Maternal diabetes programs sexually dimorphic early-onset cardiovascular dysfunction in metabolically healthy offspring.

The incidence of cardiovascular disease (CVD) in young individuals is increasing. This alarming trend underscores the need to identify at-risk groups for preventive measures. Emerging evidence suggests that maternal diabetes increases the risk for metabolic diseases and early-onset CVDs in their offspring. However, the evidence is largely observational, limited by confounding factors, and lacks crucial mechanistic insight. Here, we combine experimental, epidemiological, and clinical approaches to disentangle the effects of maternal diabetes on offspring metabolism and endothelial function. In mice, we find that maternal hyperglycemia induces early-onset endothelial dysfunction specifically in male offspring, independent of metabolic disease. In humans, a case-control study and an epidemiological study confirm elevated risk of early-onset endothelial dysfunction and related CVDs in metabolically healthy sons of mothers with type 1 diabetes. Our findings identify an underrecognized risk group for early-onset CVDs and emphasize the importance of maternal conditions in shaping the cardiovascular health of future generations.