TIME TO PEAK INSULIN LEVEL, RELATIVE BIOAVAILABILITY, AND EFFECT OF SITE OF DEPOSITION OF NEBULIZED INSULIN IN PATIENTS WITH NONINSULIN-DEPENDENT DIABETES-MELLITUS

Seven fasting patients with noninsulin-dependent diabetes mellitus (NI DDM) inhaled 1.0 U/kg of body weight of nebulized regular pork insulin by mouth or were subcutaneously (sc) injected with 0.1 U/kg of body w eight of insulin in the upper arm on two different occasions. The time to peak insulin level was compared for the two treatment modalities. Insulin bioavailability after inhalation was quantified relative to sc injected insulin, Deposition of a radiolabeled insulin surrogate aero sol (insulin diluent) in the larger central airways versus the periphe ral airways, expressed as the inner-to-outer (I:O) ratio, and in the L ung apex versus the lung base, expressed as the apex-to-basal (A:B) ra tio, was quantified with gamma scintigraphy, Ratios were related to gl ucose responses after inhalation of insulin. Times to peak insulin lev el mere similar for the two methods of treatment, averaging 43 +/- 16 and 64 +/- 40 minutes after inhalation and sc injection of insulin, re spectively. The bioavailability of inhaled insulin averaged 14.7% +/- 5.8% relative to sc injected insulin. This was significantly less than the average bioavailability of deposited drug (18.9% +/- 5.3%) relati ve to sc injected insulin (P < 0.05), I:O and A:B ratios for the surro gate aerosol averaged 1.3 +/- 0.4 and 0.7 +/- 0.2, respectively, Linea r regression analysis revealed that the maximum percentage of decrease in glucose after insulin inhalation was significantly related to the A:B ratio such that percentage decrease in glucose was greater in pati ents who demonstrated a lower A:B ratio (P = 0.003). Percentage decrea se in glucose was not related to the I:O ratio. These results indicate that the bioavailability of nebulized insulin inhaled by mouth is app roximately 20% when calculated in terms of drug deposited and suggest that increasing the distribution of insulin aerosol to the base of the lung enhances the glucose response in patients with NIDDM during the fasting state.