Characterization of β-cell Function and Insulin Sensitivity in Pre-transplant Patients With Cystic Fibrosis

Cystic fibrosis is a genetic disorder caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, leading to pulmonary infections, sinus disease, pancreatic insufficiency, hepatobiliary disease and male infertility, with respiratory failure being the primary cause of death. Cystic Fibrosis Related Diabetes (CFRD) in one of the most common complication of cystic fibrosis (CF) and it's associated with a worse respiratory and nutritional state, with a negative impact on life expectancy. It differs from type 1 diabetes and type 2 diabetes for particular characteristics making this disease a separated clinical entity.

To date, there is a lack of evidence on many aspects concerning this disease:

• the pathophysiology of the disease: decreased insulin secretion has historically been seen has the major trigger for CFRD, but data about this mechanism are scarce and conflicting. Moreover, the role of insulin-resistance seems to be not consistent, but pulmonary exacerbations are very common and, in this setting, insulin sensitivity can worsen significantly.
• the relationship between its development and particular genetic settings: certain CFTR genotypes are known to be most related to the risk of diabetes, and only few susceptibility genes for type 2 diabetes have been evaluated as potential predisposing factors for CFRD.
• the relationship between the therapeutic optimization and its impact on metabolic status and lung function: CFRD is known to be associated with worse clinical outcomes, reflected in more frequent clinical exacerbations, greater reduction in lung function, poorer nutritional status and decreased survival. It has also been demonstrated that insulin therapy can improve pulmonary function, increase body weight and reduce lung exacerbations. However, no study on the clinical impact of the optimization of insulin therapy on pulmonary outcomes and life expectancy are available in this population.
• finally, no data about potential predisposing pre-transplant risk factors for development of post-transplant DM are available

For this reason, the investigators have structured a study with the aim to:

• characterize the pathophysiological process leading to CFRD, with assessment of the relative contribution of the insulin resistance and the β-cellular secretion impairment
• define the prevalence of CFRD in relation to the mutations of the CFTR gene and to the presence of candidate genes for the development of type 2 diabetes
• perform a proteomic analysis to identify potential proteomic biomarkers among CFRD patients
• evaluate the body composition, muscle performance and respiratory outcomes in patients on insulin therapy, before and after therapeutic optimization, in a follow-up period of 24 months.
• identify eventual predisposing factors for the development of post-transplant diabetes in subjects without pre-transplant CFRD.