β-Cell secretory defects are present in pancreatic insufficient cystic fibrosis with 1-hour oral glucose tolerance test glucose ≥155 mg/dL

Abstract

Background: Patients with pancreatic insufficient cystic fibrosis (PI-CF) meeting standard criteria for normal glucose tolerance display impaired β-cell secretory capacity and early-phase insulin secretion defects. We sought evidence of impaired β-cell secretory capacity, a measure of functional β-cell mass, among those with early glucose intolerance (EGI), defined as 1-hour oral glucose tolerance test (OGTT) glucose ≥155 mg/dL (8.6 mmol/L).

Methods: A cross-sectional study was conducted in the Penn and CHOP Clinical & Translational Research Centers. PI-CF categorized by OGTT as normal (PI-NGT: 1-hour glucose <155 mg/dL and 2-hour <140 mg/dL [7.8 mmol/L]; n = 13), PI-EGI (1-hour ≥155 mg/dL and 2-hour <140 mg/dL; n = 13), impaired (PI-IGT: 2-hour ≥140 and <200 mg/dL [11.1 mmol/L]; n = 8), and diabetic (cystic fibrosis-related diabetes, CFRD: 2-hour ≥200 mg/dL; n = 8) participated. Post-prandial glucose tolerance and insulin secretion, and β-cell secretory capacity and demand were derived from mixed-meal tolerance tests (MMTTs), and glucose-potentiated arginine (GPA) tests, respectively.

Results: PI-EGI had elevated post-prandial glucose with reduced early-phase insulin secretion during MMTT compared to PI-NGT (P < .05). PI-EGI also exhibited impaired acute insulin and C-peptide responses to GPA (P < .01 vs PI-NGT), measures of β-cell secretory capacity. Proinsulin secretory ratios were higher under hyperglycemic clamp conditions in PI-IGT and CFRD (P < .05 vs PI-NGT), and correlated with 1-hour glucose in PI-CF (P < .01).

Conclusions: PI-CF patients with 1-hour OGTT glucose ≥155 mg/dL already manifest impaired β-cell secretory capacity with associated early-phase insulin secretion defects. Avoiding hyperglycemia in patients with EGI may be important for preventing excessive insulin demand indicated by disproportionately increased proinsulin secretion.

Keywords: cystic fibrosis-related diabetes; early glucose intolerance; insulin secretion; proinsulin secretory ratio; β-cell secretory capacity.

FIGURE 1

Continuous glucose monitoring (CGM) for >72 hours in representative individual subjects with PI-CF. PI-CF subjects were categorized by an oral glucose tolerance test (OGTT) as normal (NGT: 1-hour glucose <155 mg/dL [8.6 mmol/L] and 2-hour glucose <140 mg/dL [7.8 mmol/L]), early glucose tolerance (EGI: 1-hour glucose ≥155 mg/dL and 2-hour glucose <140 mg/dL), impaired (IGT: 2-hour glucose ≥140 mg/dL and <200 mg/dL [11.1 mmol/L]), or diabetic (CFRD: 2-hour glucose ≥200 mg/dL). (A) 17-year-old female with PI-NGT. (B) 20-year-old female with PI-EGI. (C) 29-year-old male with PI-IGT. (D) 27-year-old female with CFRD, controlled by diet

FIGURE 2

Plasma glucose (A) and insulin secretory rates (B) in response to the mixed-meal tolerance test (MMTT) in subjects with pancreatic insufficient CF (PI-CF). Impaired mixed-meal tolerance (A) and early-phase insulin secretion (B) were consistent with the oral glucose tolerance test categorization (NGT, normal glucose tolerance; EGI, early glucose intolerance; IGT, impaired glucose tolerance; CFRD, CF-related diabetes). Acute insulin responses to arginine as a function of the pre-stimulus plasma glucose concentration (C) derived from the glucose-potentiated arginine test indicate a downward shift consistent with reduced β-cell secretory capacity in PI-EGI that is similar as for PI-IGT, progressing further in CFRD, with no change in β-cell sensitivity to glucose (PG₅₀). Insulin sensitivity (D) calculated as M/I from the ~230 mg/dL (13 mmol/L) glucose clamp was not different across the groups of PI subjects. In A, B, and C data are given as mean ± SE, and in D as median and interquartile range (box) and mean (open squares) and range (error bars). Normal ranges are provided as the 95% CI for data derived from healthy control subjects

FIGURE 3

Relationship between oral glucose tolerance test (OGTT) 1-hour glucose and β-cell secretory capacity (ACR_max; A) and proinsulin secretory ratio (PISR; B) during the ~340 mg/dL (19 mmol/L) hyperglycemic clamp