Carbidopa ameliorates high-fat diet-induced insulin resistance by suppressing gut-derived tryptamine/phenethylamine and systemic 5-HT levels.

Obesity and type 2 diabetes mellitus (T2DM) are major global health burdens, with insulin resistance (IR) as a key pathological driver. This study explores carbidopa, a selective aromatic l-amino acid decarboxylase inhibitor, as a modulator of gut-derived metabolites to alleviate high-fat diet (HFD)-induced IR. We observed that HFD markedly increased fecal tryptamine and phenethylamine levels, which positively correlated with elevated serum 5-hydroxytryptamine (5-HT). Carbidopa treatment suppressed gut production of these metabolites, reducing circulating 5-HT and improving insulin sensitivity in HFD-fed mice. Notably, carbidopa lowered fasting blood glucose, enhanced glucose tolerance, and promoted hepatic Akt phosphorylation. Our results demonstrate that carbidopa attenuates HFD-induced IR by disrupting gut microbiota-dependent synthesis of tryptamine and phenethylamine, thereby reducing systemic 5-HT. These findings identify the gut microbiota-tryptamine/phenethylamine-5-HT axis as a pivotal pathway in IR pathogenesis and position carbidopa as a promising therapeutic candidate for metabolic disorders. Further clinical investigations are needed to validate its translational potential in T2DM management.