Abstract
The classification of type 2 diabetes and prediabetes does not consider heterogeneity in the pathophysiology of glucose dysregulation. Here we show that prediabetes is characterized by metabolic heterogeneity, and that metabolic subphenotypes can be predicted by the shape of the glucose curve measured via a continuous glucose monitor (CGM) during standardized oral glucose-tolerance tests (OGTTs) performed in at-home settings. Gold-standard metabolic tests in 32 individuals with early glucose dysregulation revealed dominant or co-dominant subphenotypes (muscle or hepatic insulin-resistance phenotypes in 34% of the individuals, and β-cell-dysfunction or impaired-incretin-action phenotypes in 40% of them). Machine-learning models trained with glucose time series from OGTTs from the 32 individuals predicted the subphenotypes with areas under the curve (AUCs) of 95% for muscle insulin resistance, 89% for β-cell deficiency and 88% for impaired incretin action. With CGM-generated glucose curves obtained during at-home OGTTs, the models predicted the muscle-insulin-resistance and β-cell-deficiency subphenotypes of 29 individuals with AUCs of 88% and 84%, respectively. At-home identification of metabolic subphenotypes via a CGM may aid the risk stratification of individuals with early glucose dysregulation.