title: Modelling the effect of insulin on the disposal of meal-attributable glucose in type 1 diabetes.
abstract: The management of postprandial glucose excursions in type 1 diabetes has a major impact on overall glycaemic control. In this work, we propose and evaluate various mechanistic models to characterize the disposal of meal-attributable glucose. Sixteen young volunteers with type 1 diabetes were subject to a variable-target clamp which replicated glucose profiles observed after a high-glycaemic-load ([Formula: see text]) or a low-glycaemic-load ([Formula: see text]) evening meal. [6,6-[Formula: see text]] and [U-[Formula: see text];1,2,3,4,5,6,6-[Formula: see text]] glucose tracers were infused to, respectively, mimic: (a) the expected post-meal suppression of endogenous glucose production and (b) the appearance of glucose due to a standard meal. Six compartmental models (all a priori identifiable) were proposed to investigate the remote effect of circulating plasma insulin on the disposal of those glucose tracers from the non-accessible compartments, representing e.g. interstitium. An iterative population-based parameter fitting was employed. Models were evaluated attending to physiological plausibility, posterior identifiability of their parameter estimates, accuracy-via weighted fitting residuals-and information criteria (i.e. parsimony). The most plausible model, best representing our experimental data, comprised: (1) a remote effect x of insulin active above a threshold [Formula: see text] = 1.74 (0.81-2.50) [Formula: see text] min[Formula: see text] [median (inter-quartile range)], with parameter [Formula: see text] having a satisfactory support: coefficient of variation CV = 42.33 (31.34-65.34) %, and (2) steady-state conditions at the onset of the experiment ([Formula: see text]) for the compartment representing the remote effect, but not for the masses of the tracer that mimicked endogenous glucose production. Consequently, our mechanistic model suggests non-homogeneous changes in the disposal rates for meal-attributable glucose in relation to plasma insulin. The model can be applied to the in silico simulation of meals for the optimization of postprandial insulin infusion regimes in type 1 diabetes.
authors.affiliation: Bioengineering and Telemedicine Group, Universidad Politécnica de Madrid, ETSI Telecomunicación - Avda. Complutense 30, 28040, Madrid, Spain. fgarcia@gbt.tfo.upm.es.|Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain. fgarcia@gbt.tfo.upm.es.
authors.forename: Fernando
authors.identifier: http://orcid.org/0000-0001-6605-9038
authors.initials: F
authors.lastname: García-García
authors.affiliation: Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
authors.forename: Roman
authors.initials: R
authors.lastname: Hovorka
authors.affiliation: Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
authors.forename: Malgorzata E
authors.initials: ME
authors.lastname: Wilinska
authors.affiliation: Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
authors.forename: Daniela
authors.initials: D
authors.lastname: Elleri
authors.affiliation: Bioengineering and Telemedicine Group, Universidad Politécnica de Madrid, ETSI Telecomunicación - Avda. Complutense 30, 28040, Madrid, Spain.|Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain.
authors.forename: M Elena
authors.initials: ME
authors.lastname: Hernando
mesh_terms: D000293:Adolescent; D001786:Blood Glucose / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000097:blood / Q000627:therapeutic use*; D008297:Male; D008954:Models, Biological; D008962:Models, Theoretical; D019518:Postprandial Period / Q000502:physiology*; D015203:Reproducibility of Results; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D007328:Insulin; D005947:Glucose
keywords: Compartmental model; Glucose disposal; Glucose tracer; Mass balance; Parameter estimation; Type 1 diabetes