Early-phase insulin secretion during mixed-meal tolerance testing predicts β-cell function and secretory capacity in cystic fibrosis

Abstract

Insulin secretion within 30 minutes of nutrient ingestion is reduced in people with cystic fibrosis (PwCF) and pancreatic insufficiency and declines with worsening glucose tolerance. The glucose potentiated arginine (GPA) test is validated for quantifying β-cell secretory capacity as an estimate of functional β-cell mass but requires technical expertise and is burdensome. This study sought to compare insulin secretion during mixed-meal tolerance testing (MMTT) to GPA-derived parameters in PwCF.

Methods: Secondary data analysis of CF-focused prospective studies was performed in PwCF categorized as 1) pancreatic insufficient [PI-CF] or 2) pancreatic sufficient [PS-CF] and in 3) non-CF controls. MMTT: insulin secretory rates (ISR) were derived by parametric deconvolution using 2-compartment model of C-peptide kinetics, and incremental area under the curve (AUC) was calculated for 30, 60 and 180-minutes. GPA: acute insulin (AIR) and C-peptide responses (ACR) were calculated as average post-arginine insulin or C-peptide response minus pre-arginine insulin or C-peptide under fasting (AIR_arg and ACR_arg), ~230 mg/dL (AIR_pot and ACR_pot), and ~340 mg/dL (AIR_max and ACR_max) hyperglycemic clamp conditions. Relationships of MMTT to GPA parameters were derived using Pearson's correlation coefficient. Predicted values were generated for MMTT ISR and compared to GPA parameters using Bland Altman analysis to assess degree of concordance.

Results: 85 PwCF (45 female; 75 PI-CF and 10 PS-CF) median (range) age 23 (6-56) years with BMI 23 (13-34) kg/m², HbA_1c 5.5 (3.8-10.2)%, and FEV1%-predicted 88 (26-125) and 4 non-CF controls of similar age and BMI were included. ISR AUC_30min positively correlated with AIR_arg (r=0.55), AIR_pot (r=0.62), and AIR_max (r=0.46) and with ACR_arg (r=0.59), ACR_pot (r=0.60), and ACR_max (r=0.51) (all P<0.001). ISR AUC_30min strongly predicted AIR_arg (concordance=0.86), AIR_pot (concordance=0.89), and AIR_max (concordance=0.76) at lower mean GPA values, but underestimated AIR_arg, AIR_pot, and AIR_max at higher GPA-defined β-cell secretory capacity. Between test agreement was unaltered by adjustment for study group, OGTT glucose category, and BMI.

Conclusion: Early-phase insulin secretion during MMTT can accurately predict GPA-derived measures of β-cell function and secretory capacity when functional β-cell mass is reduced. These data can inform future multicenter studies requiring reliable, standardized, and technically feasible testing mechanisms to quantify β-cell function and secretory capacity.

Keywords: beta-cell function; beta-cell secretory capacity; cystic fibrosis; cystic fibrosis-related diabetes; insulin secretion; pancreatic insufficiency.