Metabolic Phenotype of Stage 1 and Stage 2 Type 1 Diabetes Using Modeling of β Cell Function

Background Staging preclinical type 1 diabetes (T1D) and monitoring the response to disease-modifying treatments rely on the oral glucose tolerance test (OGTT). However, it is unknown whether OGTT-derived measures of beta cell function can detect subtle changes in metabolic phenotype, thus limiting their usability as endpoints in prevention trials. Objective To describe the metabolic phenotype of people with Stage 1 and Stage 2 T1D using metabolic modelling of beta cell function. Methods We characterized the metabolic phenotype of individuals with islet autoimmunity in the absence (Stage 1) or presence (Stage 2) of dysglycemia. Participants were screened at a TrialNet site and underwent a 5-point, 2-hour OGTT. Standard measures of insulin secretion (area under the curve, C-peptide, Homeostatic Model Assessment [HOMA] 2-B) and sensitivity (HOMA Insulin Resistance, HOMA2-S, Matsuda Index) and oral minimal model–derived insulin secretion (Phi total), sensitivity (sensitivity index), and clearance were adopted to characterize the cohort. Results Thirty participants with Stage 1 and 27 with Stage 2T1D were selected. Standard metrics of insulin secretion and sensitivity did not differ between Stage 1 and Stage 2 T1D, while the oral minimal model revealed lower insulin secretion (P < .001) and sensitivity (P = .034) in those with Stage 2 T1D, as well as increased insulin clearance (P = .006). A higher baseline Phi total was associated with reduced odds of disease progression, independent of stage (OR 0.92 [0.86, 0.98], P = .016). Conclusion The oral minimal model describes the differential metabolic phenotype of Stage 1 and Stage 2 T1D and identifies the φ total as a progression predictor. This supports its use as a sensitive tool and endpoint for T1D prevention trials.