Background Early-stage insulin resistance is compensated for by increased insulin secretion. A reliable and easy-to-use mathematical assessment of insulin secretion and disposal could be a valuable tool to identify patients at risk for the development of type 2 diabetes. Because the pathophysiology of insulin resistance is incompletely understood, assessing insulin metabolism with minimal assumptions regarding the metabolic regulation is a major challenge. Materials and Methods To assess insulin secretion and indexes for insulin disposal, our marginalized and regularized absorption approach (MRA) was applied to a sparse sampling oral glucose tolerance test (OGTT) protocol using insulin and C-peptide concentrations. Identifiability and potential bias of metabolic parameters were estimated from published data with dense sampling. This approach was applied to OGTT data from 135 obese adolescents to demonstrate its clinical applicability. Results Individual prehepatic basal and dynamic insulin secretion and clearance values were determined with a precision and accuracy greater than 10% of the nominal value. The inter-subject variability in these parameters was approximately 4 times higher than the intra-subject variability, and there was a close negative correlation between prehepatic secretion and plasma clearance. Conclusion MRA-based analysis provides reliable estimates of insulin secretion and clearance, thereby enabling detailed glucose homeostasis characterization based on restricted datasets that are obtainable during routine patient care.