title: Insulin kinetics in type-I diabetes: continuous and bolus delivery of rapid acting insulin.
abstract: We investigated insulin lispro kinetics with bolus and continuous subcutaneous insulin infusion (CSII) modes of insulin delivery. Seven subjects with type-1 diabetes treated by CSII with insulin lispro have been studied during prandial and postprandial conditions over 12 hours. Eleven alternative models of insulin kinetics have been proposed implementing a number of putative characteristics. We assessed 1) the effect of insulin delivery mode, i.e., bolus or basal, on the insulin absorption rate, the effects of 2) insulin association state and 3) insulin dose on the rate of insulin absorption, 4) the remote insulin effect on its volume of distribution, 5) the effect of insulin dose on insulin disappearance, 6) the presence of insulin degradation at the injection site, and finally 7) the existence of two pathways, fast and slow, of insulin absorption. An iterative two-stage parameter estimation technique was used. Models were validated through assessing physiological feasibility of parameter estimates, posterior identifiability, and distribution of residuals. Based on the principle of parsimony, best model to fit our data combined the slow and fast absorption channels and included local insulin degradation. The model estimated that 67(53-82)% [mean (interquartile range)] of delivered insulin passed through the slow absorption channel [absorption rate 0.011(0.004-0.029) min(-1)] with the remaining 33% passed through the fast channel [absorption rate 0.021(0.011-0.040) min(-1)]. Local degradation rate was described as a saturable process with Michaelis-Menten characteristics [VMAX = 1.93(0.62 - 6.03) mU min(-1), KM = 62.6(62.6 - 62.6) mU]. Models representing the dependence of insulin absorption rate on insulin disappearance and the remote insulin effect on its volume of distribution could not be validated suggesting that these effects are not present or cannot be detected during physiological conditions.
authors.affiliation: Department of Paediatrics, University of Cambridge, Cambridge, CB2 2QQ, UK. mew37@medschl.cam.ac.uk
authors.forename: Malgorzata E
authors.initials: ME
authors.lastname: Wilinska
authors.forename: Ludovic J
authors.initials: LJ
authors.lastname: Chassin
authors.forename: Helga C
authors.initials: HC
authors.lastname: Schaller
authors.forename: Lukas
authors.initials: L
authors.lastname: Schaupp
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Pieber
authors.forename: Roman
authors.initials: R
authors.lastname: Hovorka
mesh_terms: D000328:Adult; D000465:Algorithms; D003198:Computer Simulation; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000188:drug therapy*; D004360:Drug Therapy, Computer-Assisted / Q000379:methods*; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007328:Insulin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000097:blood* / Q000493:pharmacokinetics; D007332:Insulin Infusion Systems; D061268:Insulin Lispro; D007700:Kinetics; D008297:Male; D008954:Models, Biological; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D016896:Treatment Outcome
chemical_list: D007328:Insulin; D061268:Insulin Lispro