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

Diabetes. 2017 Jan;66(1):134-144. doi: 10.2337/db16-0394. Epub 2016 Aug 5.

Abstract

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.

MeSH terms

  • 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*
  • Proinsulin / metabolism
  • Young Adult

Substances

  • C-Peptide
  • Incretins
  • Insulin
  • Gastric Inhibitory Polypeptide
  • Glucagon-Like Peptide 1
  • Glucagon
  • Proinsulin
  • Glucose