Objective: Glucose intolerance in liver cirrhosis is associated with hepatic decompensation and increased mortality. Nadolol, a beta-blocker used for the treatment of portal hypertension, worsens glucose intolerance; however the mechanism is unclear. We examined the impact of nadolol on BCF in patients with liver cirrhosis. Methods: Twenty two cirrhotic patients participated in a double-blind randomised controlled cross-over trial of nadolol versus placebo for 3 months and, after a 1-month washout period, 3 months on the alternative. The present study includes 15 patients (10 male, 5 female, age range 45–61 years) who had measurements of insulin resistance and BCF, including five time point sampling for c-peptide, insulin and glucose during a 2 hour 75g OGTT performed at the end of each 3-month period. Mathematically-modelled components of BCF included beta-cell glucose sensitivity, beta-cell sensitivity to the rate of change of glucose (rate sensitivity) and potentiation (relative increase in insulin secretion from beginning to end of OGTT). Results: Six cirrhotic patients had impaired glucose tolerance (IGT) and 2 had diabetes at recruitment. Three normoglycaemic patients developed IGT on nadolol (p=0.15). Following 3 months treatment with nadolol, glucose sensitivity was reduced (97±16 vs 81±13pmol.min-1m-2mM-1, p=0.03) without change in rate sensitivity or potentiation; with similar basal and total insulin secretion during the OGTT. Conclusion: We show for the first time that nadolol specifically impaired pancreatic beta-cell glucose sensing ability. Further work is required to confirm whether the detrimental effect of nadolol on glucose tolerance is due to down-regulation of peroxisome proliferator-activated receptor gamma.