Metabolic phenotype of Stage 1 and Stage 2 type 1 diabetes using modelling of beta cell function.

Abstract

Context: 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.

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 (AUC C-peptide, HOMA2-B) and sensitivity (HOMA-IR, HOMA2-S, Matsuda Index) and oral minimal model derived insulin secretion (phi total), sensitivity (SI), and clearance were adopted to characterize the cohort.

Results: Thirty participants with Stage 1 and 27 with Stage 2 T1D 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<0.001) and sensitivity (p=0.034) in those with Stage 2 T1D, as well as increased insulin clearance (p=0.006). A higher baseline phi total was associated with reduced odds of disease progression, independent of Stage [OR 0.92 (0.86, 0.98), p=0.016].

Conclusion: The oral minimal model describes the differential metabolic phenotype of Stage 1 and Stage 2 T1D and identifies phi total as a progression predictor. This supports its use as a sensitive tool and endpoint for T1D prevention trials.