Metabolic Imprinting and Intergenerational Cardiometabolic Risk in Human Populations: Implications for Preconception and Maternal Health.

Abstract

The global rise in obesity and type 2 diabetes has been too rapid to be explained by genetic change alone, which points to developmental and environmental contributions to cardiometabolic risk. Metabolic conditions during sensitive windows, particularly preconception, pregnancy, and early postnatal life, appear to shape long-term metabolic regulation and disease susceptibility. In this narrative review, we synthesise human cohort studies, natural experiments, and experimental models, and we translate the resulting evidence into clinical and public health practice. Across human cohorts, maternal metabolic disturbances such as gestational diabetes and obesity are consistently associated with higher offspring risk of obesity, insulin resistance, and impaired glucose regulation, with adjusted estimates commonly between 1.4- and 2.0-fold. Epigenome-wide studies report differential DNA methylation in insulin-signalling, adipogenic, and energy-homeostasis pathways, lending biological plausibility, and experimental models show that transient early perturbations can durably alter metabolic physiology even after diet is later normalised. We read these converging findings as metabolic imprinting: relatively stable but potentially modifiable regulatory states, rather than deterministic germline inheritance. Set against current guidance from the ADA, FIGO, WHO, USPSTF, and ACOG, the evidence supports concrete actions across the reproductive life course, including preconception screening and weight optimisation, gestational diabetes screening and glycaemic management, appropriate gestational weight gain, and postpartum and offspring follow-up. Preconception and maternal metabolic health therefore emerge as practical, high-value targets for reducing the long-term cardiometabolic burden.