The Potential Physiologic Mechanisms by Which Early-Life Nutrition May Influence Type 2 Diabetes Pathophysiology in Humans

Severe nutrient deficiency in utero has been associated with elevated type 2 diabetes (T2D) odds across the life span. Optimal early-life nutrition interventions that mitigate T2D in adulthood remain unclear, largely due to limited understanding of the underlying biologic pathways. In this review, we summarize recent evidence of physiologic mechanisms by which early-life nutrition could influence T2D pathophysiology in adulthood. We focus on studies evaluating genes as effect modifiers as well as epigenetic reprogramming of gene expression, structural development of key tissues and organs, and accelerated biological aging as causal mediators. We present evidence regarding biologic alterations that are nutrition sensitive during the first 1,000 days of life and could persistently impact glucose-insulin homeostasis across decades. This review emphasizes studies published from 2015 to 2025, with large-scale biological data generated from high-throughput technologies.