Endocrine-Metabolic Crosstalk Between Diabetes Mellitus and Hypothyroidism: From Network Mechanisms to Translational...

Diabetes mellitus (DM) and hypothyroidism (HypoT) are common endocrine-metabolic disorders that frequently coexist, forming a biologically complex comorbidity rather than a simple clinical overlap. Increasing evidence suggests that DM-HypoT comorbidity arises from reciprocal disturbances in insulin action, thyroid hormone signaling, immune-inflammatory regulation, and cellular energy sensing. Thyroid hormone deficiency may impair glucose utilization, promote insulin resistance, and aggravate metabolic stress, whereas diabetes-associated hyperinsulinemia, oxidative stress, and chronic inflammation may disrupt hypothalamic-pituitary-thyroid axis activity, thyroid hormone synthesis, and peripheral hormone activation. Subclinical hypothyroidism may represent an early biochemical phenotype within this interaction and often intersects with obesity and metabolic syndrome. Additional biological nodes, including gut dysbiosis, micronutrient imbalance, AGE-RAGE signaling, and tissue-specific mitochondrial dysfunction, may further amplify endocrine-metabolic dysregulation. However, causal hierarchy, tissue specificity, phenotype heterogeneity, and responsive patient subgroups remain incompletely defined. This review synthesizes current epidemiological and mechanistic evidence and proposes an integrated pancreatic islet-immune-gut-thyroid axis framework to support mechanism-informed risk stratification, biomarker development, and translational intervention strategies for DM-HypoT comorbidity.