Comparative Evaluation of the Effect of Metformin and Insulin on Gut Microbiota and Metabolome Profiles of Type 2 Diabetic Rats Induced by the Combination of Streptozotocin and High-Fat Diet.

Nan Hu,Liying Wang,Xuping Yang,Yan Jiang,Qi Zhang,Hui Wang,Rong Chen

doi:10.3389/fphar.2021.794103

Abstract

Lately, an increasing number of studies have investigated the relationship between metformin and gut microbiota, suggesting that metformin exerts part of its hypoglycemic effect through the microbes. However, its underlying mechanism remains largely undetermined. In the present study, we investigated the effects of metformin on gut microbiota and metabolome profiles in serum and compared it with insulin treatment in rats with type 2 diabetes mellitus (T2DM). Diabetic rats (DM group) were induced by a combination of streptozotocin and high-fat diet (HFD). After 7 days, DM rats were treated with metformin (MET group) or insulin (INS group) for 3 weeks. The 16S rRNA sequencing of the gut microbiota and non-targeted metabolomics analysis of serum were conducted. A total of 13 bile acids (BAs) in serum were further determined and compared among different groups. The rat model of T2DM was well established with the typical diabetic symptoms, showing significantly increased blood glucose, AUC of OGTT, HOMA-IR, TC, TG, LDL-C and TBA. Metformin or insulin treatment could ameliorate symptoms of diabetes and partly recover the abnormal biochemical indicators. Compared with DM rats, the relative abundances of 13 genera were significantly changed after metformin treatment, while only three genera were changed after insulin treatment. The metformin and insulin treatments also exhibited different serum metabolome profiles in T2DM rats. Moreover, 64 differential metabolites were identified between MET and DM groups, whereas 206 were identified between INS and DM groups. Insulin treatment showed greater influence on amino acids, glycerophospholipids/glycerolipids, and acylcarnitine compared with the metformin treatment, while metformin had an important impact on BAs. Furthermore, metformin could significantly decrease the serum levels of CA, GCA, UDCA, and GUDCA, but increase the level of TLCA in DM rats. Insulin treatment significantly decreased the levels of CA, UDCA, and CDCA. Besides, several metabolites in serum or microbiota were positively or negatively correlated with some bacteria. Collectively, our findings indicated that metformin had a stronger effect on gut microbiota than insulin, while insulin treatment showed greater influence on serum metabolites, which provided novel insights into the therapeutic effects of metformin on diabetes.

Highlights

As a chronic metabolic disease with complex pathogenesis, type 2 diabetes mellitus (T2DM) refers to a spectrum of systemic illnesses related to glucose metabolism, lipid metabolism, and amino acid metabolism
The HOMA-IR index was remarkably decreased in the MET group and INS group compared with the DM group, indicating that the treatment of metformin and insulin significantly improved the insulin resistance of diabetic rats (Figure 1F)
glycoursodeoxycholic acid (GUDCA) and ursodeoxycholic acid (UDCA) had negative correlations with the relative abundances of (Ruminococcus)_torques_group and (Eubacterium)_hallii_group. We showed that both metformin and insulin treatment reduced the blood glucose level, ameliorated the lipid metabolism, changed the composition of gut microbiota, and altered the serum metabolome in T2DM rats induced by the combination of STZ and high-fat diet (HFD)

Summary

Introduction

As a chronic metabolic disease with complex pathogenesis, type 2 diabetes mellitus (T2DM) refers to a spectrum of systemic illnesses related to glucose metabolism, lipid metabolism, and amino acid metabolism. For more than 2 decades, metformin is a firstline treatment regimen to increase insulin sensitivity in T2DM patients its underlying mechanisms of action remain largely undetermined. It is believed that metformin improve patients’ hyperglycemia by suppressing hepatic gluconeogenesis, decreasing hepatic glucose output, elevating glucose uptake and utilization in peripheral tissues, and enhancing the energy metabolism in several organs, such as muscle, fat, and liver through activating of AMP-activated protein kinase (Kristófi and Eriksson, 2021). The half-life of metformin is approximately 3–4 h once orally administered, which is significantly shorter than the duration of its hypoglycemic effect. Metformin can not decrease blood glucose when intravenously administered. The above-mentioned findings all indicate that metformin has key impacts on the digestive tract

Methods

Results

Conclusion