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 phi total as a progression predictor. This supports its use as a sensitive tool and endpoint for T1D prevention trials.