Novel Sesquiterpene Glycoside from Loquat Leaf Alleviates Type 2 Diabetes Mellitus Combined with Nonalcoholic Fatty Liver Disease by Improving Insulin Resistance, Oxidative Stress, Inflammation, and Gut Microbiota Composition

Abstract

Nonalcoholic fatty liver disease (NAFLD) is strongly associated with type 2 diabetes mellitus (T2DM). Sesquiterpene glycosides from loquat leaf achieved beneficial effects on metabolic syndromes such as NAFLD and diabetes; however, their specific activity and underlying mechanism on T2DM-associated NAFLD have not yet been fully understood. In the present study, we found that sesquiterpene glycoside 3 (SG3), a novel sesquiterpene glycoside isolated from loquat leaf, was able to prevent insulin resistance (IR), oxidative stress, and inflammation. In db/db mice, SG3 administration (25 and 50 mg/kg/day) inhibited obesity, hyperglycemia, and the release of inflammatory cytokines. SG3 (5 and 10 μM) also significantly alleviated hepatic lipid accumulation, oxidative stress, and inflammatory response induced by high glucose combined with oleic acid in HepG2 cells. Western blotting analysis showed that these effects were related to repair the abnormal insulin signaling and inhibit the cytochrome P450 2E1 (CYP2E1) and NOD-like receptor family pyrin domain-containing 3 (NLRP3), both in vivo and in vitro. In addition, SG3 treatment could decrease the ratio of Firmicutes/Bacteroidetes and increase the relative abundance of Lachnospiraceae, Muribaculaceae, and Lactobacillaceae after a high-throughput pyrosequencing of 16S rRNA to observe the changes of related gut microbial composition in db/db mice. These findings proved that SG3 could protect against NAFLD in T2DM by improving IR, oxidative stress, inflammation through regulating insulin signaling and inhibiting CYP2E1/NLRP3 pathways, and remodeling the mouse gut microbiome. It is suggested that SG3 could be considered as a new functional additive for a healthy diet.

Keywords: CYP2E1; NAFLD; NLRP3; T2DM; gut microbiota; inflammation; loquat; oxidative stress; sesquiterpene glycoside.