title: Circadian variability of insulin sensitivity: physiological input for in silico artificial pancreas.
abstract: BACKGROUND
  Closed-loop control clinical research trials have been considerably accelerated by in silico trials using the Food and Drug Administration-accepted type 1 diabetes mellitus (T1DM) simulator. We have recently demonstrated that postprandial insulin sensitivity (SI) in T1DM subjects was lower at breakfast (B) than lunch (L) and dinner (D), but not significantly, because of the small population size. The goal of this study was therefore to incorporate this novel information into the University of Virginia/Padova T1DM simulator and to reproduce in silico the observed circadian variability.
  
  
  METHODS
  Twenty T1DM subjects received an identical mixed meal at B, L, and D. SI was calculated for each meal using the oral glucose minimal model. Seven SI daily patterns were identified, and their probabilities were estimated. Each in silico subject was linked to a time-varying SI profile, while random deviations of up to 40% were allowed.
  
  
  RESULTS
  Simulations were compared with experimental data. The integrated area above the basal glucose curve values were 2.60 ± 0.91 (B), 1.38 ± 0.91 (L), and 1.44 ± 1.07 (D) 10(4) min · mg/dL in silico versus 2.87 ± 1.65 (B), 1.98 ± 1.56 (L), and 2.16 ± 2.00 (D) 10(4) min · mg/dL in vivo. Incremental peak glucose values were 109 ± 33 (B), 80 ± 29 (L), and 81 ± 30 (D) mg/dL in silico versus 136 ± 39 (B), 126 ± 37 (L), and 125 ± 48 (D) mg/dL in vivo.
  
  
  CONCLUSIONS
  The incorporation of a time-varying SI into the simulator makes this technology suitable for running multiple-meal scenarios, thus enabling a more robust design of artificial pancreas algorithms.
authors.affiliation: 1 Department of Information Engineering, University of Padova , Padova, Italy .
authors.forename: Roberto
authors.initials: R
authors.lastname: Visentin
authors.forename: Chiara
authors.initials: C
authors.lastname: Dalla Man
authors.forename: Yogish C
authors.initials: YC
authors.lastname: Kudva
authors.forename: Ananda
authors.initials: A
authors.lastname: Basu
authors.forename: Claudio
authors.initials: C
authors.lastname: Cobelli
mesh_terms: D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D001786:Blood Glucose / Q000502:physiology; D002940:Circadian Rhythm / Q000502:physiology*; D003198:Computer Simulation; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000503:physiopathology; D005260:Female; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D062407:Meals / Q000502:physiology*; D008875:Middle Aged; D019397:Pancreas, Artificial; D015203:Reproducibility of Results; D014481:United States; D014486:United States Food and Drug Administration; D055815:Young Adult
chemical_list: D001786:Blood Glucose