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. 2021 Jun 17:15:2565-2576.
doi: 10.2147/DDDT.S307257. eCollection 2021.

Metformin in Combination with Malvidin Prevents Progression of Non-Alcoholic Fatty Liver Disease via Improving Lipid and Glucose Metabolisms, and Inhibiting Inflammation in Type 2 Diabetes Rats

Wenlan Zou #  1 , Chen Zhang #  1 , Xuefang Gu  2 , Xiaohong Li  3 , Huiming Zhu  4
Affiliations

Metformin in Combination with Malvidin Prevents Progression of Non-Alcoholic Fatty Liver Disease via Improving Lipid and Glucose Metabolisms, and Inhibiting Inflammation in Type 2 Diabetes Rats

Wenlan Zou et al. Drug Des Devel Ther. .

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) is one of the primary causes of chronic liver disease and is closely linked to insulin resistance, type 2 diabetes mellitus (T2DM), and dyslipidemia. However, no effective drug therapies have been approved to treat this disease. The present research aimed to evaluate the therapeutic effects of the combination of oral hypoglycemic drug metformin (MET) and a natural product malvidin (MAL) on hepatic damage in HFD/STZ-induced diabetic rats.

Methods: Sprague-Dawley rats were divided into five groups: normal control group (NC), diabetic control group (DC), DC+MET group, DC+MAL group, and DC+MET+MAL group and treated for eight weeks. Blood and liver tissue samples were collected for metabolic parameters, histological, and RT-qPCR analysis.

Results: Our findings indicated that hyperglycemia, insulin resistance, hyperlipidemia, and non-alcoholic fatty liver disease (NAFLD) in diabetic rats were alleviated after oral treatment with MET and MAL, particularly their combination therapy. Besides, the expression of SREBP-1c, ACC, FAS, IL-6, IL-8, and NF-κB mRNA was down-regulated by MET+MAL, and the expression of PPARα, CPT1, and LPL was up-regulated by MET+MAL.

Conclusion: The evidence of this research indicated that the combination therapy may represent an efficient strategy against NAFLD in T2DM rats via improving lipid and glucose metabolisms, and inhibiting inflammation.

Keywords: combination; diabetes mellitus; inflammation; lipogenesis; malvidin; non-alcoholic fatty liver disease.

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Conflict of interest statement

The authors declare no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Effects of MET, MAL, and MET+MAL on T2DM related characteristics in HFD/STZ-T2DM model rats. (A) The detailed experimental scheme; (B) Body weight changes during the experiment; (C) Final body weight; (D) Liver weight; (E) Liver index; (F) Food consumption; (G) Water consumption.
Figure 2
Figure 2
Effects of MET, MAL, and MET+MAL on insulin sensitivity in HFD/STZ-T2DM model rats. (A and B) Oral glucose tolerance test (OGTT); (C and D). Insulin tolerance tests (IPITT). The data were presented as mean ± SD, (n = 8 for all groups). ***P < 0.001.
Figure 3
Figure 3
Effects of MET, MAL, and MET+MAL on serum biochemical parameters in HFD/STZ-T2DM model rats. Insulin resistance relative marker, including fasting blood glucose (A), insulin (B), HOMA-IR (C), and leptin (D). Lipid metabolism parameters, including serum TC (E), serum TG (F), serum LDL-C (G), and serum HDL-C (H). The data were presented as mean ± SD, (n = 8 for all groups). ***P < 0.001;**P < 0.01; *P < 0.05.
Figure 4
Figure 4
Effects of MET, MAL, and MET+MAL on NAFLD in HFD/STZ-T2DM model rats. (A) The activity of ALT in serum of rats; (B). The activity of AST in serum of rats; (C). Hepatic levels of TC; (D). Hepatic levels of TG; (E). Lipid accumulation in the hepatic tissue of rats was evaluated by Oil red O staining, the scale bar is 200 µm; (F). Representative photos of H&E staining from liver tissue, the scale bar is 100 µm. The data were presented as mean ± SD, (n = 8 for all groups). ***P < 0.001;**P < 0.01.
Figure 5
Figure 5
Effect of combined drug therapy on hepatic gene expression involved in lipid homeostasis. The relative expression of hepatic genes involved in lipogenesis, including SREBP-1c (A), ACC (B), and FAS (C). The relative expression of hepatic genes involved in fatty acid oxidation, including PPARα (D), and CPT1 (E). The relative expression of hepatic genes involved in lipid metabolism, including LPL (F). The data were presented as mean ± SD, (n = 6 for all groups). ***P < 0.001;**P < 0.01; *P < 0.05.
Figure 6
Figure 6
Effect of combined drug therapy on serum inflammatory cytokines in HFD/STZ-T2DM model rats. The serum levels of IL-6 (A) and IL-8 (B) of rats were measured by ELISA. The data were presented as mean ± SD, (n = 8 for all groups). ***P < 0.001;**P < 0.01; *P < 0.05.
Figure 7
Figure 7
Effect of combined drug therapy on hepatic inflammation in HFD/STZ-T2DM model rats. The levels of IL-6 (A), IL-8 (B), and NF-κB (C) in hepatic tissue of rats were measured by ELISA. The data were presented as mean ± SD, (n = 8 for all groups). ***P < 0.001;**P < 0.01; *P < 0.05.
Figure 8
Figure 8
Effect of combined drug therapy on hepatic gene expression involved in inflammation. The relative expression of hepatic genes involved in hepatic inflammation, including IL-6 (A), IL-8 (B), and NF-κB (C). The data were presented as mean ± SD, (n = 6 for all groups). ***P < 0.001;**P < 0.01; *P < 0.05.
Figure 9
Figure 9
Effect of combined drug therapy on the activities of enzymes related to glucose metabolism. The activities of G6Pase (A), PEPCK (B), and GS (C) involved in glucose metabolism. The data were presented as mean ± SD, (n = 8 for all groups). ***P < 0.001;**P < 0.01; *P < 0.05.
Figure 10
Figure 10
Recommended model for the protective mechanism of the combination of MET and MAL against NAFLD. The combination of MET and MAL prevents the progression of NAFLD by regulating lipid and glucose metabolism and inhibiting hepatic inflammation. The red arrows indicate the changes in the levels of endogenous metabolites when compared to the NC group; the green arrows indicate the changes in the levels of endogenous metabolites when compared to the DC group.
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