Molecular and Clinical Pharmacology Research Laboratory, Department of Pharmacology, Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, Durban, South Africa.
Cardio-Metabolic Research Group (CMRG), Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa.
Basic Clin Pharmacol Toxicol. 2020 Sep;127(3):211-220. doi: 10.1111/bcpt.13407. Epub 2020 Apr 3.
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.
柚皮素具有许多药理作用，可能调节二甲双胍的处置。本研究的目的是评估柚皮素对有机阳离子转运体 1（OCT1）蛋白肝表达的作用及其对糖尿病患者二甲双胍相关高乳酸血症的影响。49 只雄性 Sprague Dawley 大鼠随机分为 7 组（n = 7），分别每天口服 3.0 mL/kg 体重（BW）的蒸馏水（第 1 组）或 60mg/kg BW 的柚皮素（第 2 和 5 组）或 250mg/kg BW 的二甲双胍（第 3 和 6 组），溶解在蒸馏水中。同样，第 7 组给予二甲双胍和柚皮素。第 4、5、6 和 7 组一次性腹腔注射 60mg/kg BW 的链脲佐菌素诱导糖尿病。进行葡萄糖耐量试验。治疗 8 周后处死动物，采集血液，取出肝脏进行进一步的生化分析。与对照组相比，糖尿病大鼠体重下降，多饮增加，肝糖原浓度降低。与非治疗糖尿病动物相比，柚皮素仅显著降低血浆乳酸水平，而二甲双胍仅或与柚皮素均显著增加糖尿病动物的血浆乳酸水平。与对照组相比，仅二甲双胍而非柚皮素显著增加非糖尿病大鼠的血浆乳酸水平。此外，与非治疗糖尿病大鼠相比，柚皮素与或不与二甲双胍但不是二甲双胍仅显著增加糖尿病大鼠的肝有机阳离子转运体 1（OCT1）表达。相反，仅二甲双胍而非柚皮素显著增加非糖尿病大鼠的肝 OCT1 表达。与非糖尿病大鼠相比，用二甲双胍治疗的糖尿病大鼠的血浆二甲双胍浓度显著升高，但柚皮素显著降低了这一参数。相反，当加入柚皮素时，用二甲双胍治疗的糖尿病大鼠的肝内二甲双胍浓度显著降低，但显著增加。这些结果表明，柚皮素改善了高血糖引起的肝 OCT1 表达降低，导致二甲双胍蓄积和乳酸生成增加。
