Les fluctuations glycémiques et l'inflammation dans le diabète secondaire à la fibrose kystique

Cystic fibrosis (CF) is the most common autosomal recessive genetic disease among Caucasians and it is cause by a mutation in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene. With the emergence of more aggressive therapies to treat CF, the median life expectancy of patients with CF has increased and new complications, such as CF-related diabetes (CFRD), have emerged. CFRD is associated with increased mortality. The physiopathology of this complication is not fully understood. For instance, the reason why people with CF have an accelerated decline in lung functions years before the diagnosis of CFRD is not known.   Patients with CF, even those without CFRD, have increased hyperglycemia and glucose fluctuations. In addition, a study has reported that hyperglycemia affected immune reactivity in a mouse model of the disease. Furthermore, studies have shown that lymphocytes without a functional CFTR or that have increased uptake of glucose have abnormal immune responses. Therefore, we hypothesized that patients with CF, specifically those with normal and impaired glucose tolerance, would have increased proportions of Th17 and Treg lymphocytes producing the pro-inflammatory cytokine IL-17A and that the increase in IL-17A levels would contribute to the accelerated decline of lung functions before the onset of CFRD. Increased levels of IL-17A have been found in the lungs of patients with CF and the peripheral blood of patients with type 1 (T1D) and 2 diabetes (T2D). Dysfunctional Treg lymphocytes can also produce IL-17A. These lymphocytes usually attenuate excessive immune responses but, in certain cases, can be dysfunctional and produce the pro-inflammatory cytokine IL-17A. Moreover, we hypothesized that the proportions of these cells producing IL-17A would be associated to lung functions in patients with CF and that nutrition, physical activity and body composition could influence the relationship between inflammation and glucose fluctuations.   Although an association between the proportion of lymphocytes in the peripheral blood of participants and glucose fluctuations was observed, glucose fluctuations did not affect the proportions of Th17 and Treg lymphocytes producing IL-17A stimulated with PHA and PMA or not stimulated in media containing either 5 or 25 mM of glucose for 24 or 48 hours. Furthermore, these proportions were similar between healthy individuals and patients with CF with the exception of the proportion of stimulated Treg lymphocytes producing IL-17A of healthy individuals that was greater than the proportions of non-stimulated Treg lymphocytes producing IL-17A of all participants (patients with CF and healthy individuals). This suggests that Treg lymphocytes of healthy individuals and CF patients do not respond in the same manner to stimulation by phorbol 12-myristate 13-acetate (PMA) and phytohemagglutinin (PHA). Also, the duration of incubation affected the proportions of Th17 cells producing IL-17A but did not affect the proportion of Treg producing this cytokine. Therefore, these two types of lymphocytes are differently affected in the same culture media. Also, only the proportion of calories from carbohydrates affected modestly glucose fluctuations and the proportions of Th17 and Treg lymphocytes producing IL-17A were not associated to lung functions in CF patients.   To conclude, patients with CF had increased hyperglycemia and glucose flucutations when compared to healthy individuals but this glucose variability did not affect the proportions of Th17 and Treg lymphocytes producing IL-17A ex vivo. Future studies are needed to explore the role of IL-17A in the lungs of patients with CFRD and a prospective study would be important in order to determine if an increase in IL-17A in patients without CFRD is associated to an accelerated decrease in lung functions before the onset of this complication.

Keyphrases: IL-17A, Nutrition, VEMS, Cystic fibrosis-related diabetes, Glucose fluctuations, Hyperglycemia, Th17 lymphocytes, Treg lymphocytes, Energy expenditure, Body composition, FEV1