Adeshara Krishna A, Bangar Nilima S, Doshi Paras R, Diwan Arundhati, Tupe Rashmi S
Biochemical Sciences Division, Rajiv Gandhi Institute of IT and Biotechnology, Bharati Vidyapeeth (Deemed to be University), Pune, Maharashtra State, India.
Department of Medicine, Bharati Vidyapeeth's Medical College and Bharati Hospital, Bharati Vidyapeeth (Deemed to be University), Pune, Maharashtra State, India.
Diabetes Metab Syndr. 2020 Sep-Oct;14(5):1449-1458. doi: 10.1016/j.dsx.2020.07.036. Epub 2020 Jul 28.
Persistence hyperglycemia results in the formation of advanced glycation end products (AGEs) by non-enzymatic glycation. AGEs and their receptor RAGE play an important role in generation of inflammatory molecules and oxidative stress. Metformin regulates insulin responsive gene and helps to achieve glycemic control however, no extensive study reported about its role against glycation induced oxidative stress and vascular inflammation. Therefore, present work focused on clinical relevance of three months metformin therapy in type 2 diabetes mellitus patients against glycation induced oxidative stress and vascular inflammation.
Among recruited 40 medicated-naive type 2 diabetes mellitus patients, 31 patients were continued with metformin therapy. Biomarkers of plasma protein glycation (fructosamine, protein carbonyls, β-amyloid) antioxidants and oxidative stress markers (GSH, catalase, NO, PON-1, AOPP, LPO; RAGE isoforms (sRAGE, esRAGE); inflammatory markers (IL-6, TNF-α) were determined at baseline and after 3-months of treatment. The expression profile of membrane RAGE, NF-κB, CML was studied in PBMNCs and GLUT-1 in erythrocyte ghost by western blotting.
Metformin showed maximum percent declined from baseline to three months therapy in levels of fructosamine, β-amyloid, sRAGE, inflammatory cytokines (IL-6, TNF-α) and percent increment in esRAGE and antioxidants levels. It showed reduced levels of IL-6 and TNF-α by declining expression of CML, membrane RAGE and NF-κB in type 2 diabetes mellitus patients after three months therapy.
First report in Indian diabetes mellitus patients, where metformin showed effective inhibition against glycation and receptor mediated cellular inflammation. However, these findings need to be tested in a randomized trial.
持续性高血糖会通过非酶糖基化作用导致晚期糖基化终末产物（AGEs）的形成。AGEs及其受体RAGE在炎症分子的产生和氧化应激中起重要作用。二甲双胍可调节胰岛素反应性基因并有助于实现血糖控制，然而，尚无关于其对抗糖基化诱导的氧化应激和血管炎症作用的广泛研究报道。因此，本研究聚焦于2型糖尿病患者接受三个月二甲双胍治疗对抗糖基化诱导的氧化应激和血管炎症的临床相关性。
在招募的40例初治2型糖尿病患者中，31例患者继续接受二甲双胍治疗。在基线和治疗3个月后测定血浆蛋白糖基化（果糖胺、蛋白质羰基、β-淀粉样蛋白）、抗氧化剂和氧化应激标志物（谷胱甘肽、过氧化氢酶、一氧化氮、对氧磷酶-1、晚期氧化蛋白产物、脂质过氧化）、RAGE异构体（可溶性RAGE、内源性分泌型RAGE）、炎症标志物（白细胞介素-6、肿瘤坏死因子-α）的生物标志物。通过蛋白质印迹法研究外周血单个核细胞中膜RAGE、核因子-κB、羧甲基赖氨酸的表达谱以及红细胞膜中葡萄糖转运蛋白-1的表达谱。
从基线到三个月治疗，二甲双胍治疗使果糖胺、β-淀粉样蛋白、可溶性RAGE、炎症细胞因子（白细胞介素-6、肿瘤坏死因子-α）水平下降的百分比最大，使内源性分泌型RAGE和抗氧化剂水平增加的百分比最大。治疗三个月后，二甲双胍通过降低2型糖尿病患者中羧甲基赖氨酸、膜RAGE和核因子-κB的表达，使白细胞介素-6和肿瘤坏死因子-α水平降低。
这是印度糖尿病患者中的首份报告，其中二甲双胍显示出对糖基化和受体介导的细胞炎症的有效抑制作用。然而，这些发现需要在随机试验中进行验证。
