To characterize pancreatic endocrine secretion and to examine interrelationships among alterations in alpha, beta, and pancreatic polypeptide cell function in patients with cystic fibrosis (CF), we studied 19 patients with exocrine insufficiency (EXO), including 9 receiving insulin therapy (EXO-IT); 10 patients with no exocrine insufficiency (NEXO); and 10 normal control subjects. First-phase C-peptide response to intravenously administered glucose was significantly impaired in CF patients with exocrine insufficiency (EXO-IT=0.02±0.01; EXO=0.11±0.02; NEXO=0.25±0.05; control subjects=0.30±0.04 nmol/L). Lowering fasting glucose levels with exogenous insulin administration in EXO-IT did not improve beta cell responsivity to glucose. The C-peptide response to arginine was less impaired (EXO-IT=0.12±0.02; EXO=0.15±0.02; NEXO=0.23±0.06; control subjects=0.28±0.04 nmol/L). Alpha cell function, measured as peak glucagon secretion in response to hypoglycemia, was diminished in EXO but not NEXO (EXO-IT=21±10; EXO=62±19; NEXO=123±29; control subjects=109±12 ng/L). Despite diminished glucagon response, EXO patients recovered normally from hypoglycemia. Peak pancreatic polypeptide response to hypoglycemia distinguished CF patients with exocrine insufficiency from those without exocrine insufficiency (EXO-IT=3±2; EXO=3±1; NEXO=226±68; control subjects=273±100 pmol/L). Thus CF patients with exocrine disease have less alpha, beta, and pancreatic polypeptide cell function than CF patients without exocrine disease. These data suggest either that exocrine disease causes endocrine dysfunction in CF or that a common pathogenic process simultaneously and independently impairs exocrine and endocrine function.
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The basic defect in cystic fibrosis appears to be abnormal phosphorylation-dependent activation of the chloride ion channel. I The primary pathologic finding is inspissated ductular mucus, which leads to progressive obstructive damage to the lungs, reproductive system, and pancreas. Up to 95% of CF patients have exocrine pancreatic insuffi- Supported by grants (R01-DK-39994 and M01-RR-00400) from the National Institutes of Health and a grant from the Cystic Fibrosis Foundation. Submitted for publication Aug. 20, 1990; accepted Dec. 12, 1990. Reprint requests: Antoinette Moran, MD, Department of Pediatrics, Box 391, University of Minnesota Health Science Center, 516 Delaware St., Minneapolis, MN 55455, 9/20/27290 ciency,2, 3 and approximately 50% of the CF population has impaired glucose tolerance. 46 Overt diabetes has been reported in 6% to 10% of CF patients 27 and may be associated with a significantly increased mortality rate for pulmonary disease. 7 However, despite the significant number of affected patients, the pathogenesis of defective pancreatic endocrine function in CF is poorly understood. Fibrosis of the exocrine pancreas has been proposed to lead to either disorganization or ischemic destruction of the islets of Langerhans. 4' 8-10 However, an intrinsic abnormality in pancreatic endocrine cells has also been suggested, both because the primary defect in CF is cellular and because autonomic nervous system regulation (which is important for pancreatic hormone secretion) is abnormal in CF. 1114