Metabolic Insights Into Dynamic Glucose Trajectories: Importance of Perturbation

While cardiometabolic conditions are traditionally diagnosed using static fasting assessments, physiological perturbation can unmask subclinical metabolic dysfunction well before resting abnormalities are apparent.The 75-g oral glucose tolerance test (OGTT) offers one of the few commonly used clinical tests employing this paradigm.1 Clinical interpretation of the OGTT has generally centered on 2-hour glucose excursion to define normoglycemia, impaired glucose tolerance, and diabetes in at-risk individuals.Despite decades of research establishing the value for post-OGTT glucose response to stratify future diabetes risk, its use in widespread screening in the clinical setting has been limited by time and effort.2 While contemporary approaches (e.g., continuous glucose monitors) are proposed to fill this gap and begin to resolve the heterogeneous physiologic spectrum underlying diabetes, 3, 4 they lack specificity for systemic mechanisms that may underlie early dysglycemia subtypes and define targets for preventing progression to diabetes.In this issue of Circulation Research, Heianza et al. 5 address this knowledge gap by linking 1-hour post-OGTT glucose response to circulating metabolites reflecting the resting metabolic state.The rationale for focusing on 1-hour glucose is compelling.The authors demonstrate that 1-hour glucose correlated more strongly with total glucose exposure (by AUC) than 2-hour glucose (r=0.96versus 0.79) during an OGTT.It also showed stronger relationships with measures of insulin sensitivity and β-cell function, consistent with prior literature.6 These findings reinforce an increasingly important distinction: the 1-hour post-OGTT glucose concentration is not simply a correlated measure of fasting glucose or an earlier surrogate of a 2-hour glucose excursion.Instead, focusing on the 1-hour time point may provide a unique lens into an individual's physiological reserve to metabolic challenge.