Metformin increases tauroursodeoxycholic acid levels to improve insulin resistance in diet-induced obese mice
Abstract
Abstract Metformin is widely used to surmount insulin resistance (IR) and type 2 diabetes. Evidence indicates that metformin improves insulin resistance associated with gut microbiota, but the underlying mechanism remains unclear. In the present study, metformin effectively improved insulin sensitivity and alleviated liver inflammation and oxidative stress in high-fat diet (HFD)-fed mice. Metabolomics analysis showed that metformin increased tauroursodeoxycholic acid (TUDCA) levels both in intestinal content and liver by reducing the production and activity of bile salt hydrolase (BSH). We further found that TUDCA was able to antagonize with KEAP1 to prevent its binding to Nrf2 and activate Nrf2/ARE pathway, thereby reducing intracellular ROS and improving insulin signaling. Moreover, metformin increased the proportion of Akkermanisia muciniphlia in the HFD-fed mice, while in vitro growth curve test confirmed that it’s TUDCA, not metformin, promoted the proliferation of A. muciniphlia . Subsequently, TUDCA administration could effectively ameliorate insulin resistance, activate hepatic Nrf2/ARE pathways, and increase the abundance of intestinal A. muciniphlia in ob/ob mice. These findings reveal that metformin remodels the gut microbiota, reduces oxidative stress and enhances insulin sensitivity partly due to increasing the production of TUDCA. This provides a novel mechanism by which metformin alleviates diet-induced insulin resistance and improves metabolism.
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Evidence Hub reads this as a preprint, done in animal, not in people. Its evidence level is 5 of 5 (Very low · case / narrative / animal / in vitro / in silico). Case reports, narrative reviews, and animal, cell or computer-model studies give the weakest evidence for human health.
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