Response of the Lung to Pulmonary Insulin Dosing in the Rat Model and Effects of Changes in Formulation

Abstract

The hope that pulmonary insulin will provide increased patient compliance and quality of life has created great interest in patients with diabetes, the medical community, and the general public. A pulmonary insulin product is becoming a reality with clinical trials indicating comparable glycemic control with no change in pulmonary function. However, the longterm effects of pulmonary insulin dosing are not known, and as more pulmonary formulations for insulin and other proteins are rapidly being developed the need for further safety data continues to grow. Using gene microarrays, we compared differences in the levels of mRNAs in the lung tissue of rats that were administered a subcutaneous injection or a pulmonary instillation of insulin, as well as rats receiving an pulmonary instillation of insulin and a drug delivery agent. While the insulin doses achieved comparable blood glucose depression and serum insulin concentrations, 30 mRNAs were differentially regulated in response to pulmonary dosing, including 10 mRNAs associated with an immune response and four associated with the lung's response to injury, as well as ion channels and transcription factors. When disodium 8-((N-salicyloyl-2-amino-4-chloro)phenoxy)octanoate, a drug delivery agent known to facilitate pulmonary absorption, was instilled in combination with the pulmonary insulin dose, an attenuation of this response was observed. These findings suggest that undesirable effects of pulmonary dosing may be avoided by changes in formulation and that further evaluation of the effects of chronic pulmonary administration of insulin is warranted.