Synergistic Effects of Naringenin and Metformin on Dyslipidemia and Glucose Regulation in High Fructose-Fed Rats

Background: Excessive intake of fructose can lead to insulin resistance (IR). Metformin is commonly used as a first-line treatment for type 2 diabetes, and naringenin, a flavonoid known for its anti-inflammatory properties, can potentially improve insulin resistance. However, the effects of combining these two treatments have not been evaluated. Therefore, the present study aims to investigate the combined effects of naringenin and metformin on fructose-induced insulin resistance in male rats. Materials and Methods: Male Wistar rats were divided into five groups: control (without receiving fructose), fructose-induced insulin resistance; F group (with receiving fructose for 8 weeks), fructose+metformin; FM (receiving metformin for last 4 weeks), fructose+naringenin; FN (receiving naringenin for last 4 weeks) and fructose+metformine+naringenin; FMN (receiving metformin and naringenin for last 4 weeks). At the end of the experiment, after an oral glucose tolerance test (OGTT), following deep anesthesia, blood drawing was performed to measure glucose, insulin, total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), triglyceride (TG), tumor necrosis factor-alpha (TNF-a), interleukin 6 (IL-6), free fatty acid (FFA), homeostatic model assessment for insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and liver enzymes. Results: Although metformin and naringenin each alone showed anti-hyperglycemic effects, combined treatment of metformin with naringenin could more remarkably improve glucose intolerance, decrease glucose, TNF-alpha, IL-6, FFA, TG, and TG/HDL-C ratio, and alanine aminotransferase in FMN group compared to F group (P < .05 to P < .0001). Conclusion: Our findings demonstrated that the combination therapy of metformin and naringenin, as a novel therapeutic approach, reduced insulin resistance by improving glucose and lipid metabolism, as well as inhibiting inflammation.