Objective: Extra cellular nucleotides and nucleosides are involved in regulation of skeletal muscle blood flow. Diabetes induces cardiovascular dysregulation but the extent to which the vasodilatatory capacity of nucleotides and nucleosides are affected in type 2 diabetes is unknown. The present study investigated: 1) the vasodilatatory effect of ATP, UTP, and adenosine (ADO) and 2) the expression and distribution of P2Y(2) and P2X(1) receptors in skeletal muscles of diabetic subjects. Research Design and Methods: In 10 diabetic patients and 10 age-matched controls, leg blood flow (LBF) was measured during intrafemoral artery infusion of ATP, UTP, and ADO eliciting a blood flow equal to knee-extensor exercise at 12 watts ( approximately 2.6 L/min). Results: The vasodilatatory effect of the purinergic system was 50 % lower in the diabetic group as exemplified by a LBF increase by 274+/-37 vs. 143+/-26 ml/mu;mol ATP x kg; by 494+/-80 vs. 234+/-39 ml/mumol UTP x kg; and by 14.9+/-2.7 vs. 7.5+/-0.6 ml/mumol ADO x kg in control and diabetic subjects, respectively, thus making the vasodilator potency: UTP-controls (100) > ATP-controls (55) > UTP-DM (47) > ATP-DM (29) > ADO-controls (3) > ADO-DM (1.5). The distribution and mRNA-expression of receptors were similar in the two groups. Conclusions: The vasodilatatory effect of the purinergic system is severely reduced in type 2 diabetic patients. The potency of nucleotides varies with the following rank order: UTP>ATP>>>ADO. This is not due to alterations in receptor distribution and mRNA expression, but may be due to differences in receptor sensitivity.