A pathway model of glucose-stimulated insulin secretion in the pancreatic β-cell

The pancreas plays a critical role in maintaining glucose homeostasis through the secretion of hormones from islets Langerhans. Glucose-stimulated insulin (GSIS) by pancreatic β -cell is main mechanism for reducing elevated plasma glucose. Here we present systematic modeling workflow development kinetic pathway models using Systems Biology Markup Language (SBML). Steps include retrieval information databases, curation experimental and clinical data model calibration validation, integration heterogeneous including absolute relative measurements, unit normalization, annotation. An important factor was reproducibility exchangeability model, which allowed use various existing tools. applied to construct novel data-driven GSIS based on 39 studies spanning 50 years pancreatic, islet, research humans, rats, mice, cell lines. consists detailed glycolysis phenomenological equations coupled cellular energy state, ATP dynamics (ATP/ADP ratio). Key findings our work are that there glucose-dependent increase almost all intermediates glycolysis. This glycolytic metabolites accompanied an metabolites, especially NADH. One few decreasing ADP, which, combination with ATP, results large ATP/ADP ratios increasing Insulin dependent ATP/ADP, resulting glucose-stimulated secretion. observed change robust phenomenon across sets, systems species. Model predictions response biphasic good agreement measurements. Our predicts factors affecting consumption, formation, hexokinase, phosphofructokinase, ATP/ADP-dependent have major effect GSIS. In conclusion, developed us gain insight into key mechanisms -cell.