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

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.

Figure 1

Islet cell hormone levels (A: insulin; B: C-peptide; C: proinsulin; D: glucagon) in response to bolus administration of arginine (arrows) under fasting, ∼230 mg/dL, and ∼340 mg/dL hyperglycemic clamp conditions in PS-CF (closed circles), PI-CF (open circles), and healthy control subjects (normal range given as the 95% CI and shown as gray shaded area). CF subject data are represented at mean ± SE. *P < 0.05; **P < 0.01.

Figure 2

A: AIRs to arginine as a function of the prestimulus plasma glucose concentration in PS-CF (closed circles), PI-CF (open circles), and healthy control subjects (normal, open triangles). Data are given as mean ± SE. The glucose potentiation slope (GPS), calculated as the difference in the AIR at fasted and ∼230 mg/dL glucose levels divided by the difference in plasma glucose, is impaired in PI-CF vs. both PS-CF and normal (0.3 ± 0.2 vs. 1.0 ± 0.6 and 0.7 ± 0.4; **P = 0.002). β-Cell sensitivity to glucose is determined as the PG₅₀ using the y intercept (b) of the GPS to solve the equation AIR_max/2 = GPS × PG₅₀ + b and was not different across groups. B: Box plot of insulin sensitivity (M/I) by study group, given as median and IQR (box) and mean (open squares) and range (error bars), is similar across PS-CF, PI-CF, and normal control subjects.

Figure 3

Glucose (A), ISR (B), GLP-1 (C), and GIP (D) levels during the 4-h MMTT in PS-CF (closed circles), PI-CF (open circles), and healthy control subjects (normal range given as the 95% CI and shown as gray shaded area). CF subject data are given as mean ± SE.