Citrus fruit-derived flavonoid naringenin and the expression of hepatic organic cation transporter 1 protein in diabetic rats treated with metformin.

Naringenin possesses many pharmacological effects and may modulate metformin disposition. The purpose of this study was to evaluate the role of naringenin on hepatic expression of organic cation transporter 1 (OCT1) protein and its associated effects on metformin-associated hyperlactataemia in diabetes. Forty-nine male Sprague Dawley rats randomly assigned to seven groups (n = 7) were orally treated daily with 3.0 mL/kg body-weight (BW) of distilled water (group 1) or 60 mg/kg BW of naringenin (groups 2 and 5) or 250 mg/kg BW of metformin (groups 3 and 6), respectively, dissolved in distilled water. Similarly, group 7 was given metformin and naringenin. Groups 4, 5, 6 and 7 were administered intraperitoneally with streptozotocin at a single dose of 60 mg/kg BW to induce diabetes. Glucose tolerance tests were performed. The animals were killed after 8 weeks of treatment, blood was collected, and livers excised for further biochemical analysis. Lowered body-weight, increased polydipsia and reduced hepatic glycogen concentrations were observed in diabetic rats compared to controls. Naringenin only significantly decreased plasma lactate levels, while metformin only or with naringenin significantly increased plasma lactate levels in diabetic compared to non-treated diabetic animals. Metformin only but not naringenin significantly increased plasma lactate levels in non-diabetic compared to control rats. Furthermore, naringenin with or without metformin but not metformin only significantly increased hepatic organic cation transporter 1 (OCT1) expression in diabetic compared to non-treated diabetic rats. Contrastingly, metformin only but not naringenin significantly increased hepatic OCT1 expression in non-diabetic rats compared to controls. Diabetic rats treated with metformin exhibited significantly increased plasma metformin concentrations compared to non-diabetic but naringenin significantly dropped this parameter. Conversely, hepatic metformin concentrations were significantly lower in diabetic rats treated with metformin compared to non-diabetic rats but significantly increased when naringenin was added. These results suggest that naringenin ameliorated hyperglycaemia-induced reduction in hepatic OCT1 expression leading to metformin accumulation and increased lactic acid production.