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

• Published in: Diabetes (New York, N.Y.) Vol. 66; no. 1; pp. 134 - 144
• Main Authors: Sheikh, Saba, Gudipaty, Lalitha, De Leon, Diva D., Hadjiliadis, Denis, Kubrak, Christina, Rosenfeld, Nora K., Nyirjesy, Sarah C., Peleckis, Amy J., Malik, Saloni, Stefanovski, Darko, Cuchel, Marina, Rubenstein, Ronald C., Kelly, Andrea, Rickels, Michael R.
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.01.2017
• Subjects: Adolescent; Adult; C-Peptide - metabolism; Cystic Fibrosis - metabolism; Cystic Fibrosis - pathology; Exocrine Pancreatic Insufficiency - metabolism; Female; Gastric Inhibitory Polypeptide - metabolism; Glucagon - metabolism; Glucagon-Like Peptide 1 - metabolism; Glucose - metabolism; Glucose Tolerance Test; Humans; Incretins - metabolism; Insulin - metabolism; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Male; Middle Aged; Pancreas - metabolism; Pancreas - pathology; Pathophysiology; Proinsulin - metabolism; Young Adult
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db16-0394

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 (MMTTs), 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 with PS-CF and normal control subjects, 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 min of the MMTT, insulin secretion was lower in PI-CF compared with PS-CF and normal control subjects, and glucagon-like peptide 1 and gastric inhibitory polypeptide were lower compared with PS-CF, and after 180 min, glucose was higher in PI-CF compared with normal control subjects. 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 postprandial hyperglycemia in CF.