title: Modelling endogenous insulin concentration in type 2 diabetes during closed-loop insulin delivery.
abstract: BACKGROUND
  Closed-loop insulin delivery is an emerging treatment for type 1 diabetes (T1D) evaluated clinically and using computer simulations during pre-clinical testing. Efforts to make closed-loop systems available to people with type 2 diabetes (T2D) calls for the development of a new type of simulators to accommodate differences between T1D and T2D. Presented here is the development of a model of posthepatic endogenous insulin concentration, a component omitted in T1D simulators but key for simulating T2D physiology.
  
  
  METHODS
  We evaluated six competing models to describe the time course of endogenous insulin concentration as a function of the plasma glucose concentration and time. The models were fitted to data collected in insulin-naive subjects with T2D who underwent two 24-h visits and were treated, in a random order, by either closed-loop insulin delivery or glucose-lowering oral agents. The model parameters were estimated using a Bayesian approach, as implemented in the WinBUGS software. Model selection criteria were used to identify the best model describing our clinical data.
  
  
  RESULTS
  The selected model successfully described endogenous insulin concentration over 24 h in both study periods and provided plausible parameter estimates. Model-derived results were in concordance with a clinical finding which revealed increased posthepatic endogenous insulin concentration during the control study period (P < 0.05). The modelling results indicated that the excess amount of insulin can be attributed to the glucose-independent effect as the glucose-dependent effect was similar between visits (P > 0.05).
  
  
  CONCLUSIONS
  A model to describe endogenous insulin concentration in T2D including components of posthepatic glucose-dependent and glucose-independent insulin secretion was identified and validated. The model is suitable to be incorporated in a simulation environment for evaluating closed-loop insulin delivery in T2D.
authors.affiliation: Department of Paediatrics, University of Cambridge, Cambridge, UK. yr233@cam.ac.uk.|Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK. yr233@cam.ac.uk.
authors.forename: Yue
authors.initials: Y
authors.lastname: Ruan
authors.affiliation: Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK. ht312@medschl.cam.ac.uk.
authors.forename: Hood
authors.initials: H
authors.lastname: Thabit
authors.affiliation: Department of Paediatrics, University of Cambridge, Cambridge, UK. mew37@medschl.cam.ac.uk.|Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK. mew37@medschl.cam.ac.uk.
authors.forename: Malgorzata E
authors.initials: ME
authors.lastname: Wilinska
authors.affiliation: Department of Paediatrics, University of Cambridge, Cambridge, UK. rh347@cam.ac.uk.|Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK. rh347@cam.ac.uk.
authors.forename: Roman
authors.initials: R
authors.lastname: Hovorka
mesh_terms: D000284:Administration, Oral; D001499:Bayes Theorem; D001786:Blood Glucose / Q000032:analysis; D003198:Computer Simulation; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy; D004040:Dietary Carbohydrates / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D007328:Insulin / Q000097:blood* / Q000378:metabolism; D007332:Insulin Infusion Systems; D061268:Insulin Lispro / Q000008:administration & dosage*; D000078790:Insulin Secretion; D008390:Markov Chains; D008962:Models, Theoretical; D019397:Pancreas, Artificial; D019518:Postprandial Period
chemical_list: D001786:Blood Glucose; D004040:Dietary Carbohydrates; D007004:Hypoglycemic Agents; D007328:Insulin; D061268:Insulin Lispro