Objective: Low adipocyte IRS-1 protein expression is a biomarker for insulin resistance and early atherosclerosis. However, whether IRS-1 protein expression is related to systemic arterial stiffness, is unknown. Methods and results: Ten non-diabetic male subjects with low adipocyte IRS-1 protein expression (NIRS) were matched with 10 non-diabetic males with normal IRS-1 protein expression (NIRS). Augmentation index (AIx) and time for reflection of pulse wave (Tr) were studied with pulse wave analysis, both in the fasting state and during a euglycemic hyperinsulinemic clamp. The LIRS-group showed an increased fasting insulin concentration (fP-insulin 71 +/- 4 pmol/L versus 58 +/- 5 pmol/L;p = 0.02 (mean +/- S.E.)), whereas glucose disposal rate during the clamp (8.7 +/- 0.8 mg/kg LBM/min versus 10.3 +/- 1.3 mg/kg LBM/min; n.s.) did not differ significantly. Blood pressure, lipid parameters, adiponectin, endothelin-1 and CRP concentrations were similar. However, in the basal state, AIx was increased (129 +/- 4% versus 116 +/- 2%; p < 0.02) and Tr was decreased (150 +/- 3 ms versus 171 +/- 5 ms; P < 0.01), suggesting stiffer vessels in the LIRS-group. The LIRS-group exhibited an attenuated AIx response to hyperinsulinemia compared to the NIRS-group. Conclusions: The data suggest that non-obese non-diabetic men with a low adipocyte IRS-1 protein expression have an increased systemic arterial stiffness.