Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Shaanxi Engineering and Research Center of Vaccine, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry of China, Xi'an 710061, China.
Department of Cardiology, The Second Clinical Medical College, Shanxi Medical University, Taiyuan, China.
Toxicol Appl Pharmacol. 2022 Feb 15;437:115893. doi: 10.1016/j.taap.2022.115893. Epub 2022 Jan 24.
Background Oxidative stress and inflammation play important roles in the development of diabetes. Metformin (MET) is considered as the first-line therapy for patients with type 2 diabetes (T2D). Hypothalamic paraventricular nucleus (PVN) and hypothalamic arcuate nucleus (ARC) are vital in obesity and diabetes. However, there have been few studies on the effects of MET on inflammatory reaction and oxidative stress in the PVN and ARC of T2D diabetic rats. Methods Male Sprague-Dawley (SD) rats were fed with high-fat diet (HFD), and intraperitoneally injected with low-dose streptozotocin (STZ, 30 mg/kg) at 6th week to induce T2D diabetes. After injection of STZ, they were fed with HFD continually. Starting from the 8th week of HFD feeding, T2D rats received intragastrical administration of MET (150 mg/kg/day) in addition to the HFD for another 8 weeks. At the end of the 15th week, the rats were anaesthetized to record the sympathetic nerve activity and collect blood and tissue samples. Results In comparison with control rats, T2D diabetic rats had higher levels of pro-inflammatory cytokines (PICs) and excessive oxidative stress in the PVN and ARC, accompanied with more activated astrocytes. The renal sympathetic nerve activity (RSNA) and the plasma norepinephrine (NE) increased in T2D diabetic rats. The expression of tyrosine hydroxylase (TH) increased and the expression of 67-kDa isoform of glutamate decarboxylase (GAD67) decreased in T2D diabetic rats. Supplementation of MET decreased blood glucose, suppressed RSNA, decreased PICs (TNF-α, IL-1β and IL-6) in PVN and ARC, attenuated oxidative stress and activation of astrocytes in ARC and PVN of T2D diabetic rats, as well as restored the balance of neurotransmitter synthetase. The number of Fra-LI (chronic neuronal excitation marker) positive neurons in the ARC and PVN of T2D diabetic rats increased. Chronic supplementation of MET also decreased the number of Fra-LI positive neurons in the ARC and PVN of T2D diabetic rats. Conclusion These findings suggest that the PVN and ARC participate in the beneficial effects of MET in T2D diabetic rats, which is possibly mediated via down-regulating of inflammatory molecules, attenuating oxidative stress and restoring the balance of neurotransmitter synthetase by MET in the PVN and ARC.
氧化应激和炎症在糖尿病的发展中起着重要作用。二甲双胍（MET）被认为是 2 型糖尿病（T2D）患者的一线治疗药物。下丘脑室旁核（PVN）和下丘脑弓状核（ARC）在肥胖和糖尿病中至关重要。然而，关于 MET 对 T2D 糖尿病大鼠 PVN 和 ARC 中炎症反应和氧化应激的影响的研究较少。
雄性 Sprague-Dawley（SD）大鼠给予高脂肪饮食（HFD），第 6 周经腹腔注射小剂量链脲佐菌素（STZ，30mg/kg）诱导 T2D 糖尿病。注射 STZ 后，继续给予 HFD。从 HFD 喂养的第 8 周开始，T2D 大鼠除了给予 HFD 外，还给予胃内给予 MET（150mg/kg/天）治疗 8 周。在第 15 周结束时，麻醉大鼠记录交感神经活动并收集血液和组织样本。
与对照组大鼠相比，T2D 糖尿病大鼠 PVN 和 ARC 中促炎细胞因子（PICs）水平升高，氧化应激过度，星形胶质细胞过度激活。T2D 糖尿病大鼠肾交感神经活动（RSNA）和血浆去甲肾上腺素（NE）增加。T2D 糖尿病大鼠中酪氨酸羟化酶（TH）的表达增加，67-kDa 同工型谷氨酸脱羧酶（GAD67）的表达减少。MET 的补充降低了血糖，抑制了 RSNA，降低了 PVN 和 ARC 中的 PICs（TNF-α、IL-1β 和 IL-6），减轻了 T2D 糖尿病大鼠 ARC 和 PVN 中的氧化应激和星形胶质细胞激活，并恢复了神经递质合成酶的平衡。T2D 糖尿病大鼠 ARC 和 PVN 中 Fra-LI（慢性神经元兴奋标志物）阳性神经元的数量增加。慢性补充 MET 也降低了 T2D 糖尿病大鼠 ARC 和 PVN 中 Fra-LI 阳性神经元的数量。
这些发现表明，PVN 和 ARC 参与了 MET 在 T2D 糖尿病大鼠中的有益作用，这可能是通过在 PVN 和 ARC 中下调炎症分子、减轻氧化应激和恢复神经递质合成酶的平衡来介导的。
