Genetic Dissection of Diabetes: Facing the Giant

Abstract

Cystic fibrosis (CF) is the most common inherited disorder of childhood and is caused by autosomal recessive mutations in the CF transmembrane conductance regulator ( CFTR ) gene (1). CF is most common among Caucasian individuals, with a prevalence of 1 in 2,500 newborns (2). CF can be diagnosed before birth by genetic testing or by a sweat test in early childhood (3,4). Complications of CF include bowel obstruction due to meconium ileus in newborns, poor growth, sinus infections, biliary disorders, infertility, chronic pulmonary infections, and lung disease that requires lung transplantation as CF worsens (2). Exocrine pancreatic insufficiency is observed in 90% of CF patients. Abnormal chloride channel function results in thick viscous secretions that obstruct pancreatic ducts and lead to the retention of digestive enzymes and to pancreas tissue destruction and fibrosis (5). CF-related diabetes (CFRD) is highly prevalent among CF patients and is thought to result from the progressive destruction of islets of Langerhans by pancreatic fibrosis (5). CFRD affects 2% of children, 19% of adolescents, and 40–50% of adults (6). As CFRD is associated with worse pulmonary function (7), failure to maintain weight (8), and higher mortality rates (6), the World Health Organization has recommended annual screening for CFRD using an oral glucose tolerance test. CFRD is considered a clinical entity distinct from that of type 1 diabetes or type 2 diabetes (T2D) and is included in the category “other specific types of diabetes” by the American Diabetes Association (9). Nondiabetic CF patients already display impaired first-phase of insulin secretion in response to intravenous challenges to glucose and delayed and blunted insulin secretion in response to the oral glucose tolerance test (10–12), and these abnormalities are more pronounced when glycemic status worsens (11–13). Insulin therapy is therefore the recommended treatment for CFRD …