New Criteria for Indeterminate Glucose Tolerance in Pancreatic Insufficient Cystic Fibrosis Based on Defects in β-Cell Secretory Capacity

Presentation Number: OR11-5
Date of Presentation: April 1st, 2017

Sarah C. Nyirjesy1, Saba Sheikh2, Denis Hadjiliadis1, Diva D. De Leon2, Amy J. Peleckis1, Jack N. Eiel1, Christina Kubrak2, Darko Stefanovski3, Ronald C. Rubenstein2, Michael R. Rickels1 and Andrea Kelly*2
1Hospital of the University of Pennsylvania, Philadelphia, PA, 2Children's Hospital of Philadelphia, Philadelphia, PA, 3University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA

Abstract

Patients with pancreatic insufficient cystic fibrosis (PI) who are defined as having normal glucose tolerance (PI-NGT) according to current clinical guidelines display impaired β-cell secretory capacity and early phase insulin secretion defects compared to pancreatic sufficient cystic fibrosis (PS) individuals and healthy controls. To better identify PI patients with early defects in insulin secretion, we sought evidence of impaired β-cell secretory capacity, a measure of functional β-cell mass, using a more stringent parameter for characterizing indeterminate glucose tolerance (PI-IDGT): a 1-hour plasma glucose ≥ 155mg/dL. Metabolic tests, including the mixed-meal tolerance test (MMTT), glucose potentiated arginine (GPA) test, and continuous glucose monitoring (CGM) were conducted across groups of patients with PI categorized by an oral glucose tolerance test (OGTT) as normal (1-hour plasma glucose < 155 and 2-hour < 140 mg/dL; n = 13), indeterminate (1-hour ≥ 155 and 2-hour < 140 mg/dL; n = 13), impaired (PI-IGT: 2-hour ≥ 140 and < 200 mg/dL; n = 8), and diabetic (CFRD: 2-hour ≥ 200 mg/dL; n = 8), and in PS participants (n = 9). PI-IDGT had elevated post-prandial glucose (AUCglu) during the MMTT compared to PS and those with more stringently defined normal glucose tolerance (PI-NGT; P < 0.05 for both). PI-IDGT also exhibited impaired post-prandial insulin responses (AUCins/AUCglu; P < 0.05 vs. PS and PI-NGT) as well as impaired acute insulin and C-peptide responses to glucose-potentiated arginine (P < 0.01 vs. PS and PI-NGT), measures of β-cell secretory capacity derived from the GPA test. Elevated proinsulin secretory ratios were observed under hyperglycemic clamp conditions in PI-IDGT (P < 0.05 vs. PS), suggesting the reduced functional β-cell mass is under excessive β-cell secretory demand resulting in impaired proinsulin processing. PI-IDGT displayed comparable glucose control by CGM to both PS and PI-NGT with increased glucose variability and excursions seen in PI-IGT and CFRD participants (P < 0.05 vs. PS for both). These results indicate that PI patients with 1-hour OGTT glucose as low as 155 mg/dL can already be identified with early impairments in β-cell secretory capacity that is further taxed by increased insulin secretory demand suggestive of increased endoplasmic reticulum stress during exposure to hyperglycemia. Future studies should address whether dietary and/or pharmacological interventions to reduce pancreatic β-cell stress in PI-IDGT may delay progression to development of CFRD.

 

Nothing to Disclose: SCN, SS, DH, DDD, AJP, JNE, CK, DS, RCR, MRR, AK