AIM: The aim of the present study was to demonstrate acute, local vasodilatatory effects of insulin and C-peptide on cutaneous microvascular function in Type 1 diabetic subjects. There are no published data available examining physiological effects of C-peptide delivered in this way. METHODS: The study included 20 participants with C-peptide-deficient Type 1 diabetes mellitus. Cutaneous microvascular function was assessed on the forearm using laser Doppler velocimetry. Insulin, C-peptide, acetylcholine (ACh), sodium nitroprusside (SNP) and saline were delivered through the skin using iontophoresis. The response was measured as percentage increase in flux above baseline. RESULTS: C-peptide delivered by iontophoresis produced a vasodilatatory response greater than the response to saline (289.5 +/- 265.9% vs. 105.1 +/- 163.6%, P = 0.003). The response to C-peptide was also shown to be dose dependent. Further, the size of the response to C-peptide correlated well with the size of the response to the endothelium-dependent vasodilatator ACh (r = 0.666, P = 0.001) but not with the size of the response to the endothelium-independent vasodilator SNP (r = 0.345, P > 0.05). CONCLUSIONS: Physiological effects of C-peptide on cutaneous microvascular function could be demonstrated in individuals with Type 1 diabetes. The results support both physiological activity of C-peptide and an endothelium-dependent mechanism similar to that of ACh. The technique reported may be useful in investigating vasoactive actions of C-peptide in a safe and non-invasive way.