Anti-diabetes activity of (R)-gentiandiol in KKAy type 2 mice

Swertiamarin is a major component of many traditional Chinese Swertia herbs that show significant antidiabetic activity. (R)-Gentiandiol and (S)-gentiandiol are metabolites of swertiamarin found in vivo. The antidiabetic activity of swertiamarin and its nitrogen-containing metabolites (R)-gentiandiol and (S)-gentiandiol was evaluated in this research, and their mechanism of action was investigated after evaluating the serum metabolic profile of KK/Upj-A^y type 2 mice. The pharmaceutical effects of swertiamarin, (R)-gentiandiol, and (S)-gentiandiol were tested by biochemical indices and histopathological observations. Moreover, the mechanism underlying the action of three compounds against type 2 diabetes was elucidated using a metabolomic method. It was shown that (R)-gentiandiol significantly improved pathological changes in the kidney and pancreas. The levels of total cholesterol, triglyceride, and high-density and low-density lipoprotein cholesterol improved considerably after treatment with (R)-gentiandiol, compared to their levels in model mice. However, the levels of these compounds showed no improvement after treatment with (S)-gentiandiol. In total, 15 biomarkers were identified in KK/Upj-A^y type 2 mice, and the levels of 10 biomarkers were measured after treatment with (R)-gentiandiol. (R)-Gentiandiol reduced the abnormalities in metabolic pathways, including lipid metabolism, amino acid metabolism, carbohydrate metabolism, and nucleotide metabolism. Additionally, glycine, serine, and threonine metabolism related to the regulation of glycine was affected the most. The study indicated that the antidiabetic effects of Swertia herbs may due to (R)-gentiandiol which is a metabolite of swertiamarin in vivo. This study helps clarify the active metabolites of swertiamarin, provide greater insights into the clinical antidiabetic effects of Swertia herbs and bring novel ideas for developing new drugs from antidiabetic herbs.