EP546 - ECE_1252 - Mechanistic pathways linking maternal diabetes to offspring obesity and metabolic syndrome: quantitative synthesis of impact

Abstract

Children born to mothers with diabetes—both gestational and pregestational—are at increased risk for obesity and metabolic syndrome later in life. This association is mediated by a complex interplay of prenatal and postnatal mechanisms, which have been increasingly elucidated through clinical and experimental research. Understanding the relative impact of each mechanism is critical for early identification and risk stratification of vulnerable offspring. To systematically evaluate and quantify the mechanisms by which maternal diabetes predisposes offspring to obesity and metabolic syndrome, and to determine their relative contributions based on published data. A comprehensive review was conducted of 40 studies published between 2000 and 2024 that addressed the biological and developmental mechanisms linking maternal diabetes to obesity and metabolic disorders in offspring. Mechanisms were grouped into five main categories: fetal programming via hyperglycemia and insulin exposure, altered adipose tissue development, endocrine and hormonal alterations, epigenetic imprinting, and postnatal influences including feeding behavior and microbiome changes. Quantitative synthesis and impact estimates were derived by pooling reported effect sizes or proportions across studies. Among the five categories of mechanisms identified, fetal programming emerged as the most impactful, accounting for approximately 30% of the total mechanistic contribution. This includes intrauterine hyperglycemia leading to beta-cell hyperplasia, hyperinsulinemia, and permanent alterations in energy regulation. Altered adipose tissue development contributed an estimated 25%, associated with increased fetal adiposity and adipocyte hyperplasia. Hormonal disruptions—including impaired leptin and adiponectin signaling—were responsible for approximately 20% of the effect, followed by epigenetic mechanisms such as DNA methylation of metabolic genes (15%). Postnatal factors, including altered infant feeding patterns, taste preferences, and gut microbiome dysbiosis, were estimated to contribute 10% to the total impact. These proportions reflect data synthesized from observational birth cohort studies, epigenomic analyses, and animal models. The predisposition to obesity and metabolic syndrome in offspring of diabetic mothers arises from a multifactorial process rooted in both prenatal and postnatal exposures. Quantitative analysis reveals that fetal programming and adipose tissue development are the predominant mechanisms, but endocrine, epigenetic, and environmental factors also play significant roles. These findings underscore the need for mechanistic-based risk assessments in clinical practice to guide early interventions in at-risk children