OGTT Early C-Peptide Index for Clamp-Measured Acute β-Cell Secretory Capacity

Acute glucose-stimulated β-cell secretion is a key dimension of β-cell function, but the hyperglycemic clamp used to assess it is technically demanding and resource-intensive, limiting its use at scale. We aimed to develop and validate the oral glucose tolerance test (OGTT) Early C-peptide (OEC) Index for estimating clamp-derived acute C-peptide response to glucose (ACPRg). We defined OEC as the 0–60-min incremental C-peptide area under the curve (AUC) normalized to the geometric mean of incremental and total glucose AUCs, with a fasting-glucose correction of 100/G₀. OEC was evaluated in paired OGTT–clamp data from RISE Adult Medication (baseline n=257; internal validation) and BetaFat (baseline n=70; external validation). Predictive R² and Pearson r for log-ACPRg were assessed using participant-level 5-fold cross-validation in RISE and external validation without refitting in BetaFat, with the C-peptidogenic, insulinogenic, and CIR30 indices as comparators. In RISE Adult, cross-validated R² for OEC was 0.47, 0.61, and 0.54 at baseline, 12, and 15 months, respectively, with corresponding Pearson r of 0.69, 0.78, and 0.74; nested cross-validation showed only modest attenuation. Applied without refitting in BetaFat, OEC yielded R² of 0.55, 0.41, and 0.39 at baseline, 12, and 24 months, with corresponding r of 0.76, 0.70, and 0.64. OEC had higher predictive R² point estimates than all three comparators at every visit in both cohorts. OEC provides a simple, transparent OGTT-based estimate of acute β-cell secretory capacity that retained predictive performance in BetaFat and may broaden access to physiological assessment of early β-cell function.