The aim of this study was to determine the metabolic effect and the safety of a novel oral insulin spray (Oralin) formulation at breakfast-time in subjects with type 2 diabetes with suboptimal glucose control and maintained on a combination therapy of oral hypoglycemic agents (OHAs). This was an open-label, crossover, randomized study design in subjects (n = 21) with type 2 diabetes (glycated hemoglobin A1c >8.0%). Subjects received each of the following treatments, in random order: metformin + glyburide and placebo puffs at time 0 min; or metformin + glyburide and Oralin spray (100 U) at time 0 min. Fifteen minutes later, subjects were given a standard breakfast containing 360 calories [Sustacal™ (Mead Johnson, Evansville, IN) liquid meal]. Blood samples were taken at regular intervals to measure serum glucose, insulin, and C-peptide. Time-averaged postprandial glucose increments (PPGIs) between 0 and 240 min were calculated for each treatment. Group mean PPGIs to OHAs versus Oralin in combination with OHAs were compared to determine the mean efficacy of the active treatment. The Oralin spray lowered the 2-h postprandial glucose rise significantly in comparison with the OHAs alone. The serum insulin levels were significantly higher with faster onset of action in the Oralin spray treatment when compared with the OHAs treatment. The reductions in C-peptides were also significantly greater in the Oralin arm than in the OHAs treatment. This study results demonstrated that Oralin could be used as meal insulin as an add-on therapy in combination with failing OHAs treatment in subjects with type 2 diabetes to regulate postprandial glucose levels.