To quantify the pharmacokinetic (PK) and glucodynamic (GD) impact of smoking on inhaled and subcutaneous (SC) insulin administration in healthy subjects.Methods
This study employed the euglycemic clamp procedure in a four-period, four-way randomized crossover design. Eight smoking and eight non-smoking healthy males were given SC insulin on two occasions and human insulin inhalation powder (HIIP) on two other occasions.Results
Smokers exhibited greater insulin exposure (AUC0-t′) than non-smokers, following both routes of insulin administration (HIIP, P = 0.003, 58% increase; SC, P = 0.006, 24% increase). The maximum insulin concentration (Cmax) following HIIP was greater in smokers by 172% (P = 0.001) compared with non-smokers. The glucodynamic effects were greater in smokers following HIIP, consistent with the insulin concentration difference observed. However, maximum glucose response (Rmax) following SC was decreased by 36% (P = 0.001) and obtained later [time of maximum glucose response (TRmax); P < 0.001] in smokers than in non-smokers. Smokers appeared less sensitive to insulin [total glucose infused during the clamp procedure normalised by total insulin exposure (Gtot)/AUC0-t′] than non-smokers following both SC (P = 0.001) and inhaled (P = 0.011) routes of administration.Conclusion
Smokers had substantially increased peak HIIP insulin concentration, but the glucodynamic effect was partially offset, most likely because of increased insulin resistance.