Chronic obstructive pulmonary disease and sleep: the interaction.

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death, affecting 14 millions adults in the United States. Symptoms related to sleep disturbances are common in individuals with moderate to severe COPD, particularly in the elderly, which is commonly manifested as morning fatigue and early awakenings. One major cause of morbidity in this population is abnormalities in gas exchange and resultant hypoxemia as they can lead to elevated pulmonary pressures, dyspnea and in severe cases right ventricular overload and failure. Sleep has profound adverse effects on respiration and gas exchange in patients with COPD. There are several mechanisms underlying nonapneic oxygen desaturation during sleep. They include decreased functional residual capacity, diminished ventilatory responses to hypoxia and hypercapnia, impaired respiratory mechanics, diminished arousal, respiratory muscle fatigue, diminished nonchemical respiratory drive, increased upper airway resistance, and the starting point of baseline saturation values while awake on the oxyhemoglobin dissociation curve. Smoking cessation, bronchodilation, inhaled steroids in those with a reversible component and pulmonary rehabilitation are corner stones of treatment of COPD. The goals of therapy for the clinician should be to improve lung mechanics as well as gas exchange ultimately leading to better sleep quality and health status.

Is sleep apnea a risk factor for stroke? A critical analysis.

Stroke is the 3rd leading cause of death and a major cause of serious long-term disability in the United States. There are several well established and modifiable risk factors for the development of stroke. These include arterial hypertension, cardiac disease, dyslipidemia, diabetes mellitus and smoking among others. Sleep apnea has been found at alarmingly high rates (>50%) in patients with acute stroke as well as after neurologic recovery leading some to speculate that sleep apnea had been present prior to stroke. Sleep apnea is highly prevalent in the general population with a frequency of 2% to 4%. Sleep apnea is associated with high incidence of obesity, coronary artery disease and hypertension. There are several hematologic and hemodynamic changes in sleep apnea that can play significant roles in the pathogenesis of stroke. In this review, the author provides a critical analysis of the association between sleep apnea and stroke. There is convincing evidence to believe that sleep apnea is a modifiable risk factor for stroke, however, prospective studies are needed to establish the cause-and-effect relationship. Stroke and sleep-related breathing disorders are both common and are associated with significant morbidity and mortality. Several recent large epidemiological studies have shown a strong association between these 2 disorders independent of known risk factors for stroke. Understanding the link between obstructive sleep apnea and stroke may provide a novel preventative and therapeutic approach in the management of stroke.

Randomised controlled trial of transcutaneous electrical muscle stimulation of the lower extremities in patients with chronic obstructive pulmonary disease.

BACKGROUND: Although exercise training improves exercise tolerance in most patients with chronic obstructive pulmonary disease (COPD), some patients with severe disease may not be able to tolerate exercise training due to incapacitating breathlessness. Transcutaneous electrical muscle stimulation (TCEMS) has been shown to improve muscle strength, muscle mass, and performance in paraplegics, patients with knee ligament injury, and patients with peripheral vascular disease. We hypothesised that TCEMS of the lower extremities can improve muscle strength and exercise tolerance in patients with moderate to severe COPD. METHODS: A randomised controlled trial of TCEMS of the lower extremities was performed in 18 medically stable patients of mean (SD) age 60.0 (1.5) years with a mean forced expiratory volume in 1 second (FEV(1)) of 1.03 (0.10) l (38% predicted) and residual volume/total lung capacity (RV/TLC) of 59 (2)%. Stimulation of the lower extremities was performed three times a week, 20 minutes each session, for six continuous weeks. Quadriceps and hamstring muscle strength, exercise capacity, and peak oxygen uptake were measured at baseline and after 6 weeks of stimulation. RESULTS: TCEMS improved both the quadriceps strength (by 39.0 (20.4)% v 9.0 (8.1)%, p=0.046) and hamstring muscle strength (by 33.9 (13.0)% v 2.9 (4.7)%, p=0.038) in the treated (n=9) and sham treated (n=9) groups, respectively. The improvement in muscle strength carried over to better performance in the shuttle walk test in the treated group (36.1% v 1.6% in the treated and sham groups respectively, p=0.007, Mann-Whitney U test). There was no significant change in lung function, peak workload, or peak oxygen consumption in either group. Muscle stimulation was well tolerated by the patients with no dropouts and better than 95% compliance with the protocol. CONCLUSIONS: TCEMS of peripheral muscles can be a useful adjunct to the comprehensive pulmonary rehabilitation of patients with COPD.

Gender differences in the expression of sleep-disordered breathing : role of upper airway dimensions.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is a common disorder that is characterized by repetitive episodes of upper airway narrowing and collapse. Obesity is a major risk factor for OSA. Compared with men, women have greater total body fat and are more obese, and yet the prevalence of OSA is much higher in men. The airway size and compliance and pharyngeal muscle tone are important determinants of upper airway patency during sleep. The discrepancy between greater frequency of obesity and lower prevalence of OSA in women has not been explained and suggests a different pathogenetic mechanism underlying this condition. Most clinical studies in OSA have either combined the sexes or have described results from men only. The object of this study was twofold: (1) to examine the effect of obesity on pharyngeal size in both men and women, and (2) to determine the role of upper airway dimensions in the expression of sleep-disordered breathing (SDB) and its relationship to gender. DESIGN: Prospective study of subjects referred for evaluation of SDB. SETTING: University-based sleep center. SUBJECTS: Seventy-eight male patients (mean +/- SE age, 49.2 +/- 1.5 years) and 52 female patients (mean age, 47.4 +/- 1.5 years). MEASUREMENTS AND RESULTS: All subjects underwent in-laboratory polysomnography with measurement of upper airway size using the acoustic reflectance method. Although the two groups were similar in age, the female patients were slightly heavier than the male patients (body mass index [BMI], 36.0 +/- 1.7 kg/m(2) vs 33.3 +/- 0.8 kg/m(2), respectively; p < 0.0001). Despite similar clinical presentation of snoring and excessive daytime sleepiness, women had mild OSA (respiratory disturbance index [RDI], 9.2 +/- 2.7 events per hour) or increased upper airway resistance syndrome compared with men with more severe OSA (RDI, 28.0 +/- 3.5 events per hour; p < 0.0001). In contrast, women had a significantly smaller oropharyngeal junction and pharynx than men (p < 0.02). Upper airway size correlated significantly with the severity of sleep apnea in men only. There was no correlation between BMI and pharyngeal size in either gender. CONCLUSIONS: This study demonstrates that the static properties of upper airway in awake men but not women correlate with the severity of sleep apnea. This suggests inherent structural and functional differences in upper airway during sleep between men and women with more favorable airway mechanics in women.

Sleep-related breathing disorders and risk of stroke.

BACKGROUND: Stroke and sleep-related breathing disorders are both common and are associated with significant morbidity and mortality. Several recent large epidemiological studies have shown a strong association between these 2 disorders independent of known risk factors for stroke. This article will outline the scientific basis for this relationship and suggest sleep-related breathing disorders as modifiable risk factors for stroke. SUMMARY OF REVIEW: Several studies have shown a characteristic circadian rhythmicity in stroke. We have discussed the influence of normal sleep states as well as the effect of sleep-related breathing disorders on cerebral hemodynamics. The hemodynamic, metabolic, and hematologic changes during sleep-related breathing disorders in the form of decreased cerebral perfusion and increased coagulability are possible pathogenetic mechanisms for stroke. There are accumulating lines of evidence that sleep apnea disorder may indeed cause diurnal hypertension. However, the increased risk of stroke in patients with sleep-related breathing disorders appears to be independent of coexisting hypertension; the presence of hypertension would increase the risk even further. Furthermore, several studies have documented high prevalence of sleep apnea disorders in patients with transient ischemic attacks and stroke. CONCLUSIONS: Sleep-related breathing disorder appears to contribute as a risk factor for stroke through hemodynamic and hematologic changes. Because of the high prevalence of sleep apnea disorder in this population, patients with transient ischemic attacks and stroke should undergo evaluation for these disorders.

Sleep-related breathing disorders and cardiovascular disease.

Sleep-related breathing disorders, ranging from habitual snoring to the increased upper airway resistance syndrome to sleep apnea, are now recognized as major health problems. The majority of patients have excessive daytime sleepiness and tiredness. Neuropsychological dysfunction results in poor work performance, memory impairment, and even depression. Until recently, the coexistence of cardiovascular and cerebrovascular diseases with sleep-related breathing disorders was thought to be the result of shared risk factors, such as age, sex, and obesity. However, in the past 5 years several epidemiologic studies have demonstrated that sleep-related breathing disorders are an independent risk factor for hypertension, probably resulting from a combination of intermittent hypoxia and hypercapnia, arousals, increased sympathetic tone, and altered baroreflex control during sleep. Sleep apnea may lead to the development of cardiomyopathy and pulmonary hypertension. Early recognition and treatment of sleep-related breathing disorders may improve cardiovascular function.

Nitric oxide production and absorption in trachea, bronchi, bronchioles, and respiratory bronchioles of humans.

Different volumes of dead-space gas were collected and analyzed for nitric oxide (NO) content, either immediately after inspiration or after a period of breath holding on clean air or NO mixtures. This allowed calculation of NO equilibrium, NO production, and NO absorption. In seven young, healthy, adult nonsmokers, the mean NO equilibrium values in parts per billion (ppb) were 56 +/- 11 (SE) in the trachea, 37 +/- 6 in the bronchi, 21 +/- 3 in the bronchioles, and 16 +/- 2 in the respiratory bronchioles. At any given NO concentration, the NO absorption rate (in nl/min) equaled the NO concentration (in ppb) times A (the absorption coefficient in l/min). A values (in l/min) were 0.11 +/- 0.01 in the trachea, 0.17 +/- 0. 04 in the bronchi, 0.66 +/- 0.09 in the bronchioles, and 1.35 +/- 0. 32 in the respiratory bronchioles. NO equilibrium concentrations and production rates in one 74-yr-old subject were three to five times as high as those found in the young subjects. Mouth equilibrium NO concentrations were 3 and 6 parts per million in two subjects who had oral production rates of 6 and 23 nl/min, respectively. In conclusion, production and absorption of NO occur throughout the first 450 ml of the airways.

Quality of life in patients with obstructive sleep apnea: effect of nasal continuous positive airway pressure--a prospective study.

BACKGROUND: Obstructive sleep apnea (OSA) is a common condition and is associated with excessive daytime sleepiness and neuropsychological dysfunction. There is limited evidence on the effect of OSA on the quality of life and its response to nasal continuous positive airway pressure (nCPAP) treatment. STUDY OBJECTIVE: To determine the effect of nCPAP on the quality of life in patients with OSA. DESIGN: Prospective determination of nCPAP effect in a case-series analysis. PATIENTS: We studied 29 patients (23 were male and 6 were female) with a mean (+/-SE) age of 4.4+/-2.3 years, a body mass index 36.3+/-2.0 kg/height (m)2, and a diagnosis of OSA with respiratory disturbance index (RDI; apnea/hypopnea) of 77+/-9 events/h. MEASUREMENTS AND RESULTS: The quality of life was assessed by administering a Medical Outcomes Study Short Form-36 questionnaire before and after 8 weeks of nCPAP therapy in polysomnographically documented OSA. All dimensions of the quality of life were significantly impaired when compared with an age- and gender-matched population, expressed as a percentage of normative data: physical functioning, 75%; vitality, 41%; role functioning (physical, 54%; emotional, 61%; social, 66%); general health, 88%; and mental health, 76%. nCPAP therapy significantly improved the sleep-disordered breathing and sleep fragmentation. The nCPAP level for the group was 9.4+/-0.7 cm H2O. Eight weeks of nCPAP therapy improved vitality (75%), social functioning (90%), and mental health (96%). The magnitude of improvement was related to the degree of quality of life impairment prior to treatment, rather than to the severity of disease as measured by the RDI and arousal indices. CONCLUSIONS: All aspects of the quality of life, from physical and emotional health to social functioning, are markedly impaired by OSA. nCPAP therapy improved those aspects related to vitality, social functioning, and mental health.

Production and absorption of nitric oxide gas in the nose.

Some nitric oxide gas (NO) produced in the sinuses and nasal cavity is absorbed before leaving the nose. To measure production and absorption, we introduced NO at different concentrations into one nostril while sampling the NO leaving the opposite nostril with the soft palate closed. The quantity of NO gas produced in six normal subjects (amount leaving plus the amount absorbed) averaged 352 nl/min and was the same at gas flows ranging from 8 to 347 ml/min and at 10 l/min. An absorption coefficient A was calculated by dividing the amount of NO absorbed by the concentration leaving the nose. A ranged from 17 ml/min at a nasal gas flow of 8 ml/min to an A of 24 ml/min at a nasal gas flow of 347 ml/min. The calculated rates of production and absorption did not change when gas flow rate was increased, suggesting diffusion equilibrium. The amount of uptake of NO in the nasal mucosa can be explained by its solubility coupled with tissue and blood reactivity.

Sleep in asthma.

The nocturnal worsening of asthma is a major cause of morbidity and mortality from this disease. The physiologic changes that occur during normal sleep can have adverse effects on breathing patterns, arousal responses, and airway clearance in asthmatics. Understanding of these alterations in airway mechanics and airway inflammation may lead to better management of this disease.

Guillain-Barré syndrome: rehabilitation outcome and recent developments.

Guillain-Barré syndrome is the most common polyneuropathy causing major disability and respiratory failure. Respiratory complications are the main cause of death. Improved respiratory care and new treatment strategies such as plasmaphoresis and immunoglobulin have been shown to improve outcome. We studied the course and outcome of 37 patients with Guillain-Barré syndrome who were admitted to a rehabilitation and respiratory care facility over a 10-year period. There were 21 males and 16 females with a mean age of 62+/-3 years. Fourteen patients developed respiratory failure requiring endotracheal intubation and mechanical ventilation. The mean duration of mechanical ventilation was 38+/-10 days. All patients were successfully liberated from the ventilator. However, 83 percent of the patients were moderately to severely disabled at the time of discharge. Thirteen out of 37 (35 percent) developed long-term disability. None of the patients died over the period of follow-up. These results indicate that early recognition and treatment of respiratory complications in Guillain-Barré syndrome could reduce the morbidity and mortality of this condition.

Adaptation of lung antioxidants to cigarette smoking in humans.

We investigated the effect of free radical scavengers, micronutrient antioxidants, on antioxidant enzyme activities in cigarette smokers. We measured the intracellular superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities and vitamin E and beta-carotene levels in the bronchoalveolar cells of 14 smokers before and after 6 weeks of supplementation with vitamins E and C and beta-carotene. Eight nonsmokers served as control subjects. CAT and GPx activities were higher in BAL cells from smokers compared with nonsmokers (20.5 +/- 2.3 vs 9.6 +/- 1.3 U/10(6) cells; p = 0.027; 0.90 +/- 0.10 vs 0.46 +/- 0.12 U/10(6) cells; p = 0.049, respectively), while there was no difference in SOD activity between the two groups. Likewise, vitamin E and beta-carotene concentrations were markedly higher in smokers' lung lavage cells (403.3 +/- 81.0 in smokers vs 16.6 +/- 5.3 ng/10(6) cells in nonsmokers, and 1.23 +/- 0.21 in smokers vs 0.15 +/- 0.04 ng/10(6) cells in nonsmokers, respectively). The serum levels of vitamin E and C and beta-carotene increased by 2.0-, 1.6-, and 8.9-fold in smokers after supplementation, which were similar to nonsmokers. Similarly, BAL cell vitamin E increased from 403.3 +/- 81.0 to 477.4 +/- 97.7 ng/10(6) cells and beta-carotene increased from 1.23 +/- 0.21 to 4.32 +/- 0.45 ng/10(6) cells (p < 0.05). Despite increased concentrations of vitamins in serum as well as beta-carotene levels in BAL cells, there was no significant down regulation in SOD, CAT, or GPx activities in the lung lavage cells. These data suggest that augmentation of micronutrient antioxidants in smokers and nonsmokers does not appear to have an effect on antioxidant enzyme activities, suggesting a differential regulation of these defenses.

Inhibition of phospholipase D and superoxide generation by glucose in diabetic neutrophils.

Diabetics are prone to infection, in part, due to neutrophil dysfunction and impaired superoxide generation. The mechanism of impaired superoxide generation in diabetes remains unknown. We report herein that neutrophils from poorly controlled diabetics have impaired ability to generate superoxide in response to N-formyl-Met-Leu-Phe (FMLP) but not to 4 beta-phorbol 12-myristate 13-acetate (PMA). Phosphatidic acid, a phospholipase D (PLD) -mediated product of membrane phosphatidylcholine is decreased in response to FMLP. The impaired superoxide generation and activation of phospholipase D are readily reversible once the diabetic neutrophils are incubated in normal glucose concentration. These data show that decreased superoxide generation by neutrophils in insulin-dependent diabetics is, in part, due to impaired activation of phospholipase D and is solely due to high glucose concentrations.

Effect of nitrous acid on lung function in asthmatics: a chamber study.

Nitrous acid, a component of photochemical smog and a common indoor air pollutant, may reach levels of 100 ppb where gas stoves and unvented portable kerosene heaters are used. Nitrous acid is a primary product of combustion and may also be a secondary product by reaction of nitrogen dioxide with water. Because the usual assays for nitrogen dioxide measure several oxides of nitrogen (including nitrous acid) together, previous studies of indoor nitrogen dioxide may have included exposure to and health effects of nitrous acid. To assess the respiratory effects of nitrous acid exposure alone, we carried out a double-blinded crossover chamber exposure study with 11 mildly asthmatic adult subjects. Each underwent 3-hr exposures to 650 ppb nitrous acid and to filtered room air with three 20-min periods of moderate cycle exercise. Symptoms, respiratory parameters during exercise, and spirometry after exercise were measured. A statistically significant decrease in forced vital capacity was seen on days when subjects were exposed to nitrous acid. This effect was most marked at 25 min and 85 min after exposure began. Aggregate respiratory and mucous membrane symptoms were also significantly higher with nitrous acid. We conclude that this concentration and duration of exposure to nitrous acid alters lung mechanics slightly, does not induce significant airflow obstruction, and produces mild irritant symptoms in asthmatics.

Sleep apnea in patients with hemispheric stroke.

Sleep pattern and breathing in humans are altered following cerebrovascular accidents involving the brainstem. Sleep apnea is a well-established complication of stroke involving the brainstem. On the other hand, the effect of cerebral stroke on sleep and breathing has not been well defined. The diffuse cerebral symptoms such as cognitive deficits, depression or fatigue, after hemispheric stroke mimic those present in patients with sleep apnea. To define the breathing pattern in patients with stroke involving cerebral hemispheres without brainstem lesion and without the prior history of sleep-disordered breathing, we studied 10 patients within 1 year of their stroke. The data collected during polysomnography from the stroke patients were compared with a group of subjects matched for age, body mass index, presence of hypertension, and smoking history without stroke. Patients with stroke had an abnormal sleep architecture with significantly lower slow wave sleep and rapid eye movement (REM) sleep when compared with controls. Sleep was fragmented because of the presence of increased respiratory disturbances. Stroke patients had a respiratory disturbance index of 52 +/- 10 events per hour when compared with 3 +/- 1 in controls (p < .05). Majorities of respiratory events were obstructive apneas and were associated with arterial oxygen desaturations and arousals. The pathogenic mechanism of sleep-disordered breathing in patients with hemispheric stroke seems to be related to the physiological effect of sleep on already compromised upper airway muscle control. Patients with stroke and diffuse cerebral symptoms should be investigated for the possibility of sleep-disordered breathing.

Human exposure to oxides of nitrogen at ambient and supra-ambient concentrations.

Oxides of nitrogen (NOx) are a ubiquitous group of air pollutants found in outdoor air as well as indoor environments. The main source of these contaminants is from the combustion of biofuel. Low level and chronic exposure occurs mainly in indoor environments. Acute and high level exposure can occur in a variety of industrial, agricultural, mining, and military settings. The adverse effect of chronic and low level exposure on lung function has been suggested by several epidemiologic studies. However, the results of controlled human exposure to ambient concentrations of NOx have been inconsistent. On the other hand, acute exposure to high levels of NOx has a relatively predictable clinical response in the form of airway irritation, development of pulmonary edema and, in some cases chronic airway disease. There are several lines of evidence to support the role of nutritional antioxidants in amelioration of oxidant lung damage induced by NOx.

Daytime oxygen saturation does not predict nocturnal oxygen desaturation in patients with chronic obstructive pulmonary disease.

Nocturnal hypoxemia occurs commonly in patients with chronic obstructive pulmonary disease (COPD). Because pulmonary hypertension and cardiac arrhythmias are associated with this phenomenon, the detection and treatment of nocturnal hypoxemia should be part of the management of COPD patients. The ability to predict nocturnal hypoxemia by evaluating an awake patient would be desirable economically and logistically because continuous nocturnal oximetry is not widely available and because it is costly and labor intensive. We sought to determine whether awake oximetry would be precise enough to be clinically useful in predicting the degree of nocturnal oxygen desaturation in patients with COPD. We studied 71 patients with COPD. During sleep, the arterial oxygen saturation (SaO2) decreased by an average of 9% with a maximum decrease of 21% (awake SaO2 93.0 +/- 0.4% vs nocturnal lowest SaO2 84.0 +/- 0.7%, p = 0.0001). The nocturnal oxygen desaturation in each patient, however, was poorly predicted from awake SaO2. The standard error of estimate was large with a value of 5.3%. These data suggest that awake SaO2 is not a good predictor of nocturnal oxygen desaturation in individual patients. The lack of a simple relationship between awake SaO2 and nocturnal SaO2 is due to a complex interplay of various physiologic and pathologic mechanisms involved in the control of breathing and oxygenation during sleep.

Inhibition of protein kinase C of human neutrophils by phosphatidylcholines.

Pulmonary surfactant phospholipids, particularly phosphatidylcholines (PCs), inhibit superoxide generation in neutrophils. The activation of neutrophils is in part dependent on protein kinase C (PKC). To investigate the mechanism of action of PCs in inhibition of neutrophil activation, we studied the effect of PCs, commonly found in pulmonary surfactant, on the distribution of PKC in intact resting and stimulated neutrophils as well as on their kinase activity in vitro. In general, in contrast to PCs with saturated fatty acyl moieties, PCs with unsaturated fatty acyl moieties inhibited PKC activity in vitro. To determine the effect of PCs on the activation of PKC in intact neutrophils, neutrophils preincubated with PCs for 2 hours were stimulated by 1,2-sn-dioctanoylglycerol (diC8) or 4-beta-phorbol 12-beta-myristate 13-alpha-acetate (PMA). The cytosolic PKC activity did not change in cells preincubated with PCs after stimulation with diC8 (3.76 +/- 0.83 units vs 3.90 +/- 1.48 units), as would be expected in control cells (3.06 +/- 0.41 units to 1.01 +/- 0.29 units). In contrast to diC8, PMA-induced translocation of PKC to the membrane was unaffected by PCs. These data suggest that specific PCs not only inhibit neutrophil PKC in vitro but can also affect its translocation in response to stimulation by diacylglycerol in intact neutrophils.

Glucose suppresses superoxide generation in normal neutrophils: interference in phospholipase D activation.

In neutrophils, N-formyl-Met-Leu-Phe (FMLP) stimulates a respiratory burst with subsequent generation of superoxide anion (O2-.) by NADPH oxidase. Signal transduction involved in this process includes FMLP receptor stimulation of phosphoinositide hydrolysis with formation of inositol 1,4,5-trisphosphate and diacylglycerol and phosphatidylcholine hydrolysis with formation of phosphatidic acid. Generation of these second messengers would lead to activation of NADPH oxidase and generation of O2-.. Neutrophils from diabetic subjects and normal neutrophils exposed to glucose have diminished ability to activate the respiratory burst in response to various agonists. The mechanism of this suppression remains unknown. We report herein that treatment of neutrophils with 15 and 50 mM glucose significantly suppresses the O2-. formation in response to receptor-mediated stimulation. The decreased O2-. generation is associated with marked inhibition of phospholipase D (PLD) activity, with limited hydrolysis of phosphatidylcholine and formation of phosphatidic acid. Sorbitol (50 mM), a nonmetabolizable sugar with a similar osmotic effect, has no influence on O2-. generation or PLD activation. The 4 beta-phorbol 12-myristate 13-acetate (PMA)-induced O2-. generation as well as PLD activation are unaffected by glucose. Furthermore, the intracellular Ca2+ transient in response to FMLP is not influenced by glucose. Taken together, these data suggest that glucose differentially interferes with activation of PLD but not phospholipase C. And, the fact that PMA-induced activation of PLD is not altered by glucose further suggests that a protein kinase C independent step leading to the activation of PLD may be altered by glucose.