Effects of inhaled human insulin on airway lining fluid composition in adults with diabetes

Abstract

Inhaled human insulin (Exubera1 (human insulin of rDNA origin) Inhalation Powder) causes small, early and reversible changes in pulmonary function in subjects with diabetes mellitus. The present study assessed whether changes occur in cellular and soluble constituents of airway lining fluid consistent with inflammation as a possible cause for Exubera1-associated lung function alterations.Two 31-week, open-label, sequential design phase 2 studies were conducted, one with 20 subjects with type 1 and one with 24 subjects with type 2 diabetes. After run-in, all subjects received subcutaneous insulin for 12 weeks, followed after 1 week by 12 weeks of Exubera1. Bronchoalveolar lavage fluid cell counts and protein constituents were determined at baseline, after 12 weeks of subcutaneous insulin and after 12 weeks of Exubera1.Baseline cellular and soluble constituents of lavage fluid were similar to those reported for nondiabetic adults. Exubera1 produced no consistent clinically or statistically significant changes in total or differential lavage fluid cell counts or protein concentrations, even though Exubera1-associated changes in pulmonary function are known to be fully manifest within 12 weeks.Therefore, 12 weeks of Exubera1 treatment is not associated with evidence of pulmonary inflammation. The treatment effects on lung function observed in Exubera1 trials are not caused by lung inflammation.

Trough Insulin Levels in Bronchoalveolar Lavage Following Inhaled Human Insulin (Exubera) in Patients with Diabetes Mellitus

“…21 In the present analysis, baseline-adjusted concentrations of free and total insulin after 12 weeks of EXU therapy are compared with concentrations after 12 weeks of…”

“…21 In brief, the study included subjects with type 1 diabetes mellitus (T1DM) between 18 and 55 years of age and subjects with type 2 diabetes (T2DM) between 30 and 55 years of age. Patients had to have normal DL CO , total lung capacity, forced vital capacity (FVC), and FEV 1 , [22][23][24] and an FEV 1 /FVC ratio of >70%.…”

“…Initial processing of the BAL fluid was conducted at the five local sites. 21 Concentrations of free and total insulin in plasma and BAL fluid were determined by a sandwich enzyme-linked immunosorbent assay, using monoclonal antibodies against human insulin (Mercodia, Winston Salem, NC). For the determination of total insulin, insulin-antibody complexes were dissembled by quick acidification/neutralization of the sample.…”

“…20 Other components of this bronchoalveolar lavage (BAL) study reported that EXU therapy is not accompanied by signs of pulmonary inflammation at the macroscopic or microscopic level. 21 To better understand the transport of insulin and other potentially therapeutic proteins across the air-blood barrier, as well as the mechanisms of the changes in pulmonary function observed during inhaled insulin therapy, it is crucial to study the alveolar concentrations of insulin during EXU therapy.…”

Nanomedicine for treatment of diabetes in an aging population: State-of-the-art and future developments

“…During the treatment in several studies non-inflammatory related changes of the lung function were observed and additionally coughing after the treatment was an often observed side-effect [52]. While the lung provides a large surface area for micro-and nano-particles uptake the drug-particle surface will be changed by proteins and lipids from lung surfactant as it was observed for NPs [53].…”