Impact of Smoking on the Metabolic Action of Subcutaneous Regular Insulin in Type 2 Diabetic Patients

Abstract

Background and Aims: Smoking has repeatedly been associated with alterations in both insulin sensitivity and insulin absorption in type 2 diabetes, which should lead to differences in the pharmacokinetic (PK) and pharmacodynamic (PD) properties of regular insulin (RI). However, a direct comparison of the PK/PD-effects of RI has never been performed in these patients. Therefore, the aim of this exploratory study was to investigate the time-action profile of RI in a small group of smoking and matching non-smoking patients with type 2 diabetes using the euglycemic glucose clamp technique, which is seen as the gold standard for PD/PK investigations. Material and Methods: Nine smokers (more than 10 cigarettes per day) and nine non-smokers matched for gender, age, and BMI (without significant differences in HbA_1c, diabetes duration or blood pressure) were enrolled in the study. Patients’ blood glucose was stabilized overnight at 7.2 mmol/l using a Biostator. Smokers were required to smoke one cigarette within ninety minutes prior to injection of 18 U RI s. c. in the morning. Glucose infusion rates (GIR) were registered for the subsequent 480 min. Results: Injection of 18 U of RI resulted in significantly higher insulin concentrations in smokers compared to non-smokers, in particular in the later part of the experiment (Insulin-AUC_{240 - 480} 10.5 ± 2.3 (mean ± SD) vs. 7.8 ± 1.6 μU/ml/min, p < 0.05). This was also reflected in the PD results with a higher metabolic effect in smokers in the last four hours of the experiment (GIR-AUC_{240 - 480} 0.9 ± 0.4 vs. 0.6 ± 0.3 g/kg, p < 0.05). Pharmacokinetic analyses revealed a trend towards a lower insulin clearance in smokers (1.1 ± 0.2 vs. 1.4 ± 0.4 l/min, p = 0.08). Conclusions: This pilot study conducted in a small group of patients with type 2 diabetes shows that regular insulin exhibits a longer-lasting rise in insulin concentrations and a higher metabolic effect four to eight hours after injection in smokers compared to non-smokers. This suggests that hyperinsulinemia in smoking type 2 diabetic patients is at least partly caused by a deterioration in insulin clearance.