The objective of this study was to assess the insulin-independent effects of incretin hormones on glucose and glycerol metabolism and hemodynamics under eu- and hyperglycemic conditions. Young, healthy males (n=10) underwent three trials in a randomized, controlled, cross-over study. Each trial consisted of a 2-stage (eu- and hyperglycemia) pancreatic clamp (using somatostatin to prevent endogenous insulin secretion). Glucose and lipid metabolism were measured via infusion of stable glucose and glycerol isotopic tracers. Hemodynamic variables (femoral, brachial and common carotid artery blood flow; and flow-mediated dilation [FMD] of brachial artery) were also measured. The three trials differed by the following additional infusions: (I) Saline (control; CON); (II) GLP-1 (0.5 pmol/kg/min); and (III) GIP (1.5 pmol/kg/min). No between-trial differences in glucose infusion rates (GIR), glucose or glycerol kinetics were seen during euglycemia, whereas hyperglycemia resulted in increased GIR and glucose rate of disappearance (Rd) during GLP-1 compared to CON and GIP (P<0.01 for all). However, when normalized to insulin levels, no differences between trials were seen for GIR or glucose Rd. Besides a higher femoral blood flow during hyperglycemia in GIP (vs. CON and GLP-1, P<0.001), no between-trial differences were seen for the hemodynamic variables. In conclusion, GLP-1 and GIP have no direct effect on whole body glucose metabolism or hemodynamics during euglycemia. On contrary, during hyperglycemia, GIP increases femoral artery blood flow with no effect on glucose metabolism, whereas GLP-1 increases glucose disposal, potentially, however, due to increased insulin levels.