The aim of this study was to compare the glucose pharmacodynamics after oral spray insulin (Oral-lyn , Generex Biotechnology, Toronto, ON, Canada) and subcutaneous (sc) injection of regular insulin in 10 subjects with type 1 diabetes mellitus (T1DM). Basal therapy was twice-daily insulin glargine. Preprandial (30 min) regular insulin was given for 3 days, followed by 9 days of Oral-lyn, eight to 12 puffs immediately pre- and postprandially. Adjustments for glycemia were made using standard snacks and additional regular insulin or Oral-lyn. Peripheral glucose measurements were self-monitored in duplicate. Serum concentrations of fructosamine and hemoglobin A1c (HbA1c) were determined at the start and the end of the study period. Average glucose concentrations (in mmol/L) for the 3-day regular insulin and 9-day Oral-lyn periods, respectively, were: pre-breakfast (B), 5.06 and 3.89; 1-h post-B, 8.39 and 7.67; post-B, 6.00 and 6.33; pre-lunch (L), 5.50 and 4.72; 1-h post-L, 7.83 and 7.89; 2-h post-L, 5.89 and 6.33; pre-dinner (D), 5.61 and 5.17; 1-h post-D, 7.22 and 7.83; and 2-h post-D, 6.11 and 6.67. Areas under the curve for both treatments were not significantly different (P = 0.6875). Fructosamine (mean +/- SD, 338.7 +/- 77.4 micromol/L and 321.7 +/- 63.4 micromol/L), and HbA1c (mean +/- SD, 7.5 +/- 1.5% and 7.2 +/- 1.2%) did not change significantly. Regular insulin and Oral-lyn had similar glucodynamic effects in subjects with T1DM receiving twice-daily insulin analogue as baseline therapy. Intensive monitoring and timely corrections with additional snacks, additional sc regular insulin, or Oral-lyn puffs resulted in appropriate glycemic control as assessed by individual daily glycemic responses and, especially, normal preprandial glycemia. Protein glycation decreased, but not significantly.