Reduced β-Cell Secretory Capacity in Pancreatic-Insufficient, but Not Pancreatic-Sufficient, Cystic Fibrosis Despite Normal Glucose Tolerance

Patients with pancreatic insufficient cystic fibrosis (PI-CF) are at increased risk for developing diabetes. We determined β-cell secretory capacity and insulin secretory rates from glucose-potentiated arginine and mixed meal tolerance tests (MMTT), respectively, in pancreatic sufficient cystic fibrosis (PS-CF), PI-CF, and normal control subjects, all with normal glucose tolerance, in order to identify early pathophysiologic defects. Acute islet cell secretory responses were determined under fasting, 230 mg/dL, and 340 mg/dL hyperglycemia clamp conditions. PI-CF subjects had lower acute insulin, C-peptide and glucagon responses compared to PS-CF and normal, indicating reduced β-cell secretory capacity and α-cell function. Fasting proinsulin-to-C-peptide and proinsulin secretory ratios during glucose-potentiation were higher in PI-CF, suggesting impaired proinsulin processing. In the first 30 minutes of the MMTT, insulin secretion was lower in PI-CF compared to PS-CF and normal, and glucagon like peptide-1 and gastric inhibitory polypeptide were lower compared to PS-CF, and after 180 minutes, glucose was higher in PI-CF compared to controls. These findings indicate that despite “normal” glucose tolerance, adolescents and adults with PI-CF have impairments in functional islet mass and associated early phase insulin secretion, which with decreased incretin responses likely leads to the early development of post-prandial hyperglycemia in CF.