title: Minimal modeling of insulin secretion in the perfused rat pancreas: a drug effect case study.
abstract: The experimental protocol of the perfused rat pancreas is commonly used to evaluate β-cell function. In this context, mathematical models become useful tools through the determination of indexes that allow the assessment of β-cell function in different experimental groups and the quantification of the effects of antidiabetic drugs, secretagogues, or treatments. However, a minimal model applicable to the isolated perfused rat pancreas has so far been unavailable. In this work, we adapt the C-peptide minimal model applied previously to the intravenous glucose tolerance test to obtain a specific model for the experimental settings of the perfused pancreas. Using the model, it is possible to estimate indexes describing β-cell responsivity for first (ΦD) and second phase (ΦS, T) of insulin secretion. The model was initially applied to untreated pancreata and afterward used for the assessment of pharmacologically relevant agents (the gut hormone GLP-1, the potent GLP-1 receptor agonist lixisenatide, and a GPR40/FFAR1 agonist, SAR1) to quantify and differentiate their effect on insulin secretion. Model fit was satisfactory, and parameters were estimated with good precision for both untreated and treated pancreata. Model application showed that lixisenatide reaches improvement of β-cell function similarly to GLP-1 (11.7- vs. 13.1-fold increase in ΦD and 2.3- vs. 2.8-fold increase in ΦS) and demonstrated that SAR1 leads to an additional improvement of β-cell function in the presence of postprandial GLP-1 levels.
authors.affiliation: Department of Information Engineering, University of Padua, Paduaa, Italy; and.
authors.forename: Michela
authors.initials: M
authors.lastname: Riz
authors.forename: Morten Gram
authors.initials: MG
authors.lastname: Pedersen
authors.forename: Gianna Maria
authors.initials: GM
authors.lastname: Toffolo
authors.forename: Guido
authors.initials: G
authors.lastname: Haschke
authors.forename: Hans-Christoph
authors.initials: HC
authors.lastname: Schneider
authors.forename: Thomas
authors.initials: T
authors.lastname: Klabunde
authors.forename: Daniel
authors.initials: D
authors.lastname: Margerie
authors.forename: Claudio
authors.initials: C
authors.lastname: Cobelli
mesh_terms: D000465:Algorithms; D000818:Animals; D052216:Glucagon-Like Peptide 1 / Q000819:agonists / Q000378:metabolism* / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000819:agonists / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008954:Models, Biological; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism / Q000494:pharmacology; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism; D018027:Receptors, Glucagon / Q000819:agonists / Q000378:metabolism*; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D000067758:Glucagon-Like Peptide-2 Receptor
chemical_list: D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D020559:Monomeric GTP-Binding Proteins; D010455:Peptides; D043562:Receptors, G-Protein-Coupled; D018027:Receptors, Glucagon; C473035:G-protein-coupled receptor 40, rat; C000593835:Glp1r protein, rat; C479460:lixisenatide; D000067758:Glucagon-Like Peptide-2 Receptor; C487879:SAR1 protein, rat
keywords: biphasic insulin secretion; lixisenatide; minimal model; perfused pancreas; β-cell function