In vivo therapeutic effect of combination treatment with metformin and Scutellaria baicalensis on maintaining bile acid homeostasis.

Young-Won Chin,Wendong Huang,Shambhunath Bose,Young-Mi Kim,Soo-Kyoung Lim,Jing-Hua Wang,Hojun Kim,Kyungsun Han,Han-Seok Choi

doi:10.1371/journal.pone.0182467

Abstract

The radix of Scutellaria baicalensis (SB) is a herb widely used in traditional Chinese medicine to treat metabolic diseases. Several main components, including baicalin and wogonoside, possess anti-dyslipidemia, anti-obesity and anti-diabetic effects. We hypothesized that co-administration of SB extract and metformin exerts a better effect on obesity-induced insulin resistance and lipid metabolism than treatment with metformin alone. We compared the effect of metformin (100 mg/10 mL/kg/day) alone with co-administration of metformin (100 mg/5 mL/kg/day) and SB extract (200 mg/5 mL/kg/day) on Otsuka Long Evans Tokushima Fatty rats, a useful model of type II diabetes with obesity, and used Long-Evans Tokushima Otsuka rats as a control. Weight, fasting glucose, oral glucose tolerance test, intraperitoneal insulin tolerance test, and serum total cholesterol were measured after 12 weeks of drug administration. We observed a synergetic effect of metformin and SB on lowering cholesterol level by excretion of bile acid through feces. We found that this accompanied activation of FXR, CYP7A1 and LDLR genes and repression of HMGCR in the liver. Although there were no significant changes in BSH-active gut microbiota due to high variability, functional prediction with 16S sequences showed increased primary and secondary bile acid biosynthesis in the combination treatment group. Further study is needed to find the specific strains of bacteria which contribute to FXR-related cholesterol and bile acid regulations.

Highlights

The level of serum total cholesterol in rats exposed to metformin and Scutellaria baicalensis (SB) combination (MetSB group), but not metformin alone, was significantly lower compared to the OLETF group (Table 1, S1 dataset)
To determine insulin sensitivity and ability to clear away blood glucose, Oral glucose tolerance test (OGTT) and intraperitoneal insulin tolerance test (IPITT) were conducted before the sacrifice (Fig 2)
In OGTT, the areas under the curves (AUC) of both metformin and MetSB groups was significantly lower compared to OLETF group there was no significant difference in this parameter between the former two groups

Summary

Introduction

A first-line medication for type II diabetes mellitus, stimulates AMP-activated protein kinase (AMPK) activity in the liver, decreasing hepatic glucose production while. There are efforts to find effective cocktail drugs with metformin to give a broader treatment opportunity for metabolic diseases. We hypothesized that co-administration of SB extract and metformin could exert a better effect on obesity-induced insulin resistance and lipid metabolism than treating with metformin alone. We used PCR array analysis to screen for genes related to fatty liver and insulin resistance after combination treatment with metformin and SB. Growing evidence suggests intestinal microbiota is important in development of metabolic syndrome [13]. Intestinal microbiota interact with drug responses [16]. Considering the extensive interaction between host metabolism, intestinal microbiota and drug administration, we analyzed representative microbiota by 16S rDNA bacterial pyrosequencing analysis. We propose a possible synergetic effect involving intestinal microbial change when metformin is co-administered with SB

Materials and methods

Results

Discussion