Beneficial Effects of Gegen Qinlian Decoction and Its Food–Medicine Homologous Alternative Formulas Against Type 2 Diabetes Mellitus: Insights from Multi-Omics Analysis

Background/Objectives: Herbal formulas are unsuitable for routine dietary use. This study evaluates Qige Pipa Decoction (QPD), a food–medicine homologous formula containing edible components, comparing its anti-diabetic effects with the classic Gegen Qinlian Decoction (GQD) to explore its potential as a sustainable dietary intervention for T2DM. Methods: T2DM mice received QPD, GQD, or metformin for 6 weeks. Parameters included glycemic control, histopathology, gut microbiota (16S rRNA), serum metabolomics, liver transcriptomics, and chemical profiling (UPLC-Q-TOF-MS). Results: Both formulas comparably improved glycemia and insulin resistance. QPD uniquely enriched beneficial gut bacteria (e.g., Roseburia) and suppressed pro-inflammatory taxa. Metabolomics revealed decreased Carnitine C20:1 and increased phospholipids in the QPD group. Transcriptomics showed QPD enriched the AGE-RAGE signaling pathway. Chemically, QPD showed relatively higher signal intensities for glycosides and organic acids, while GQD showed relatively higher signal intensities for alkaloids. Conclusions: QPD exhibits anti-diabetic efficacy similar to GQD but through distinct regulatory mechanisms. Its food-medicine homologous composition provides a theoretical rationale for its exploration as a sustained dietary adjunct. However, the absence of safety biomarkers in this study precludes definitive conclusions regarding long-term tolerability, necessitating dedicated toxicological assessment in future trials.