Déterminer le lien entre l’hyperglycémie et/ou l’hypoinsulinémie et la dégradation clinique observée avant le diagnostic du Diabète Associé à la Fibrose Kystique

Cystic Fibrosis (CF) is a genetic disease that results in progressive destruction of the lungs and eventually death. The primary secondary complication is CF-related diabetes (CFRD). Accelerated clinical deterioration (loss of weight and lung function) is observed before diagnosis. The main objective of my PhD project is to determine, through the oral glucose tolerance test (OGTT), if there is a link between hyperglycemia and/or hypoinsulinemia and the clinical deterioration observed before the onset of CFRD. We will thus assess the importance of the intermediate OGTT time-points in simplifying the diagnosis of dysglycemia as well as in establishing novel markers that are indicative of patients at risk of clinical deterioration. The OGTT is the standard method used in CF for the diagnosis of CFRD. We have shown that blood glucose values obtained at 90-minutes of the OGTT would be sufficient to predict glucose tolerance in adult patients with CF, otherwise determined using 2-h OGTT values. We provide glucose levels at 90-minutes of the OGTT greater than 9.3 mmol/L and greater than 11.5 mmol/L for detecting glucose intolerance and CFRD, respectively.  A major cause of CFRD is the defect of insulin secretion. Women with CF are at higher risk of developing CFRD than men, we therefore explored if their insulin secretion is comparable. Contrary to our hypothesis, we observed that women with CF had a total insulin secretion higher than men with CF, but at levels comparable to healthy women.  The newly established glucose tolerance group named indeterminate (INDET: 60-min OGTT > 11.0 mmol/L but 2h-OGTT < 7.8 mmol/L) is at high risk of developing CFRD. However, nothing is known about the clinical characteristics of this group in adult patients with CF. We observed that the INDET group has lowered lung function comparable to the newly diagnosed CFRD group and none of the glycemic and insulinemic parameters can explain this observation.  In a pediatric population of patients with CF, an association has been reported between high blood sugar at 60-min of the OGTT and decreased lung function. In our group of adult patients with CF, there is a negative association between blood glucose levels at 60-min of the OGTT and lung function and a positive correlation between insulin at 60-min of the OGTT and body mass index (BMI). In addition, patients with a 60-min OGTT glucose value > 11.0 mmol/L have both low lung function and insulin sensitivity, while those with a 60-min OGTT insulin value < 43.4 μU/mL have lowered BMI and lung function.  In conclusion, we are the first group to show that 1) the OGTT can be shortened by 30 minutes without compromising the categorization of glucose tolerance, 2) women with CF demonstrate preservation of their insulin secretion capacity, 3) the INDET group presents early abnormalities in lung function comparable to the de novo CFRD group and 4) blood glucose and insulin values in the first hour of the OGTT are associated with both key elements of clinical deterioration. It is crucial to elucidate the important pathophysiological mechanisms involved in order to better predict the occurrence of clinical deterioration before CFRD onset.

Keyphrases: Insuline, Glucose, Cystic fibrosis, Cystic fibrosis related diabetes, Insulin, Oral glucose tolerance test, Weight, Lung function