INSULIN SENSITIVITY IN CYSTIC-FIBROSIS

Cystic fibrosis (CF) patients demonstrate a spectrum of pancreatic bet a-cen abnormalities. Those with no exocrine insufficiency (NEXO) have normal insulin secretion. Exocrine-insufficient CF patients with overt diabetes (EXO-IT) have impaired insulin secretion and fasting hypergl ycemia. Exocrine-insufficient patients without diabetes (EXO) have imp aired insulin secretion but maintain normoglycemia. We postulated that EXO individuals compensate for insulin deficiency by increasing insul in sensitivity and investigated glucose utilization in CF. To examine hepatic and peripheral insulin sensitivity, euglycemic-hyperinsulinemi c clamp studies were performed by using the hot GINF isotope dilution technique. Insulin was sequentially infused at 0.25, 1.0, and 10.0 mU . kg(-1) min(-1). Glucose-mediated glucose uptake (GMGU) was assessed on another day with hyperglycemic clamp studies, during which insulin and somatostatin were infused to hold insulin-mediated glucose uptake constant between the two clamp studies. Skeletal muscle GLUT4 levels w ere assessed in EXO and control patients with Western blotting. Three patterns of peripheral and hepatic insulin sensitivity were seen that were related to the degree of pancreatic beta-cen dysfunction. NEXO in dividuals had normal peripheral and hepatic insulin sensitivity. EXO i ndividuals had enhanced peripheral insulin sensitivity that was not as sociated with a change in skeletal muscle glucose transporter abundanc e compared with control patients; paradoxically, EXO subjects demonstr ated hepatic insulin resistance. EXO-IT had peripheral and hepatic ins ulin resistance. GMGU was diminished in both EXO and EXO-IT subjects. The unique combination of increased hepatic glucose production and inc reased peripheral glucose utilization seen in EXO may be a metabolic a daptation to increased peripheral energy needs. Increased glucose util ization is not attributable to a change in skeletal muscle GLUT4 or gl ycogen levels. Insulin resistance in CF patients with overt diabetes m ay be related to severe hyperglycemia secondary to impairment of insul in secretion.