Mechanisms of insulin resistance in cystic fibrosis

Cystic fibrosis (CF) is associated with a high incidence of diabetes. Studi es evaluating causes of CF-related diabetes (CFRD) have consistently docume nted decreased insulin secretion. In patients with CFRD, insulin sensitivit y has been documented to be decreased, but controversy exists in patients w ith normal or impaired glucose tolerance (IGT). We undertook this study 1) to reexplore insulin sensitivity in patients with IGT and 2) to evaluate po tential mechanisms of insulin resistance in CF, including GLUT-4-translocat ion, elevation of serum cytokines, and free fatty acid (FFA) levels. We rec ruited nine CF subjects with impaired glucose tolerance (IGTCF) and nine ag e-, gender-, and body mass index-matched control volunteers. Each underwent a hyperinsulinemic euglycemic clamp (200 mU.m(-2).min(-1)) to measure insu lin sensitivity. A muscle biopsy was obtained at maximal insulin stimulatio n for measure of GLUT-4 translocation with sucrose gradients. An oral gluco se tolerance test and National Institutes of Health (NIH) clinical status s cores were measured in all volunteers. We also measured tumor necrosis fact or (TNF)-alpha levels and FFA in all subjects. Additionally, we report the results of TNF-alpha and FFA in 32 CF patients previously studied by our gr oup. Results were that glucose disposal rate (GDR) was significantly lower in the CFIGT subjects than in controls, indicative of impaired insulin acti on. GLUT-4 translocation was impaired in CF and correlated with GDR. TNF-al pha levels were higher in all CF subjects than in controls and correlated w ith GDR. There was no difference in FFA between CF and control subjects. Mo dified NIH clinical status scores were inversely correlated with GDR and TN F-alpha levels. We conclude that IGTCF patients have decreased peripheral i nsulin sensitivity. Mechanisms include elevation of TNF-alpha and impaired translocation of GLUT-4.