title: 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/m(2), 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 15 min according to a model predictive control algorithm. Two complementary insulin assays facilitated discrimination between exogenous (lispro) and endogenous plasma insulin concentrations measured every 15-60 min. 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 (t(max)) was 109.6 (75.5-120.5) min [median (interquartile range)] and the metabolic clearance rate (MCR(I)) 1.26 (0.87-1.56)×10(-2) l/kg/min. MCR(I) was negatively correlated with fasting C-peptide (r(s)=-0.84; P=.001) and with fasting plasma insulin concentration (r(s)=-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.
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Cambridge, UK; Department of Paediatrics, University of Cambridge, Cambridge, UK.
authors.forename: Yue
authors.initials: Y
authors.lastname: Ruan
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Cambridge, UK.
authors.forename: Hood
authors.initials: H
authors.lastname: Thabit
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Cambridge, UK.
authors.forename: Kavita
authors.initials: K
authors.lastname: Kumareswaran
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Cambridge, UK; Department of Paediatrics, University of Cambridge, Cambridge, UK. Electronic address: rh347@cam.ac.uk.
authors.forename: Roman
authors.initials: R
authors.lastname: Hovorka
mesh_terms: D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D003198:Computer Simulation; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy*; D004360:Drug Therapy, Computer-Assisted / Q000379:methods; D025461:Feedback, Physiological; D006801:Humans; D007332:Insulin Infusion Systems; D061268:Insulin Lispro / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
chemical_list: D001786:Blood Glucose; D061268:Insulin Lispro
keywords: Artificial pancreas; Bayesian estimation; Insulin lispro; Mathematical modelling; Pharmacokinetics; Type 2 diabetes