二甲双胍对肝脏糖异生的抑制作用。与胰岛素的协同作用。
Inhibition of hepatic gluconeogenesis by metformin. Synergism with insulin.
作者信息
Wollen N, Bailey C J
机构信息
Department of Pharmaceutical Sciences, Aston University, Birmingham, U.K.
出版信息
Biochem Pharmacol. 1988 Nov 15;37(22):4353-8. doi: 10.1016/0006-2952(88)90617-x.
The antihyperglycemic agent, metformin (dimethylbiguanide), inhibits hepatic gluconeogenesis. To investigate the mechanism involved, glucose production from collagenase-isolated hepatocytes of starved rats was determined after 1 hr incubations with different substrates. In the absence of insulin, glucose production from 10(-2) M lactate-10(-3) M pyruvate, 10(-2)M M alanine, 10(-2) M glutamine and 5 x 10(-3) M glycerol was decreased (35-78%) by high concentrations (10(-2) and 10(-3) M) of metformin. Lower concentrations of metformin were not effective in the absence of insulin, but a therapeutic concentration (10(-5) M) of metformin acted synergistically with insulin (10(-8) M) to suppress gluconeogenesis from each of the substrates by an additional 10-14% compared with insulin (10(-8) M) alone. The synergistic antigluconeogenic effect of metformin (10(-5) M) with insulin (10(-8) M) was achieved without alteration of the contents of NADH and NAD+ in digitonin-separated cytosolic and mitochondrial-rich hepatocyte fractions. Mitochondrial ATP was also unaltered by the metformin (10(-5) M)-insulin (10(-8) M) combination. However, the antigluconeogenic effect of 10(-2) M metformin alone was associated with an increased (by 109%) mitochondrial NADH:NAD+ ratio. Thus reduced gluconeogenesis by high concentrations of metformin (e.g. 10(-2) M) may involve changes of redox state. However, therapeutic concentrations of metformin (e.g. 10(-5) M) potentiate the antigluconeogenic effect of insulin to a similar extent from a range of substrates, without altering energy status or redox state.
抗高血糖药物二甲双胍（二甲双胍）可抑制肝糖异生。为研究其作用机制，将饥饿大鼠经胶原酶分离的肝细胞与不同底物孵育1小时后，测定葡萄糖生成量。在无胰岛素的情况下，高浓度（10⁻²和10⁻³ M）的二甲双胍可使10⁻² M乳酸 - 10⁻³ M丙酮酸、10⁻² M丙氨酸、10⁻² M谷氨酰胺和5×10⁻³ M甘油的葡萄糖生成量降低（35 - 78%）。低浓度的二甲双胍在无胰岛素时无效，但治疗浓度（10⁻⁵ M）的二甲双胍与胰岛素（10⁻⁸ M）协同作用，与单独使用胰岛素（10⁻⁸ M）相比，可使每种底物的糖异生进一步抑制10 - 14%。二甲双胍（10⁻⁵ M）与胰岛素（10⁻⁸ M）的协同抗糖异生作用在不改变洋地黄皂苷分离的富含细胞溶质和线粒体的肝细胞组分中NADH和NAD⁺含量的情况下实现。二甲双胍（10⁻⁵ M） - 胰岛素（10⁻⁸ M）组合也未改变线粒体ATP。然而，单独使用10⁻² M二甲双胍的抗糖异生作用与线粒体NADH:NAD⁺比值增加（109%）有关。因此，高浓度二甲双胍（如10⁻² M）减少糖异生可能涉及氧化还原状态的变化。然而，治疗浓度的二甲双胍（如10⁻⁵ M）可在不改变能量状态或氧化还原状态的情况下，从一系列底物中以类似程度增强胰岛素的抗糖异生作用。
Zotero 插件