591-P: Glucose Dynamics during OGTT Identify Metabolic Subphenotypes in Individuals with Glucose Dysregulation

Type 2 diabetes (T2D) is a heterogeneous disorder, with a complex physiologic basis. Muscle insulin resistance, beta-cell dysfunction, and impaired incretin effect may be present to differing degrees. Identifying the underlying physiology of glucose dysregulation in a given individual would allow for tailored treatment. We hypothesized that glucose dynamics (i.e., glucotypes) during a frequently-sampled 3-hour OGTT could identify the underlying pathophysiology of glucose dysregulation. If true, glucotypes from OGTT and/or continuous glucose monitoring devices may extend current diagnostic approaches for T2D by defining the dominant metabolic subphenotype.

A total of 33 participants underwent gold-standard metabolic tests including: OGTT with blood sampled every 5-10 min for 180 min with c-peptide deconvolution, isoglycemic intravenous glucose infusion (IIGI), and modified insulin suppression test (IST), to quantify beta-cell function, incretin effect, and insulin resistance. Glucotypes were constructed from a time series with glucose values from the OGTT. Missing timepoints were imputed using cubic smoothing splines. Each series was Z-normalized to focus on the shape of the curve rather than the amplitude. Singular value decomposition was performed and the first two principal components were used in cluster analysis, and related to gold-standard metabolic tests.

Cluster analysis of glucose dynamics variables revealed 2 separable clusters identifying individuals classified as insulin resistant or sensitive based on IST. Beta-cell dysfunction was also distinguishable by cluster analysis. Although impaired incretin effect status was identified using the deconvolution of the c-peptide from the OGTT and IISI, it was not clearly separable through glucotypes.

Glucotypes may be used to identify metabolic subphenotypes in glucose-dysregulated states, with the potential to personalize treatment approaches that address the dominant physiologic defect.