TyG-Centered Endocrine-Metabolic Architecture in Patients with Thyroid Dysfunction: A Systems Phenotyping Study

Area of Science:

• Endocrinology
• Metabolic Syndrome
• Systems Biology

Background:

• Metabolic dysfunction involves complex interactions including insulin resistance, dyslipidemia, and inflammation.
• The triglyceride-glucose (TyG) index is a recognized marker for insulin resistance.
• Characterizing the endocrine-metabolic architecture associated with TyG in thyroid dysfunction requires advanced approaches.

Purpose of the Study:

• To characterize the endocrine-metabolic architecture linked to the TyG index in patients with thyroid dysfunction.
• To explore the utility of the TyG index as a descriptor of metabolic health within distinct phenotypic partitions.
• To investigate the relationship between metabolic and thyroid axes using a systems-phenotyping approach.

Main Methods:

• A systems-phenotyping approach was used on 387 adults evaluated for thyroid dysfunction.
• Unsupervised clustering methods (PCA, K-means, GMM, Ward) were applied to primary metabolic variables.
• Latent profile analysis and a Gaussian graphical model (GGM) were employed to analyze metabolic and thyroid variables.

Main Results:

• Three distinct, overlapping metabolic phenotypes were identified: metabolically preserved (MP), intermediate hepatic-dominant (IHD), and severe insulin-resistance-dominant (SIRD).
• TyG index values increased monotonically across these phenotypes (medians 8.24, 8.74, 8.87), serving as a single-number summary of metabolic gradient.
• Metabolic and thyroid variables formed near-orthogonal blocks, suggesting distinct regulatory axes.

Conclusions:

• Systems phenotyping revealed three clinically relevant metabolic partitions in thyroid dysfunction patients.
• The TyG index serves as a pragmatic descriptor for multidimensional endocrine-metabolic risk stratification.
• Hepatic dysregulation can be an early stage of insulin resistance, and thyroid autoimmunity acts as a parallel modulatory layer.