Nondiabetic patients with end-stage renal disease (ESRD) have disturbed glucose metabolism, the underlying pathophysiology of which is unclear. To help elucidate this, we studied patients with ESRD and either normal or impaired glucose tolerance (10 each NGT or IGT, respectively) and 11 controls using an oral glucose tolerance test and an isoglycemic intravenous glucose infusion on separate days. Plasma glucose, insulin, glucagon, and incretin hormones were measured repeatedly, and gastrointestinal-mediated glucose disposal (GIGD) based on glucose amounts utilized, and incretin effect based on incremental insulin responses, were calculated. The GIGD was significantly reduced in both ESRD groups compared with controls. Incretin effects were 69% (controls), 55% (ESRD with NGT), and 41% (ESRD with IGT), with a significant difference between controls and ESRDs with IGT. Fasting concentrations of glucagon and incretin hormones were significantly increased in patients with ESRD. Glucagon suppression was significantly impaired in both groups with ESRD compared with controls, while the baseline-corrected incretin hormone responses were unaltered between groups. Thus, patients with ESRD had reduced GIGD, a diminished incretin effect in those with IGT, and severe fasting hyperglucagonemia that seemed irrepressible in response to glucose stimuli. These factors may contribute to disturbed glucose metabolism in ESRD.