Cinnamic acid improves insulin sensitivity in prediabetic mice through branched-chain amino acid metabolic reprogramming.

BACKGROUND

Insulin resistance is a key pathological feature in the early stages of type 2 diabetes mellitus (T2DM), often associated with obesity and metabolic dysfunction. Cinnamic acid (CA) is a natural compound found abundantly in cinnamon and other dietary sources, has demonstrated antidiabetic potential. However, its preventive role in improving insulin sensitivity during the prediabetic stage and the underlying mechanisms remain poorly understood.

METHODS

This study evaluated the preventive effects of cinnamic acid in a high-fat diet (HFD)-induced prediabetic mouse model. Male C57BL/6 N mice were divided into control and intervention groups and treated with CA for 12 weeks. Glucose and insulin tolerance tests, histopathological analysis, serum biochemistry, transcriptomics, metabolomics, and molecular docking and dynamics simulations were performed.

RESULTS

CA significantly improved glucose tolerance, lowered fasting glucose and improved insulin sensitivity, and reduced adiposity in HFD-fed mice. Integrated transcriptomic and metabolomic analyses indicated enhanced branched-chain amino acid (BCAA) degradation in adipose tissue following CA treatment, marked by upregulation of key metabolic enzymes and decreased local and systemic BCAA levels. Molecular docking and dynamics confirmed stable binding between CA and target enzymes involved in BCAA catabolism. Furthermore, CA reduced inflammatory markers, increased adiponectin signaling, and restored GLUT4 expression in adipose tissue.

CONCLUSIONS

CA prevents HFD-induced impairment of insulin sensitivity in prediabetic mice by promoting BCAA catabolism and alleviating adipose inflammation. These findings support its potential as a safe and cost-effective nutrition-based intervention for early prevention of metabolic disorders.