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二甲双胍(metformin,MET)常用于肥胖胰岛素抵抗患者改善胰岛素抵抗降低血糖,但MET可增加脑内β-淀粉肽(β-amyloid,Aβ)表达,目前机制不清.Aβ沉积作为阿尔茨海默病(Alzheimer’sdisease,AD)始发病理生理学改变,在AD中发挥重要作用.为研究MET对脑内Aβ表达的影响及机制,采用饮食诱导肥胖大鼠模型(OB组)予MET灌胃4 W后(MET组),观察海马内Aβ42及相关因子肿瘤坏死因子α(TNF-α)、过氧化物酶体增殖物激活受体γ(peroxisome proliferator-activatedreceptorγ,PPARγ)、胰岛素降解酶(insulin degrading enzyme,IDE)的表达.结果显示,OB组大鼠血糖水平较对照组(CTL组)无明显差异,胰岛素含量明显升高(P<0.01),并存在胰岛素抵抗;OB组大鼠海马内TNF-α、Aβ42水平较CTL组上调,PPARγ、IDE表达下降(P<0.05).MET组胰岛素及胰岛素抵抗均较OB组降低(P<0.05),海马内TNF-α、Aβ42表达增加(P<0.01);PPARγ,IDE表达较OB组减少(P<0.01).上述结果提示,二甲双胍作为治疗肥胖胰岛素抵抗的一线用药,可改善胰岛素抵抗,但增加海马内炎性因子TNF-α表达、减少PPARγ水平,降低其调控IDE转录作用,使IDE表达减少,伴随Aβ42降解减少沉积增加,从而可能增加AD发病风险.
Metformin (metformin, MET) is commonly used in patients with obesity to improve insulin resistance and reduce blood glucose, but MET can increase the expression of β-amyloid (Aβ) in the brain, and the mechanism is unclear.Aβ deposition as Alzheimer’s disease (Alzheimer’s disease, AD), and play an important role in AD.In order to study the effect of MET on Aβ expression in the brain and its mechanism, a diet-induced obesity rat model (OB group) (MET group). The levels of Aβ42 and TNF-α, PPARγ, insulin degrading enzyme , IDE) .The results showed that there was no significant difference in blood glucose level between the OB group and the control group (CTL group), but the insulin level was significantly higher (P <0.01) α and Aβ42 were significantly higher than those in CTL group (P <0.05), while the levels of PPARγ and IDE in hippocampus were significantly lower than those in OB group (P <0.05) ); PPARγ, IDE expression decreased compared with the OB group (P <0.01) .Results Metformin as a first-line treatment of obesity insulin resistance can improve insulin resistance, but increase the expression of the inflammatory factor TNF-α in the hippocampus, reduce the level of PPARγ, reduce its regulation of IDE transcription, reduce the expression of IDE, reduce the deposition of Aβ42 degradation Increase, which may increase the risk of AD.