Insulin deficiency largely underlies cystic fibrosis related diabetes (CFRD). CF liver disease (CFLD) is a risk factor for CFRD development, but the mechanisms linking these mortality-increasing comorbidities are unknown. This pilot study sought to characterize prandial glucose metabolism and islet function in youth across glycemia and CFLD spectrums.
Glucose, insulin, c-peptide (CP) and glucagon were obtained during a 3-hr oral glucose tolerance test in youth (9M/11F, ages 12-21y) with pancreatic insufficient CF from two centers. Fasting insulin sensitivity (HOMA-IR) and insulin clearance (CP:insulin), and prandial glucose and glucagon excursion (AUC180), insulin sensitivity (Matsuda index), β-cell sensitivity to glucose, insulin secretory rates (ISR; by parametric deconvolution of CP kinetics) and disposition index (DI, composite of insulin secretion and insulin sensitivity) were calculated. CFLD status was defined using CFLD guidelines: CFLD with portal hypertension (CFLDPH), CFLD without portal hypertension (CFLD) and no liver disease (CFnoLD).
CFLDPH (n=3), CFLD (n=3) CFnoLD (n=14) did not differ in age, BMI-Z, or HbA1c. CFRD was present in 2 CFLDPH, 0 CFLD, 4 CFnoLD. Fasting glucose was greater in CFLDPH vs. CFLD or CFnoLD (p<0.05). HOMA-IR and fasting CP:insulin were reduced in CFLDPH vs. CFLD and CFnoLD, but post-meal glucose-AUC180 and indices of insulin sensitivity and clearance were similar. ISR and DI tended to be lower in CFLDPH vs. CFLD (p=0.008 and p=0.077) and CFnoLD (p=0.071 and p=0.058), respectively. β-cell sensitivity was reduced in CFLDPH vs. CFLD (p<0.05). Fasting and AUC180 glucagon did not differ among groups.
In this limited group of youth, reduced fasting insulin sensitivity and magnified insulin secretory defects are present in CFLDPH, the more severe form of CFLD, and may explain their heightened CFRD risk. Larger studies are warranted to define pathogenesis and inform glycemic treatment targets in individuals with severe CFLD.
M.S. Rayas: None. K.S. Hughan: Research Support; Self; Novo Nordisk Inc. R. Javaid: None. D. leung: None. D. Stefanovski: None. A. Kelly: None. M. Salehi: None.
Cystic Fibrosis Foundation (RAYAS16GEO, HUGHAN16GE0, MOR16CFF); National Institutes of Health (5T32DK00772923)