Pharmacokinetics of insulin lispro in type 2 diabetes during closed-loop insulin delivery

Abstract

Insulin pharmacokinetics is not well understood during continuous subcutaneous insulin infusion in type 2 diabetes (T2D). We analyzed data collected in 11 subjects with T2D [6 male, 9 white European and two of Indian ethnicity; age 59.7(12.1) years, BMI 30.1(3.9)kg/m2, fasting C-peptide 1002.2(365.8)pmol/l, fasting plasma glucose 9.6(2.2)mmol/l, diabetes duration 8.0(6.2) years and HbA1c 8.3(0.8)%; mean(SD)] who underwent a 24-h study investigating closed-loop insulin delivery at the Wellcome Trust Clinical Research Facility, Cambridge, UK. Subcutaneous delivery of insulin lispro was modulated every 15min according to a model predictive control algorithm. Two complementary insulin assays facilitated discrimination between exogenous (lispro) and endogenous plasma insulin concentrations measured every 15–60min. Lispro pharmacokinetics was represented by a linear two-compartment model whilst parameters were estimated using a Bayesian approach applying a closed-form model solution. The time-to-peak of lispro absorption (tmax) was 109.6 (75.5–120.5)min [median (interquartile range)] and the metabolic clearance rate (MCRI) 1.26 (0.87–1.56)×10−2l/kg/min. MCRI was negatively correlated with fasting C-peptide (rs=−0.84; P=.001) and with fasting plasma insulin concentration (rs=−0.79; P=.004). In conclusion, compartmental modelling adequately represents lispro kinetics during continuous subcutaneous insulin infusion in T2D. Fasting plasma C-peptide or fasting insulin may be predictive of lispro metabolic clearance rate in T2D but further investigations are warranted.