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.
Loquat (Eriobotrya japonica Lindl.), a subtropical fruit tree native to Asia, is not only known to be nutritive but also beneficial for the treatment of diabetes in the south of China. To expand its development, this study was undertaken concerning the potential therapeutic role of total sesquiterpene glycosides (TSGs) from loquat leaves in insulin resistance (IR), the major causative factor of type 2 diabetes mellitus (T2DM). Male C57BL/6 mice were fed on high-fat diet (HFD) to induce IR and then were given TSG by oral administration at 25 and 100 mg/kg/day, respectively. TSG notably improved metabolic parameters including body weight, serum glucose, and insulin levels and prevented hepatic injury. Moreover, inflammatory response and oxidative stress were found to be remarkably alleviated in IR mice with TSG supplement. Further research in liver of IR mice demonstrated that TSG repaired the signalings of insulin receptor substrate-1 (IRS-1)/glucose transporter member 4 (GLUT4) and AMP-activated protein kinase (AMPK), which improved glucose and lipid metabolism and prevented lipid accumulation in liver. It was also observed that TSG suppressed the expression of transient receptor potential vanilloid 1 (TRPV1), whereas the signaling pathway of sirtuin-6 (SIRT6)/nuclear factor erythroid 2-related factor 2 (Nrf2) was significantly promoted. Based on the results, the current study demonstrated that TSG from loquat leaves potentially ameliorated IR in vivo by enhancing IRS-1/GLUT4 signaling and AMPK activation and modulating TRPV1 and SIRT6/Nrf2 signaling pathways.
• SG1 prevents obesity, ameliorates insulin resistance, and reduces systemic inflammation. • SG1 keeps the gut microbial diversity. •The efficacy of SG1 in the treatment of T2DM is strongly linked with the enhancement of several gut genera.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.