We read with great interest the letter to the editor regarding our September publication (Cumulative Effect of Hyperglycemia and Insulin Resistance on Cardiac Dysfunction: The Coronary Artery Risk Development in Young Adults [CARDIA] Study). We appreciate the thoughtful comments by EI Dabour et al. and their recognition of the significance of our work. In our study, we demonstrated that the cumulative burden of fasting glucose and insulin resistance is associated with diastolic dysfunction in a young adult cohort. Our findings highlight the importance of early diabetes prevention and effective glycemic control in preserving cardiac function and reducing the risk of cardiovascular disease later in life.
We agree that incorporating other glycemic measures, such as glycemic variability (GV), could further elucidate the relationship between glucose metabolism and cardiac function. Indeed, prior studies suggest that postprandial glucose spikes and other GV indices may be associated with vascular dysfunction and risk of cardiovascular disease. , However, whether these markers provide stronger predictive value for cardiac dysfunction and can be feasibly implemented in large population-based studies remains uncertain. Although several observational studies have linked higher GV, more frequent or larger postprandial spikes, lower time-in-range (TIR), and greater glucose coefficient of variation or standard deviation with subclinical atherosclerosis and adverse cardiovascular outcomes, prospective or causal evidence and standardized definitions are still limited. ,,,, Consequently, GV remains an emerging but not yet fully established clinical predictor of cardiovascular risk.
Furthermore, measuring GV in large epidemiologic cohorts poses major feasibility and methodological challenges. True within-day GV assessment requires dense glucose sampling via continuous glucose monitoring (CGM), which is costly, data-intensive, and burdensome for participants—making large-scale implementation impractical. , Even when feasible, short-term CGM captures only brief snapshots that may not reflect long-term variability, and issues such as data loss, calibration errors, and inconsistent wear patterns introduce additional noise. , As a result, most cohort studies rely on visit-to-visit variability in fasting glucose or HbA1c as proxies, which are easier to obtain but biologically distinct from acute glucose fluctuations. Moreover, GV measures lack standardization. There are more than ten indices that exist, often correlated with mean glucose, hindering cross-study comparability. Confounding by disease severity, medication complexity, and glycemic control further complicates causal interpretation. Together, these factors limit the scalability, reproducibility, and causal inference of GV as an independent epidemiologic predictor of ASCVD risk.
With regard to the concept of metabolic memory, we agree that investigating long-term exposure to hyperglycemia and its association with molecular markers—such as circulating DNA methylation signatures suggested by EI Dabour et al.—would be of great interest. Such analyses could provide unique mechanistic insights into why young adults with or at risk for type 2 diabetes appear to have a higher risk of cardiac dysfunction and subsequent cardiovascular disease than those with later-onset disease. This line of research is particularly important, as the heightened cardiovascular risk observed in young-onset type 2 diabetes remains incompletely understood.
In summary, we appreciate the thoughtful insights provided by EI Dabour et al. Our study underscores the impact of cumulative fasting glucose and insulin resistance on diastolic dysfunction in young adults, highlighting the importance of early diabetes prevention and glycemic control using commonly measured clinical markers, namely fasting glucose and fasting insulin. While measures such as glycemic variability and postprandial glucose may offer additional mechanistic insights, their feasibility and standardization in large population studies remain limited. Further research, including longitudinal assessments of metabolic memory and molecular markers, will be critical to better understand the heightened cardiovascular risk in young adults with or at risk for type 2 diabetes and to inform strategies for early intervention.
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