In patients with cystic fibrosis, CF-related diabetes mellitus (CFRD) has been associated with increased morbidity and mortality. Whether glucose intolerance is also associated with poor outcomes is unclear. To better define these relationships we prospectively followed a group of 152 patients with CF without diabetes for 4 yr. Patients were classified as having normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or CFRD without fasting hyperglycemia (CFRD-No FH). FEV1, FVC, and body mass index (BMI) were measured at baseline and quarterly. At baseline 45% of the patients had NGT, 38.8% had IGT, and 15.8% had CFRD-No FH. FEV1, FVC, and BMI at baseline were comparable among these groups (all p > 0.1). After 4 yr an overall decline in FEV1 and FVC occurred, with no change in BMI. The rates of decline for FEV1 and FVC correlated with the glucose tolerance groups, with the highest rates of decline occurring among the CFRD-No FH group. In addition, patients in the lowest quartile for insulin production at baseline experienced the highest rates of pulmonary function decline over time, suggesting a relationship between insulin deficiency and clinical deterioration. We conclude that the degree of glucose intolerance is a strong determinant of future lung function decline in patients with CF.
In patients with cystic fibrosis (CF) progressive destruction of the pancreatic tissue from fatty infiltration and fibrosis leads to progressive loss of islet cells (1), resulting in a spectrum of glucose metabolism abnormalities (2). In patients with fasting hyperglycemia (FH: fasting plasma glucose greater than 7.0 mmol/L), CF-related diabetes (CFRD) is usually diagnosed and treated with insulin therapy. Patients who do not have fasting hyperglycemia fall into one of three different categories according to the results of a standard oral glucose tolerance test (OGTT): normal glucose tolerance (NGT, 2-h plasma glucose < 7.8 mmol/L), impaired glucose tolerance (IGT, 2-h plasma glucose between 7.8 and 11.1 mmol/L), and CFRD without fasting hyperglycemia (CFRD-No FH, 2-h plasma glucose > 11.1 mmol/L).
Previous studies have clearly associated the presence of CFRD with shortened survival and increased morbidity. These studies have raised the question of whether the prediabetic state per se contributes to clinical decline, or whether the sickest patients are simply the most likely to develop diabetes. Finkelstein and colleagues (3), in a retrospective study of 448 patients, reported a significantly shortened survival in patients with CF and diabetes, with less than 25% surviving to 30 yr of age. In contrast, 60% of a control group of patients with CF without diabetes survived to 30 yr of age. Clinical deterioration, as assessed by NIH score, was apparent 2 yr before the diagnosis of diabetes was made (3). The Cystic Fibrosis Foundation Patient Registry, which annually reports clinical data on more than 21,000 patients with CF in the United States, reported for 1997 that patients with CF and diabetes have a 6-fold greater mortality rate, and are more likely to be malnourished and have significant pulmonary dysfunction than are patients with CF without diabetes (4). In Denmark, where annual glucose tolerance testing is performed, patients with CF were found to have a significant decline in pulmonary function and weight for as long as 6 yr before the diagnosis of diabetes (5). Interestingly, these parameters not only improved but returned to levels seen 4 to 6 yr earlier once therapy with insulin was instituted, suggesting a cause and effect relationship between insulin deficiency and clinical health decline (6).
These retrospective studies do not provide enough evidence to define the temporal sequence of the association between CFRD and health decline in patients with CF. It is possible that only the sickest patients are at risk for the development of diabetes, and that the development of diabetes is simply part of their decline. Alternatively, the presence of chronic insulin deficiency, implied in a “prediabetic” state, may result in the development of detrimental changes in health status.
Only through prospective evaluation of patients with CF with baseline stable health status and without diabetes will we be able to better define the roles abnormal glucose tolerance and insulin deficiency play in the progression of CF. In addition, although beneficial effects in lung function and nutritional status were demonstrated in patients with CFRD after the start of insulin therapy (5), no extrapolation can be made to patients who are in a prediabetic state until more information is obtained about the risks related to such a state. With this information a clearer assessment of the risk-benefit ratio can be made and appropriate outcomes could be defined for the design of controlled prospective clinical trials of potential therapeutic strategies.
In order to evaluate the potential role of glucose tolerance abnormalities in the course of patients with CF, we prospectively followed pulmonary function and nutritional parameters over a 4-yr period in 152 patients without FH after a baseline OGTT was performed.
Only patients without FH and with stable lung health status were entered into the study. Lung health stability was defined as no drop in FEV1 by more than 10% in the preceding 6 mo and no recent hospitalization or intravenous antibiotic therapy for pulmonary exacerbation. Glucose tolerance was not performed until at least 2 mo had elapsed since the last hospitalization for an acute illness. The tests and clinic routine followed in the study were already part of our standards of care for patients with CF. The treatment program followed by our patients is fairly uniform and includes daily bronchial drainage, nebulizations with bronchodilators and mucolytic agents, chronic suppressive antibiotics for those infected with respiratory pathogens, aggressive nutritional support, and frequent pulmonary function and microbiologic monitoring. All patients followed at our center give informed consent permitting their records to be used for research purposes.
Glucose tolerance was determined at baseline by a standard OGTT. After an overnight fast, patients were given 1.75 g of glucose per kg of body weight (up to 75 g) by mouth. A venous blood specimen for glucose and insulin levels was obtained at baseline, and every 30 min for 2 h. According to the results of the test, patients were classified as follows. (1) Normal glucose tolerance (NGT): fasting plasma glucose levels below 7.0 mmol/L and 2-h glucose below 7.8 mmol/L. (2) Impaired glucose tolerance (IGT): fasting plasma glucose levels below 7.0 mmol/L and 2-h glucose between 7.8 and 11.1 mmol/L. (3) CFRD-No FH: fasting plasma glucose levels below 7.0 mmol/L and 2-h glucose above 11.1 mmol/L.
In addition, the 2-h areas under the curve (AUC) for insulin and glucose were calculated for each subject.
At the time of the OGTT, all subjects had their weight and height measured, and they performed spirometry according to the standard procedures in place at our center (7). For the next 4 yr, and as part of their routine care, the subjects had the same measurements performed on at least a quarterly basis. All these measurements were entered into a computerized database (8). For study purposes, the %-predicted FEV1 (%FEV1), %-predicted FVC (%FVC), and body mass index (BMI) were recorded. In addition, information on the subject's demographic characteristics, results of respiratory secretions cultures, and use of corticosteroids were recorded.
Trends in FEV1, FVC, and BMI throughout the study period were analyzed by mixed linear regression, using maximum likelihood methods for estimation (9). Because of the longitudinal nature of the data, repeated measures on the same subjects over time, a mixed linear model procedure properly accounted for the within- and between-subject variability. In addition, the average rates of change in the parameters measured were calculated for the different categories of patient characteristics felt to be of importance. The covariance matrix structure was selected by generating models with different types of structure. Then, the model with the Schwartz' Bayesian Criterion closest to zero was selected as the one that gave the best fit for the data (9). An α level of 0.05 was used as the cutoff for statistical significance, and all analyses were performed with the SAS statistical package (SAS Institute, Cary, NC).
The study group comprised 77 female and 75 male patients. By age group, 47 subjects (31%) were younger than 12 yr of age at baseline, 40 (26.3%) were 12 to 18 yr of age, 24 (15.8%) were 18 to 24 yr of age, and 41 (27%) were older than 24 yr of age. Subject characteristics are presented in Table 1.
|Age, yr||17.66 ± 11||18.06 ± 8.7||23.2 ± 8.7*||17.7 ± 10|
|FEV1, % pred||91.95 ± 22.7||92.43 ± 27.1||79 ± 27.3||89.32 ± 26.2|
|FVC, % pred||109.9 ± 18.8||112.6 ± 22.2||101.0 ± 22.2||109.57 ± 20.9|
|BMI, kg/m2||20.03 ± 4.0||20.01 ± 3.3||20.04 ± 2.0||20.03 ± 3.5|
|Pseudomonas sp. in cultures, %||40||45||65*||47|
|Pancreatic sufficiency, %||8||10||6||9|
|Hospitalization rate‡||0.50 ± 0.11||0.72 ± 0.08||0.64 ± 0.07||0.60 ± 0.08|
Sixty-nine (45.4%) of the subjects were found to have NGT, 59 (38.8%) had IGT, and 24 (15.8%) had CFRD-No FH. There was no statistically significant difference in the distribution of the glucose tolerance categories by sex or by ΔF508 homozygocity (p > 0.1). By age group, there was a tendency for older patients to be more likely to have IGT or CFRD-No FH (p = 0.06). Only six patients were receiving supplemental tube feeding; two had NGT, three had IGT, and one had CFRD-No FH.
At the time of the OGTT 34 (22%) of the patients were receiving oral corticosteroids as a chronic anti-inflammatory (doses from 0.25 to 0.8 mg/kg) on a daily or alternate day basis, and with younger patients being more likely to be receiving steroids (p = 0.001). There was no significant difference in the distribution of the OGTT classification by steroid therapy status (p = 0.4).
Patients in the CFRD-No FH group were more likely to be chronically infected with Pseudomonas sp. (p = 0.03), but other potential pathogens (including B. cepacia) were similarly distributed (p > 0.1). During the study period, the rates of hospitalization for pulmonary exacerbations were comparable between the glucose tolerance groups (p > 0.1).
The median insulin AUC observed at baseline was 17,370 pmol/L/h (range, 270 to 78,390 pmol/L/h). There were no significant differences in the median insulin AUCs between the patients in the NGT, IGT, and CFRD-No FH groups (15,570, 19,710, and 16,650 pmol/L/h, respectively; p > 0.1). In contrast, there were significant differences in the median glucose AUCs (283.3, 520.8, and 697 mmol/L/h, respectively; p < 0.01). Insulin AUC did not differ by patient characteristics such as age, sex, genotype, microbiology, or steroid therapy status (all p > 0.1).
Pulmonary function. At baseline, there were no statistically significant differences in FEV1 and FVC between the three glucose tolerance groups. At the end of the observational period all groups had experienced a drop in their pulmonary function parameters. The mean %FEV1 and %FVC were, respectively: NGT, 91.2 ± 24.1 and 105.6 ± 18.6; IGT, 89.1 ± 29.9 and 106.8 ± 23.1; and CFRD-No FH, 70.5 ± 31.5 and 92.9 ± 24.3.
By mixed linear regression analysis during the study period a mild but significant decline in %FEV1 occurred in the group as a whole, at a rate of −0.8/yr (p = 0.001). By OGTT classification, patients with NGT had no significant change in their %FEV1 throughout the observation period (rate, 0.17/yr), whereas patients with IGT and CFRD-No FH experienced a significant decline in their %FEV1 (rates, −1.36 and −2.44/yr, respectively). The differences between the rates seen in these groups and the rate seen in the NGT group was highly significant (both p = 0.0001). Also, the difference between the rate for the IGT and the CFRD-No FH group was significant (p = 0.03).
Because there were important differences in the baseline age distribution and steroid therapy use between the groups, these variables were introduced into the regression model to adjust for their possible confounding effects. In addition, adjustment was performed for sex and baseline BMI, microbiology, and FEV1. In the final model generated, the differences noted between the OGTT categories in the FEV1 rate of decline persisted (Figure 1).
By insulin AUC quartile, and also after adjustment for sex and baseline age, BMI, microbiology, and FEV1, those subjects in the lower quartile had the highest rates of decline (Figure 2), as opposed to subjects in the higher quartiles. Very similar rates of decline were seen for subjects in the higher two quartiles, suggesting a threshold effect.
The trends for %FVC were similar to those noted for %FEV1 (Figure 1). Overall, during the study period, a mild but significant decline occurred (rate −1.78/yr, p = 0.0001). By OGTT group, the rates seen were significantly lower for the NGT group (−1.18/yr, p = 0.0006 versus IGT or CFRD-No FH groups), and marginally comparable for the IGT and CFRD-No FH groups (−2.11 and −2.79/yr, respectively, p = 0.1). Adjustment for the potential confounding effects of gender and baseline age, BMI, microbiology, use of corticosteroids, and FEV1 did not introduce major modifications in the trends seen. As for FEV1, the adjusted rates of decline increased with decreasing insulin AUC quartile, suggesting a linear relationship with insulin production (Figure 2).
Body mass index. There were no significant differences between the groups at baseline. A trend toward a mild increase in BMI was observed during the study period; however, this was not statistically significant (rate of change of 0.2 kg/m2/yr, p = 0.2). No significant differences were noted in the trends for BMI according to OGTT category or insulin AUC.
Glucose tolerance. On only 84 patients (55%) were data on repeated OGTT available by the end of the study period. No change in OGTT category occurred in 60% of these patients. For the rest of the patients, a change toward the worst by one category (from IGT to NGT or from NGT to CFRD-NoFH) occurred in 19% of the subjects and a change toward the better (from NGT to IGT or from CFRD-NoFH to NGT) occurred in another 18%. In the remainder, a change from NGT to CFRD-NoFH occurred from baseline to the end of the study period. We continue to prospectively follow this patient population to obtain more complete estimates of change in OGTT class over time and the potential clinical implications of this change.
A pattern of decline in pulmonary function directly proportional to the severity of glucose intolerance at baseline was apparent over a 4-yr observation period. This effect was independent of baseline characteristics such as sex, age, BMI, respiratory secretions microbiology, use of corticosteroids, and FEV1. In addition, the degree of insulin deficiency as assessed by the 2-h AUC was strongly correlated with the higher rates of decline. Because subjects at baseline were no different in terms of pulmonary function and nutritional status, these data strongly support the concept that the insulin deficient state per se leads to detrimental pulmonary outcomes. These observations complement previous observations by ourselves and others of increased morbidity and mortality in patients with CF and diabetes (3-5). Lanng and colleagues (5) reported in their patients with CFRD over a 6-yr period a decline in FVC and FEV1 of 1.6%/yr and of 1.1%/yr when compared with a group of control patients with CF.
How might insulin deficiency influence pulmonary function in CF? One mechanism by which insulin deficiency might impact pulmonary function in patients with CF is by adversely affecting nutrition by promoting a catabolic state. Insulin is a potent anabolic hormone and its absence is clearly associated with protein catabolism. Patients with CF have been shown to have chronically elevated rates of protein catabolism as demonstrated by 13-C leucine kinetics, 3-methylhistidine excretion, and urinary nitrogen balance studies (10-15). Negative protein balance may contribute to morbidity and mortality in CF since FEV1 correlates with lean body mass (16), and reversal of protein catabolism stabilizes pulmonary function and decreases the number of hospitalizations for acute pulmonary exacerbations (17). Protein catabolism in CF may be directly related to the severity of glucose intolerance (18).
The group of patients studied was not overtly malnourished, and more subtle manifestations of abnormal nutritional status may have been present. Malnutrition per se is known to impair pulmonary function, even in patients with no underlying pulmonary disease, by diminishing diaphragm and intercostal muscle mass and strength (19, 20). In addition, in patients with CF nutritional status has been shown to be an important determinant of clinical status and lung disease progression (21). Damaging endobronchial proteolytic enzyme activity and oxidant species burden, well known to be present in patients with CF (17, 22, 23), even at the very early stages of the disease (24, 25), have been clearly shown to correlate with lung dysfunction (18, 26). The inability to counterbalance this process accelerates the progression of the lung damage (27). Nutrition is probably involved in the maintenance of adequate antiproteolytic and antioxidant protection mechanisms, with the presence of an anabolic state playing a key role in the ability to maintain a positive balance. Thus, the insulin-deficient state in patients with CF may impair the ability to maintain an adequate balance and determine significant lung destruction from endobronchial enzymatic activity and unopposed oxidant injury.
Hyperglycemia may also have a negative impact on lung function. Several cross-sectional studies in patients with type 1 and type 2 diabetes have found mild abnormalities in FVC and FEV1, lung elastic recoil, pulmonary diffusing capacity, and capillary blood volume (28-33), as compared with healthy control subjects. Animal models of diabetes suggest that there are abnormalities in lung connective tissue synthesis and turnover that are more prominent in the absence of insulin replacement. Thickening of the alveolar wall, from increased deposition of collagen fibers, and reduced degradation of connective tissue, have been observed in rats made diabetic by treatment with streptozotocin (34). These findings correlate with studies in human diabetes, where thickening of the alveolar epithelial and endothelial basement membranes have been noted (35). Although lung disease is not a major complication for patients without CF but with diabetes, diabetes-related changes in pulmonary function may assume greater pathologic significance in patients with underlying lung disease.
In summary, we present evidence that the degree of impairment of glucose tolerance and the degree of deficiency in insulin secretion at baseline correlate with the rate of lung function decline in patients with CF, suggesting a direct cause and effect relationship between insulin deficiency and clinical decline. Further studies are necessary to elucidate the mechanism by which this decline in health status develops and to determine whether intervention with insulin or other diabetes treatments might prevent these derangements.
Supported by a Cystic Fibrosis Foundation Center Grant.
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Presented in abstract form at the 12th Annual North American Cystic Fibrosis Conference, Montreal, Canada, October 1998.