Journal
DIABETES
Volume 66, Issue 1, Pages 134-144Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db16-0394
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Funding
- Cystic Fibrosis Foundation
- National Institute of Diabetes and Digestive and Kidney Diseases [R01DK97830, K23DK107937, P30DK19525, T32DK007314]
- National Center for Advancing Translational Sciences [UL1TR000003]
- Joanne and Raymond Welsh Research Fellowship
- Human Metabolism Resource of the University of Pennsylvania Institute for Diabetes, Obesity, and Metabolism
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Patients with pancreatic-insufficient cystic fibrosis (PI-CF) are at increased risk for developing diabetes. We determined beta-cell secretory capacity and insulin secretory rates from glucose-potentiated arginine and mixed-meal tolerance tests (MMTTs), respectively, in pancreatic sufficient 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 beta-cell secretory capacity and alpha-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.
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