Physiopathologie du diabète secondaire à la fibrose kystique : études transversales et prospectives

Abstract Abnormal glucose tolerance is a frequent co-morbidity in cystic fibrosis patients (CF), and is associated with a worse prognosis.  However, the most pertinent factors to predict the clinical status and the physiopathology of glucose intolerance remain unclear.  The aim of this study was to investigate the roles of impaired insulin secretion and insulin resistance in the progression of glucose intolerance from the normal state up to diabetes (CFRD) using an ongoing prospective observational cohort of non-diabetic CF patients.  We demonstrated that CF patients displayed a reduced first phase insulin secretion across glucose tolerance categories (normal; intolerance and CFRD).  Moreover, variation in insulin resistance has a significant impact on glucose tolerance in this population.  Finally, early in the course of the disease, increased glucose area under the curve (AUC) and reduced first phase insulin secretion are better predictors of clinical status than conventional glucose tolerance categories. Numerous indices to evaluate insulin secretion have been proposed, but their validity has not been explored in cystic fibrosis (CF).  The aim of this study was to validate surrogate indices of insulin secretion calculated from fasting values or the oral glucose tolerance test (OGTT) in CF patients against the gold standard, the intravenous glucose tolerance test (IVGTT).  This is an essential step to study the physiopathological role of defective insulin secretion in the development of CFDR in large cohort.  We showed that all insulin secretion indices correlated significantly with the IGVTT in control individuals.  However, while OGTT-derived indices correlated significantly with the gold standard test in all CF groups, this was not the case for fasting-derived indices.  Since the OGTT is required on a regular basis in CF patients to screen for CFRD, OGTT-derived indices should be used to evaluate insulin secretion. Abnormal insulin secretion combined with recommended high fat intake could be associated with dysregulation of glucose and lipid metabolisms in CF patients.  Thus, the second objective was to examine postprandial glucose and lipid profiles during an OGTT and a standardized high-fat test meal (TM) in CF patients.  CF patients presented higher glucose excursion compared to controls after the OGTT and TM.  This excursion was significantly reduced in both amplitude and length during the TM for CF patients.  In addition, control and CF patients presented similar profiles for both triglycerides and fatty acids.  These results exclude lipotoxicity as a major player in ß cell defect for these patients. Circulating adiponectin levels are negatively associated with glucose intolerance, inflammation and central adiposity.  Since these conditions are common in CF patients, we examined whether adiponectin values are altered in this population.  CF patients did not show any changes in adiponectin levels despite insulin resistance, glucose intolerance and sub-clinical inflammation.  Thus, CF appears to be one of the rare conditions in which discordance between adiponectin values and insulin resistance or inflammation is evident.  In conclusion, CF patients are characterized by a high prevalence of glucose abnormalities due to an insulin secretion defect but also the contribution of insulin resistance.   Key words: Adiponectin, Cystic fibrosis, diabetes, glucose intolerance, Oral glucose tolerance test, insulin resistance, insulin secretion.

Keyphrases: Adiponectin, Cystic fibrosis, Oral glucose tolerance test, insulin resistance, Insulin secretion