Insulin resistance and metabolic dysfunction in thyroid nodules and differentiated thyroid cancer

The global rise in obesity, metabolic syndrome (MetS), insulin resistance (IR), and type 2 diabetes mellitus (T2DM) is reshaping the epidemiology of thyroid disorders, particularly thyroid nodular disease and differentiated thyroid cancer (DTC). This review summarizes emerging evidence linking metabolic dysfunction to thyroid nodule growth and tumorigenesis.

Chronic hyperinsulinemia in IR states activates mitogenic pathways, including PI3K/AKT/mechanistic target of rapamycin (mTOR) and MAPK/ERK. These effects are amplified in thyrocytes overexpressing insulin receptor isoform A (INSR-A) and insulin-like growth factor 1 receptor (IGF1R). Dysfunctional adipose tissue further increases risk through enhanced leptin signaling, reduced adiponectin-mediated AMPK activation, and persistent systemic inflammation and oxidative stress. Environmental factors such as endocrine-disrupting chemicals and gut microbiota alterations add additional susceptibility. Clinical evidence supports these mechanistic links: patients with thyroid nodules consistently show higher HOMA-IR values, and large cohort studies identify MetS as an independent predictor of thyroid nodularity. Female-specific susceptibility appears to be mediated by estrogen receptor activity, adipokine profiles, and postmenopausal fat redistribution. Therapeutically, metformin shows promise via AMPK activation and mTOR inhibition, exerting both metabolic and antiproliferative effects, although randomized trials specific to thyroid cancer outcomes remain limited. Concerns about GLP-1 receptor agonists and thyroid safety are largely theoretical; current data suggest their established cardiometabolic benefits may outweigh potential risks.

Converging epidemiological, molecular, and translational evidence underscores the complex interplay between metabolic dysfunction and thyroid diseases. Integrating metabolic health into prevention, risk stratification, and treatment strategies will be essential for advancing precision management of thyroid nodules and DTC.