Lung function alterations are the main factors responsible for the high mortality of patients with cystic fibrosis (CF). In recent decades, the specialized treatment of CF has significantly increased their life expectancy,1 and the current average survival is more than 30 years. Lung transplantation is the only therapy available in the final stages of this lung disease.2 With the increased survival in CF, more and more patients have the possibility of developing extra-pulmonary complications. CF-related diabetes (CFRD) is the most frequent comorbidity and constitutes at the same time a marker for poorer prognosis and greater mortality.3,4 The prevalence of CFRD increases with age3,5,6 and its appearance is usually preceded by moderate alterations in the metabolism of carbohydrates, while there are reports of worsened lung function and nutritional state years before its diagnosis.3,7–9 The treatment of CFRD with insulin seems to improve the respiratory and nutritional states of these patients.5,10,11 There are few studies about the duration of this beneficial effect. In patients with CF who require lung transplantation, the prevalence of CFRD is 28.6%.12 We present the beneficial and prolonged effect of insulin therapy on lung function and on nutritional state in a male with CF who started with insulin at the time of his diagnosis with CFRD, coinciding with the indication of lung transplantation.

After the start of the treatment with insulin, a progressive improvement was observed in lung function and nutritional state (Table 1) and within 4 months the patient no longer met the criteria for lung transplantation. The doses of corticosteroids were gradually reduced, and five months after the start of insulin therapy, corticosteroid treatment was able to be suspended without the patient presenting any lung exacerbations during their withdrawal. Home oxygen therapy was also suspended and the spirometry parameters improved to the levels prior to the diagnosis of CFRD (Table 1). Ten months later, the patient was able to do regular exercise.

Four years after the diagnosis of diabetes, the patient had another flare-up of ABPA and required oral corticosteroid therapy for 18 months (initial doses of 1.2mg/kg/day and later 0.2mg/kg/day). As a consequence of the immunosuppression caused by the steroids, he presented two pulmonary exacerbations, therefore during this period both the lung function and metabolic control worsened (Table 1, Fig. 1). Once said processes were controlled, all the parameters improved. Since then, the patient has not again needed either antibiotic or corticosteroid treatment.

Fig. 1.

HbA1c values during follow-up after the diagnosis of diabetes.

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The control of the diabetes was good from the start of the therapy, with an initial insulin dose of 0.5U/kg/day and adequate levels of HbA1c (Fig. 1). This control experienced alterations coinciding with the lung exacerbations, and it was necessary to increase the dose of insulin to 0.85–1U/kg/day. Afterwards, the patient recovered good glycemic control with a mean insulin dose of 0.7U/kg/day.

Currently, at the age of 27, the patient's CFRD is controlled with the administration of 3 doses of regular insulin before the 3 main meals, together with 2 doses of delayed-action insulin analog detemir (Levemir®) before breakfast and dinner (total dose 0.7U/kg/day). The metabolic control is very good (HbA1c 6.5%), presenting no diabetic complications. Eight years after the diagnosis of CFRD, the patient does not meet lung transplantation criteria, maintains an FVC of 2.08l (43%) and an FEV1 of 1.0l (47%), does not require oxygen therapy and has a good quality of life.

Several studies have emphasized the beneficial effect of insulin on lung function in patients with CFRD, ascribed not only to its normoglycemia effect but also to the anabolic effect itself of insulin.16 The deficit of insulin increases the risk for lung infection, worsens nutritional state and leads to a reduction in intercostal and diaphragmatic muscle mass, all of which are factors that contribute to the declining lung function in CF patients.17 Therefore, very recently the American Diabetes Association, the American Cystic Fibrosis Foundation and the American Pediatrics Society have published a new Consensus-Guide about the screening and treatment of the hydrocarbonated alterations in CF, with the objective of promoting actions as early as possible in order to protect lung function and the nutritional state of these patients.13 The Guide indicates that, in patients with CF, screening should be done annually starting at the age of 10 by means of an oral overload of glucose. The most innovative agreement is the early use of insulin, even in CFRD without fasting hyperglycemia. It is also pointed out that the use of insulin can even be very positive in phases prior to hydrocarbonated alteration, before the diagnosis of diabetes. Another position of this Consensus is not to use oral anti-diabetic medication in these patients with CF. Dietetic changes and physical exercise pay a secondary role in CFRD, where diet should not be restricted and exercise should be adapted to the possibilities of each patient.

In our patient, the good control of CFRD seems to have played a positive role in the improvement of his lung function. A fact that should be kept in mind in this case is that said benefit meant that he no longer met the criteria for lung transplantation. Over the course of the following eight years and to date, there have been no indications for lung transplantation in this patient, except for a limited period of 6 months in the fourth year after CFRD diagnosis, coinciding with the ABPA and pulmonary exacerbations.

CFRD affects 12%–35% of the CF population, and its prevalence increases with age.6,10 Lung transplantation is the only therapy for definitively controlling the final stage of the lung disease in CF, although it has high mortality18 and there are strict criteria for the selection of the candidates.14,15 Our patient presented factors that are more often associated with the development of CFRD, such as age, the use of systemic corticosteroid therapy and a genotype at risk (mutations R553X and ΔF508).3,7 On the other hand, he had two predictive factors for less severe lung disease: late CF diagnosis and pancreatic exocrine sufficiency (which usually exist in patients with less severe CF mutations and without diabetes). Nevertheless, these factors did not protect him from a rapid deterioration in his lung function. Worsened lung function has been demonstrated months and even years before diagnosis of CFRD,7,8,11 a fact which has been confirmed in all age groups.19

Although the ABPA in this patient before the diagnosis of CFRD could be considered a risk factor for the abrupt respiratory deterioration, the good response of the patient to steroid treatment, made evident by the significant decline in the total serum IgE values, makes it unlikely that ABPA is the main cause of the pulmonary deterioration that the patient experienced. The absence of important side effects of corticosteroid therapy, such as myopathy, also leads us to believe that the corticosteroid therapy also was not an important risk factor that would explain the rapid lung deterioration of the patient. Furthermore, oral steroids, due to their powerful anti-inflammatory action, are occasionally used in the advanced stages of this disease in an attempt at stopping the respiratory deterioration, despite their possible side effects, such as increased pulmonary exacerbations and hyperglycemia. On the other hand, in this patient the pulmonary exacerbations responded positively to antibiotics, but the functional deterioration did not. The coincidence in time of the diagnosis of CFRD and the initiation of insulin therapy with the noticeable improvement in lung function make diabetes the main candidate for the causal factor of the severe respiratory function deterioration, and the insulin is the main candidate for the causal factor of the marked and maintained clinical recuperation of the patient. Along these lines, previous studies have demonstrated significant improvements in pulmonary function during treatment with insulin in patients with CFRD.5,10,11,17 The need to maintain insulin treatment in order to achieve good metabolic control once the pulmonary exacerbations are overcome confirms the diagnosis of diabetes, excluding the corticosteroid treatment as the only cause of the initial hyperglycemia, even more so when the dose of methylprednisolone was low at the moment of the diagnosis of CFRD. Although there are no prospective studies on the duration of the beneficial effect of insulin in CF, the results of the clinical parameters in the evolution of our patient support the idea that, at least in some CF patients, insulin therapy leads to a maintained improvement of the lung disease.20

The genotype–phenotype correlation in CF has been studied for the majority of the clinical characteristics of the disease, and a significant direct correlation has not been found.21,22 Our patient possesses the two most frequent mutations of the CFTR gene associated with diabetes in CF (ΔF508 and R553X). The high prevalence of this genotype in CF goes against a causal relationship with the exceptional evolution that we present here. Furthermore, in an extensive international cohort of 399 patients with CF, the genotypic combination ΔF508/R553X did not correlate with a poor evolution of the lung disease.21 Thus, it is possible that other genes other than CFTR can influence in the pulmonary evolution of patients with CF.23,24

In conclusion, the clinical evolution of our patient supports what has already been reported about the role that insulin and the good metabolic control of CFRD can play in the lung function and nutritional state of these patients. This upholds the need to regularly screen for alterations in the hydrocarbonated metabolism of patients with CF that experience a decline in lung function of unclarified causes, as early treatment of CFRD with insulin can have a positive impact.