Wójcicka Grażyna, Jamroz-Wiśniewska Anna, Czechowska Grażyna, Korolczuk Agnieszka, Marciniak Sebastian, Bełtowski Jerzy
Department of Pathophysiology, Medical University of Lublin, ul. Jaczewskiego 8b, 20-090 Lublin, Poland.
Department of Neurology, Medical University of Lublin, ul. Jaczewskiego 8, 20-090 Lublin, Poland.
Eur J Pharmacol. 2016 Oct 15;789:187-194. doi: 10.1016/j.ejphar.2016.07.034. Epub 2016 Jul 21.
Antidiabetic agents per se, apart from their glucose-lowering effect, can have an important impact on modifying the cardiovascular risk. The present study was undertaken to determine whether the known cardio-protective effects of metformin are linked to its potential ability to affect activities of HDL's paraoxonase (PON1) and platelet activating factor acetylohydrolase (PAF-AH) or via its interaction with the asymmetric dimethylarginine (ADMA)- dimethylarginine dimethylaminohydrolase (DDAH) axis. Normal and streptozotocin (STZ)-induced diabetic rats were treated with metformin (300mg/kg; 4 weeks). The activity of PON1, PAF-AH and DDAH were measured spectrophotometrically. The plasma ADMA level was determined by ELISA method. In STZ-induced diabetic rats the long-term administration of metformin normalized reduced PON1 activity assayed toward paraoxon (+42.5%, P<0.05), phenyl acetate (+22.35%, P<0.05) and γ-decanolactone (+108.0%, P<0.01), without affecting elevated PAF-AH activity in the plasma. Moreover, metformin increased DDAH activity in the renal cortex (+38.24%, P<0.01). Additionally metformin administration caused the increase in PON1 activity in the liver (+29.2%, P<0.01) accompanied by the reduction in the lipid peroxidation (-59.8%, P<0.001). Similarly, in non-diabetic treated rats the increase in liver PON1 activity was observed toward both paraoxon (+80.19%, P<0.001) and phenyl acetate (+29.3%, P<0.05), respectively. The present study has demonstrated that insulin-sensitizer metformin is important for preserving antioxidant HDL function in diabetes. Metformin might also exert its effect against diabetic complications by improving DDAH activity in the kidney and increasing PON1 activity in the liver.
抗糖尿病药物本身，除了具有降血糖作用外，还可能对改变心血管风险产生重要影响。本研究旨在确定二甲双胍已知的心脏保护作用是否与其影响高密度脂蛋白（HDL）对氧磷酶（PON1）和血小板活化因子乙酰水解酶（PAF-AH）活性的潜在能力有关，或者是否通过其与不对称二甲基精氨酸（ADMA）-二甲基精氨酸二甲胺水解酶（DDAH）轴的相互作用有关。用二甲双胍（300mg/kg；4周）治疗正常大鼠和链脲佐菌素（STZ）诱导的糖尿病大鼠。用分光光度法测定PON1、PAF-AH和DDAH的活性。采用酶联免疫吸附测定（ELISA）法测定血浆ADMA水平。在STZ诱导的糖尿病大鼠中，长期给予二甲双胍可使对氧磷（+42.5%，P<0.05）、苯乙酸（+22.35%，P<0.05）和γ-癸内酯（+108.0%，P<0.01）测定的降低的PON1活性恢复正常，而不影响血浆中升高的PAF-AH活性。此外，二甲双胍可增加肾皮质中的DDAH活性（+38.24%，P<0.01）。另外，给予二甲双胍可使肝脏中的PON1活性增加（+29.2%，P<0.01），同时脂质过氧化作用降低（-59.8%，P<0.001）。同样，在接受治疗的非糖尿病大鼠中，分别观察到肝脏中对氧磷（+80.19%，P<0.001）和苯乙酸（+29.3%，P<0.05）的PON1活性增加。本研究表明，胰岛素增敏剂二甲双胍对于在糖尿病中维持抗氧化HDL功能很重要。二甲双胍还可能通过改善肾脏中的DDAH活性和增加肝脏中的PON1活性来发挥其抗糖尿病并发症的作用。
