Department of Biochemistry, Laboratory of Liver Metabolism, University of Maringá, 87020900 Maringá, Paraná, Brazil.
Fitoterapia. 2014 Jan;92:148-62. doi: 10.1016/j.fitote.2013.11.003. Epub 2013 Nov 15.
It is well known that hyperglycaemia is the initiating cause of tissue damage associated with type 2 diabetes mellitus and that enhanced hepatic gluconeogenesis may account for the increase in blood glucose levels. The purpose of this work was to investigate the possible actions and mechanisms of three related citrus flavanones, namely hesperidin, hesperetin and naringenin, on hepatic gluconeogenesis and related parameters using isolated perfused rat liver. Hesperetin and naringenin (but not hesperidin) inhibited gluconeogenesis from lactate plus pyruvate, alanine and dihydroxyacetone. The inhibitory effects of these flavanones on gluconeogenesis from lactate and pyruvate (hesperetin IC50 75.6 μM; naringenin IC50 85.5 μM) as well as from alanine were considerably more pronounced than those from dihydroxyacetone. The main cause of gluconeogenesis inhibition is the reduction of pyruvate carboxylation by hesperetin (IC50 134.2 μM) and naringenin (IC50 143.5 μM) via inhibition of pyruvate transport into the mitochondria. Secondary causes are likely inhibition of energy metabolism, diversion of glucose 6-phosphate for glucuronidation reactions and oxidation of NADH by flavanone phenoxyl radicals. The influence of the structural differences between hesperetin and naringenin on their metabolic effects was negligible. Analytical evidence indicated that the presence of a rutinoside moiety in hesperidin noticeably decreases its metabolic effects, confirming that hesperetin and naringenin interact with intracellular enzymes and mitochondrial or cellular membranes better than hesperidin. Thus, the inhibition of the gluconeogenic pathway by citrus flavanones, which was similar to that of the drug metformin, may represent an attractive novel treatment strategy for type 2 diabetes.
众所周知，高血糖是与 2 型糖尿病相关的组织损伤的起始原因，而增强的肝糖异生可能是导致血糖水平升高的原因。本研究旨在使用离体灌注大鼠肝脏，研究三种相关的柑橘类黄酮（橙皮苷、橙皮素和柚皮苷）对肝糖异生及相关参数的可能作用和机制。橙皮素和柚皮苷（而非橙皮苷）抑制了来自乳酸加丙酮酸、丙氨酸和二羟丙酮的糖异生。这些黄酮类化合物对来自乳酸和丙酮酸（橙皮素 IC50 为 75.6 μM；柚皮苷 IC50 为 85.5 μM）以及来自丙氨酸的糖异生的抑制作用明显强于来自二羟丙酮的抑制作用。糖异生抑制的主要原因是通过抑制丙酮酸向线粒体的转运，降低了橙皮素（IC50 为 134.2 μM）和柚皮苷（IC50 为 143.5 μM）对丙酮酸羧化的作用。次要原因可能是抑制能量代谢、将葡萄糖 6-磷酸用于葡糖醛酸反应以及黄酮类化合物酚氧基自由基氧化 NADH。橙皮素和柚皮素之间结构差异对其代谢作用的影响可以忽略不计。分析证据表明，橙皮苷中芦丁基的存在明显降低了其代谢作用，证实橙皮素和柚皮苷与细胞内酶以及线粒体或细胞膜的相互作用优于橙皮苷。因此，柑橘类黄酮对糖异生途径的抑制作用与药物二甲双胍相似，可能代表 2 型糖尿病的一种有吸引力的新治疗策略。
