OBJECTIVE -To compare the dose-response relationship following inhalation of regular insulin delivered via the Aerodose insulin inhaler with that following subcutaneously injected regular insulin in patients with type 2 diabetes.RESEARCH DESIGN AND METHODS -Twenty-four patients with type 2 diabetes (21 nonsmoking men, aged 36 -80 years) each received two of three doses of 80, 160, or 240 units inhaled regular insulin, delivered via a clinical Aerodose insulin inhaler, and two of three corresponding doses of 8, 16, or 24 units by subcutaneous injection under isoglycemic clamp conditions on 4 separate study days in an incomplete block design study. Glucose infusion rates (GIRs) and serum insulin concentrations were monitored over the following 8 h.RESULTS -Inhaled insulin exhibited significantly shorter time-to-peak insulin levels (T max 77 Ϯ 66 vs. 193 Ϯ 104 min, P Ͻ 0.001) and time-to-peak metabolic effects (T GIRmax 240 Ϯ 94 vs. 353 Ϯ 60 min, P Ͻ 0.001) compared with subcutaneously injected insulin. Comparison of total insulin absorption (insulin area under the curve [AUC]) versus total metabolic effect (GIR-AUC) from 0 to 8 h (group means) revealed overlapping dose-response relationships for both inhaled and subcutaneous injection treatments. Comparison of slopes revealed no significant differences between the inhaled and subcutaneous injection treatment groups (P ϭ 0.6). No significant differences in either relative bioavailability or relative biopotency were found among doses, indicating a consistent subcutaneous injection-to-inhaled dosing conversion ratio among doses. No serious adverse events or clinically relevant changes in lung function were observed.CONCLUSIONS -The overlapping dose-response curves of inhaled and subcutaneous treatments together with a consistent relative bioavailability and relative biopotency for inhaled insulin across doses suggest that the Aerodose insulin inhaler will deliver a pharmacologically predictable insulin dose to patients with diabetes similar to that observed following subcutaneous injection. Diabetes Care 26:2842-2847, 2003D emonstrating that inhaled insulin can be titrated similar to subcutaneous injection is an important prerequisite to showing the clinical viability of this novel mode of insulin delivery. Although several specialized aerosol delivery systems are currently in various stages of development for pulmonary delivery of insulin (1-3), a head-to-head comparison of the dose response of inhaled and subcutaneously injected insulin has not been reported. The Aerodose insulin inhaler is developed to deliver aerosolized liquid insulin to meet the preprandial insulin needs of patients with diabetes. The aim of the present study was, therefore, to compare the dose-response relationship of inhaled and subcutaneously injected insulin and to determine the resulting inhalation-to-subcutaneous injection conversion ratio across three doses in patients with type 2 diabetes. RESEARCH DESIGN ANDMETHODS -A single-center, openlabel, randomized, active-controlled, crossover s...