TY - JOUR
T1 - Reduced β-cell secretory capacity in pancreatic-insufficient, but not pancreatic-sufficient, cystic fibrosis despite normal glucose tolerance
AU - Sheikh, Saba
AU - Gudipaty, Lalitha
AU - De Leon, Diva D.
AU - Hadjiliadis, Denis
AU - Kubrak, Christina
AU - Rosenfeld, Nora K.
AU - Nyirjesy, Sarah C.
AU - Peleckis, Amy J.
AU - Malik, Saloni
AU - Stefanovski, Darko
AU - Cuchel, Marina
AU - Rubenstein, Ronald C.
AU - Kelly, Andrea
AU - Rickels, Michael R.
N1 - Funding Information:
This work was supported by the Cystic Fibrosis Foundation (to A.K. and M.R.R.), the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK97830 to A.K. and M.R.R., K23DK107937 to S.S., P30DK19525 [University of Pennsylvania Diabetes Research Center], and T32DK007314 [University of Pennsylvania Training Grant in Diabetes, Endocrine and Metabolic Diseases]), the National Center for Advancing Translational Sciences (UL1TR000003 [Penn-CHOP Clinical and Translational Research Centers]), the Joanne and Raymond Welsh Research Fellowship (to L.G.), and the Human Metabolism Resource of the University of Pennsylvania Institute for Diabetes, Obesity, and Metabolism.
Publisher Copyright:
© 2017 by the American Diabetes Association.
PY - 2017/1/1
Y1 - 2017/1/1
N2 - 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 pancreaticsufficient 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 a-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.
AB - 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 pancreaticsufficient 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 a-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.
UR - http://www.scopus.com/inward/record.url?scp=85007321693&partnerID=8YFLogxK
U2 - 10.2337/db16-0394
DO - 10.2337/db16-0394
M3 - Article
C2 - 27495225
AN - SCOPUS:85007321693
SN - 0012-1797
VL - 66
SP - 134
EP - 144
JO - Diabetes
JF - Diabetes
IS - 1
ER -