration of disease was less than 5 years with those whose duration was longer than 15 years. We also compared clearance rates among diabetics according to their FBG and [HbA.sub.1c].

Although the differences were not statistically significant, we did find that NMC rates were in fact slower in patients with higher levels of both FBG and [HbA.sub.1c] We also found that patients who had diabetes for less than 5 years had a slower rate of clearance than patients who had had diabetes for more than 15 years. We also compared NMC values in diabetic adults and children and found that age made no difference on saccharin transport, a finding that is similar to that reported by Sakakura et al. [11] Although these differences lack statistical power, we believe that the trends we observed point to the probability that the slower rate of NMC is due to two short-term effects of diabetes: hyperglycemia and osmotic diuresis, with the loss of water and electrolytes. The increase in the rate of NMC with the increasing duration of disease supports this probability.

The decrease in the rate of NMC in diabetic patients could be due to a decrease in ATPase activity, poor stimulation (due to neuropathy), osmotic diuresis (with its loss of water and electrolytes), and altered carbohydrate metabolism. Further studies on large series of patients are needed to confirm or refute these suspicions. We believe that the pathogenesis of this process will eventually become obvious as we gain experience with electron microscopic studies on patients with diabetes mellitus.

References

(1.) Foster DW. Diabetes mellitus. In: Wilson JD, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 12th ed. New York: McGraw-Hill Inc., 1991:1739-59.

(2.) Yue WL. Nasal mucociliary clearance in patients with diabetes mellitus. J Laryngol Otol 1989;103:853-5.

(3.) Puchelle E, Aug F, Pham QT, Bertrand A. Comparison of three methods for measuring nasal mucociliary clearance in man. Acta Otolaryngol (Stockh) 1981;91:297-303.

(4.) Kennedy DW, Zinreich SJ. Endoscopic sinus surgery. In: Paparella MM, Shumrick DA, Gluckman JL, Meyerhoff WL, eds. Otolaryngology. 3rd ed. Philadelphia: W.B. Saunders Co., 1991:1861-72.

(5.) Englender M, Chamovitz D, Harell M. Nasal transit time in normal subjects and pathologic conditions. Otolaryngol Head Neck Surg 1990;103:909-12.

(6.) Liote H, Zahm JM, Pierrot D, Puchelle E. Role of mucus and cilia in nasal mucociliary clearance in healthy subjects. Am Rev Respir Dis 1989;140:132-6.

(7.) Druce HM. Nasal physiology. Ear Nose Throat J 1986;65:201-5.

(8.) Ballenger JJ. Acquired ultrastructural alterations of respiratory cilia and clinical disease: A review. Ann Otol Rhinol Laryngol 1988;97:253-8.

(9.) Sleigh MA, Blake JR, Liron N. The propulsion of mucus by cilia. Am Rev Respir Dis 1988;137:726-41.

(10.) Parker GS, Mehlum DL, Bacher-Wetmore B. Ciliary dyskinesis: The immotile cilia syndrome. Laryngoscope 1983;93:573-7.

(11.) Sakakura Y, Ukai K, Majima Y, et al. Nasal mucociliary clearance under various conditions. Acta Otolaryngol (Stockh) 1983;96:167-73.

                Mean nasal mucociliary clearance rates and
             nasal and oral pH levels in diabetic patients and
                           nondiabetic controls

                       Diabetic                     Nondiabetic
                       Patients                      Controls
                        (n=32)                        (n=10)
NMC (mm/min) 5.17 [plus or minus] 1.98 [*] 7.19 [plus or minus] 2.30 [*]
Nasal pH     7.06 [plus or minus] 0.51     7.10 [plus or minus] 0.51
Oral pH      5.42 [plus or minus] 0.55 [*] 6.45 [plus or minus] 0.55 [*]


(*.)Statistically significant difference between diabetic patients and
controls (p [Less than] 0.05).
          Mean NMC rates and pH levels in the diabetic patients,
            classified by fasting blood glucose concentrations

                          FBG                         FBG
                [less than] 11.1 mmol/L        11.1-19.4 mmol/L
                         (n=8)                      (n=19)
NMC (mm/min)   5.96 [plus or minus] 2.50   4.83 [plus or minus] 1.68
Nasal pH       7.31 [plus or minus] 0.45   6.92 [plus or minus] 0.53
Oral pH      6.00 [plus or minus] 0.59 [*] 5.23 [plus or minus] 0.42


                          FBG
              [greater than] 19.4 mmol/L
                         (n=5)
NMC (mm/min)   5.25 [plus or minus] 2.20
Nasal pH       7.00 [plus or minus] 0.00
Oral pH      5.20 [plus or minus] 0.27 [*]


(*.)The only statistically significant difference was in the oral pH levels
between the group whose FBG levels were [less than]11.1 mmol/L and the
group whose FBG levels were [greater than]19.4 mmol/L (P [less than]0.05).
          Mean NMC rates and PH levels in the diabetic patients,
                   classified by glycosylated hemoglobin
                     ([HbA.sub.1c]) concentrations [*]

            [HbA.sub.1c] [less than]7%    [HBA.sub.1c] 7-12%
                      (n=7)                      (n=6)
NMC(mm/min) 5.76 [plus or minus] 2.20  6.22 [plus or minus] 1.59
Nasal pH    7.00 [plus or minus] 0.00  7.00 [plus or minus] 0.00
Oral pH     5.42 [plus or minus] 0.73  5.50 [plus or minus] 0.44


            [Hba.sub.1c] [greater than] 12%
                         (n=19)
NMC(mm/min)     4.63 [plus or minus] 1.91
Nasal pH        7.05 [plus or minus] 0.64
Oral pH         5.39 [plus or minus] 0.54


(*.)There were no statistically significant differences in any parameter
among the three groups.
               Mean NMC rates and pH levels in the diabetic
              patients, classified by duration of disease [*]

             Duration [less than]5 yr      Duration 5-15 yr
                     (n=21)                     (n=6)
NMC (mm/min) 5.06 [plus or minus] 2.14 5.37 [plus or minus] 2.25
Nasal pH     6.97 [plus or minus] 0.55 7.00 [plus or minus] 0.00
Oral pH      5.47 [plus or minus] 0.48 5.58 [plus or minus] 0.86


            Duration [greater than]15 yr
                       (n=5)
NMC (mm/min) 5.41 [plus or minus] 0.99
Nasal pH     7.30 [plus or minus] 0.44
Oral pH      5.00 [plus or minus] 0.00


(*.)There were no statistically significant differences in any parameter
among the three groups.
               Mean NMC rates and pH levels in the diabetic
                      patients, classified by age [*]


                    Age 7-15 yr              Age 16-65 yr
                      (n=l0)                    (n=22)
NMC (mm/min) 5.39 [plus or minus] 2.44 5.08 [plus or minus] 1.79
Nasal pH     7.10 [plus or minus] 0.31 7.00 [plus or minus] 0.55
Oral pH      5.60 [plus or minus] 0.51 5.34 [plus or minus] 0.56


(*.)There were no statistically significant differences in any parameter
between the two groups.