PMID- 38444582 OWN - NLM STAT- MEDLINE DCOM- 20240307 LR - 20240309 IS - 1664-2392 (Print) IS - 1664-2392 (Electronic) IS - 1664-2392 (Linking) VI - 15 DP - 2024 TI - Early-phase insulin secretion during mixed-meal tolerance testing predicts beta-cell function and secretory capacity in cystic fibrosis. PG - 1340346 LID - 10.3389/fendo.2024.1340346 [doi] LID - 1340346 AB - 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 beta-cell secretory capacity as an estimate of functional beta-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/m(2), 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 beta-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 beta-cell function and secretory capacity when functional beta-cell mass is reduced. These data can inform future multicenter studies requiring reliable, standardized, and technically feasible testing mechanisms to quantify beta-cell function and secretory capacity. CI - Copyright (c) 2024 Sheikh, Stefanovski, Kilberg, Hadjiliadis, Rubenstein, Rickels and Kelly. FAU - Sheikh, Saba AU - Sheikh S AD - Division of Pulmonary and Sleep Medicine, Children's Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States. FAU - Stefanovski, Darko AU - Stefanovski D AD - Department of Clinical Studies-New Bolton Center, University of Pennsylvania School of Veterinary Medicine, Kennett Square, PA, United States. FAU - Kilberg, Marissa J AU - Kilberg MJ AD - Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States. FAU - Hadjiliadis, Denis AU - Hadjiliadis D AD - Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States. FAU - Rubenstein, Ronald C AU - Rubenstein RC AD - Division of Allergy and Pulmonary Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States. FAU - Rickels, Michael R AU - Rickels MR AD - Division of Endocrinology, Diabetes & Metabolism, Department of Medicine and Institute for Diabetes, Obesity & Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States. FAU - Kelly, Andrea AU - Kelly A AD - Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States. LA - eng GR - K23 DK107937/DK/NIDDK NIH HHS/United States GR - P30 DK019525/DK/NIDDK NIH HHS/United States GR - R01 DK097830/DK/NIDDK NIH HHS/United States GR - UL1 TR001878/TR/NCATS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20240220 PL - Switzerland TA - Front Endocrinol (Lausanne) JT - Frontiers in endocrinology JID - 101555782 RN - 0 (C-Peptide) RN - 0 (Insulin) RN - 94ZLA3W45F (Arginine) RN - IY9XDZ35W2 (Glucose) SB - IM MH - Female MH - Humans MH - Young Adult MH - Adult MH - Insulin Secretion MH - *Cystic Fibrosis MH - C-Peptide MH - Prospective Studies MH - Insulin MH - Arginine MH - Glucose PMC - PMC10912512 OTO - NOTNLM OT - beta-cell function OT - beta-cell secretory capacity OT - cystic fibrosis OT - cystic fibrosis-related diabetes OT - insulin secretion OT - pancreatic insufficiency COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2024/03/06 06:43 MHDA- 2024/03/07 06:42 PMCR- 2024/01/01 CRDT- 2024/03/06 03:49 PHST- 2023/11/17 00:00 [received] PHST- 2024/02/05 00:00 [accepted] PHST- 2024/03/07 06:42 [medline] PHST- 2024/03/06 06:43 [pubmed] PHST- 2024/03/06 03:49 [entrez] PHST- 2024/01/01 00:00 [pmc-release] AID - 10.3389/fendo.2024.1340346 [doi] PST - epublish SO - Front Endocrinol (Lausanne). 2024 Feb 20;15:1340346. doi: 10.3389/fendo.2024.1340346. eCollection 2024.