Bidirectional Relationship between Thyroid Hormones and Insulin Regulation in Neonates: Molecular Mechanisms

Abstract

Thyroid hormones and insulin are key regulators of neonatal metabolic adaptation, acting through a reciprocal endocrine network that supports glucose homeostasis, growth and cellular maturation after birth. During the transition from intrauterine to extrauterine life, neonates require rapid metabolic reorganisation, and thyroid hormones, particularly triiodothyronine (T3), contribute to this process by influencing pancreatic β-cell maturation, hepatic glucose production and peripheral insulin sensitivity. Experimental findings indicate that T3 supports β-cell functional development through transcriptional activation of genes such as MAFA, thereby facilitating glucose-stimulated insulin secretion. Conversely, insulin signalling may influence thyroid hormone action during the neonatal period by modulating growth-related pathways, including insulin-like growth factors, and by affecting tissue-level thyroid hormone metabolism. This reciprocal regulation involves deiodinases, thyroid hormone receptors and intracellular cascades such as PI3K/Akt, which integrate endocrine and metabolic responses during early life. Disruption of thyroid function associated with maternal disease, prematurity or environmental influences may disturb this balance, leading to altered insulin sensitivity, impaired glucose metabolism and possible long-term metabolic consequences. This review synthesises evidence on the molecular mechanisms underlying the bidirectional relationship between thyroid hormones and insulin regulation in neonates, with emphasis on transcriptional regulation, epigenetic modification, hormone-receptor interactions, glucose transport, hepatic glucose output and peripheral insulin action. It also considers how intrauterine influences and neonatal endocrine immaturity may shape thyroid-insulin crosstalk in clinically vulnerable infants soon after birth. Understanding these interconnected mechanisms may assist in clarifying neonatal metabolic programming and may support more integrated approaches to the diagnosis and management of endocrine and metabolic disturbances in early life.