Increased oxidative stress and apoptosis in the hypothalamus of diabetic male mice in the insulin receptor substrate-2 knockout model.
Increased oxidative stress and apoptosis in the hypothalamus of diabetic male mice in the insulin receptor substrate-2 knockout model.
复制标题
胰岛素受体底物-2敲除模型中糖尿病雄性小鼠下丘脑中氧化应激和凋亡的增加。
DOI：
10.1242/dmm.023515
复制
发表时间：
2016-05-01
影响因子：
4.3
通讯作者：
Frago LM
中科院分区：
文献类型：
--
作者：
Baquedano E;Burgos-Ramos E;Canelles S;González-Rodríguez A;Chowen JA;Argente J;Barrios V;Valverde AM;Frago LM
胰岛素受体底物-2缺陷（IRS2−/−）小鼠被认为是研究糖尿病发展的良好模型，因为IRS蛋白介导胰岛素样生长因子- i （IGF-I）和胰岛素对代谢、有丝分裂发生和细胞存活的多效性作用。下丘脑可能在糖尿病的早期发病中起关键作用，因为它参与控制葡萄糖稳态和能量平衡。由于糖尿病IRS2 - / -小鼠下丘脑中的一些炎症标志物升高，我们的目的是分析与IRS2缺失相关的糖尿病是否会导致下丘脑损伤，并分析所涉及的细胞内机制。只有糖尿病IRS2−/−小鼠显示下丘脑细胞死亡和caspase-8和-3活化增加。凋亡调节因子FADD、Bcl-2、Bcl-xL、p53表达升高，p- i - κ b、c-FLIPL表达降低。这伴随着一氧化氮-4和过氧化氢酶水平的增加，这些酶与氧化应激有关。总之，糖尿病IRS2−/−小鼠的下丘脑显示氧化应激和炎症标志物的增加，最终通过大量激活外源性凋亡途径导致细胞死亡。相反，非糖尿病IRS2 - / -小鼠没有显示下丘脑的细胞死亡，可能是由于循环IGF-I水平的增加和下丘脑IGF-IR磷酸化的增强，这将导致生存途径的刺激。总之，irs2缺陷雄性小鼠的糖尿病与下丘脑氧化应激和细胞凋亡增加有关。总结：只有患有糖尿病的irs2缺陷的雄性小鼠下丘脑出现凋亡，这与氧化应激和炎症信号的增加有关。控制炎症和氧化应激可以预防糖尿病引起的脑损伤。
Insulin receptor substrate-2-deficient (IRS2−/−) mice are considered a good model to study the development of diabetes because IRS proteins mediate the pleiotropic effects of insulin-like growth factor-I (IGF-I) and insulin on metabolism, mitogenesis and cell survival. The hypothalamus might play a key role in the early onset of diabetes, owing to its involvement in the control of glucose homeostasis and energy balance. Because some inflammatory markers are elevated in the hypothalamus of diabetic IRS2−/− mice, our aim was to analyze whether the diabetes associated with the absence of IRS2 results in hypothalamic injury and to analyze the intracellular mechanisms involved. Only diabetic IRS2−/− mice showed increased cell death and activation of caspase-8 and -3 in the hypothalamus. Regulators of apoptosis such as FADD, Bcl-2, Bcl-xL and p53 were also increased, whereas p-IκB and c-FLIPL were decreased. This was accompanied by increased levels of Nox-4 and catalase, enzymes involved in oxidative stress. In summary, the hypothalamus of diabetic IRS2−/− mice showed an increase in oxidative stress and inflammatory markers that finally resulted in cell death via substantial activation of the extrinsic apoptotic pathway. Conversely, non-diabetic IRS2−/− mice did not show cell death in the hypothalamus, possibly owing to an increase in the levels of circulating IGF-I and in the enhanced hypothalamic IGF-IR phosphorylation that would lead to the stimulation of survival pathways. In conclusion, diabetes in IRS2-deficient male mice is associated with increased oxidative stress and apoptosis in the hypothalamus. Summary: Only IRS2-deficient male mice that become diabetic show apoptosis in the hypothalamus and this is associated with an increase in oxidative stress and inflammatory signals. Controlling inflammation and oxidative stress could prevent diabetes-induced brain injury.