Lutein augments the hypoglycemic effect of metformin through the gut microbiota-imidazole propionate axis in type 2 diabetic model mice.

Our objective was to investigate the potential of lutein in enhancing the efficacy of metformin in diabetes treatment and the underlying mechanisms involved. Here, the study was conducted with type 2 diabetic mice, which was induced by a high-fat diet with streptozotocin. Twenty-four diabetic model mice were divided into four groups: model control group, metformin group, lutein group, and lutein combined with metformin (Lut_Met) group. Six C57BL/6 mice were assigned to the normal control group and provided a normal chow diet. First, we found that the blood glucose concentration, area of the curve of the oral glucose tolerance test, and homeostasis model assessment for insulin resistance and imidazole propionate (ImP) levels of the Lut_Met group were significantly lower than those of the metformin group at the 8th week. Additionally, a significant positive correlation was observed between the reduction in blood glucose and the ImP levels in the Lut_Met group. The Firmicutes/Bacteroidota ratio in the Lut_Met group was significantly lower than that in the model control and metformin groups. In addition, the abundance of Eggerthella lenta in the Lut_Met group was significantly lower than that in the metformin group and showed a positive relationship with ImP levels. Moreover, compared with the metformin treatment, Lut_Met intervention had a significant impact on the AMPK signaling pathway. Further western blot analyses revealed that the ratio of phosphorylated AMPK/β-Actin to AMPK/β-Actin in the Lut_Met group was significantly greater than that in the metformin group. In conclusion, lutein has the potential to enhance the favorable effects of metformin on blood glucose metabolism and insulin resistance in a mouse model of diabetes. The underlying mechanisms are likely associated with the modulation of the gut microbiota-ImP axis and AMPK phosphorylation.