Hyperglycemia-associated alterations in cellular signaling and dysregulated mitochondrial bioenergetics in human metabolic disorders.
Hyperglycemia-associated alterations in cellular signaling and dysregulated mitochondrial bioenergetics in human metabolic disorders.
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DOI：
10.1007/s00394-016-1212-2
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发表时间：
2016-12
影响因子：
5
通讯作者：
Kream RM
中科院分区：
文献类型：
--
作者：
Stefano GB;Challenger S;Kream RM
未经治疗或难治性糖尿病的严重程度在功能上与游离血浆葡萄糖浓度升高有关，临床定义为高血糖。手术上，长期高血糖的病理生理表现可分别分为胰岛素依赖型和胰岛素独立型、1型和2型糖尿病表型。因此，经验生物医学研究的主要领域集中在阐明驱动关键细胞信号系统的潜在机制，这些系统在糖尿病相关慢性高血糖患者中显着改变。目前，我们提供了一项以翻译为导向的关键研究综述，评估高血糖对两个主要信号通路的异常影响，这些信号通路与线粒体生物能量学的靶向破坏有关：(1)晚期糖基化终产物(AGEs)/及其晚期糖基化终产物的同源受体（RAGEs），以及(2)己糖胺生物合成途径（HBP）。在临床前模型中，研究人员观察到，暴露于高血糖浓度的培养血管内皮细胞产生的活性氧（ROS）水平增加，这在功能上与age的形成和同源rage的表达增加有关。重要的是，研究发现，AGEs形成抑制剂、线粒体复合体II或氧化磷酸化解偶联剂可显著降低高血糖对ROS产生和细胞损伤的影响，从而与线粒体功能的多个水平建立起关键联系。高血糖介导的血管内皮细胞线粒体ROS/超氧化物生成的增强在功能上与葡萄糖分流到HBP相关，从而导致促炎信号过程的长期激活。此外，将培养细胞暴露在高血糖条件下，会导致hbp介导的线粒体呼吸复合物I、III和IV蛋白亚基的抑制增强，这与正常的细胞生物能量学和ATP产生密切相关。越来越多的证据表明，慢性高血糖与AGEs/RAGEs和HBP信号通路的异常表达有关，这些信号通路与ROS的病理生理形成和线粒体生物能量学功能失调的促炎过程有关。
The severity of untreated or refractory diabetes mellitus has been functionally linked to elevated concentrations of free plasma glucose, clinically defined as hyperglycemia. Operationally, the pathophysiological presentations of prolonged hyperglycemia may be categorized within insulin-dependent and insulin-independent, type 1 and type 2 diabetic phenotypes, respectively. Accordingly, major areas of empirical biomedical research have focused on the elucidation of underlying mechanisms driving key cellular signaling systems that are significantly altered in patients presenting with diabetes-associated chronic hyperglycemia. Presently, we provide a translationally oriented review of key studies evaluating the aberrant effects of hyperglycemia on two major signaling pathways linked to debilitating cellular and systemic effects via targeted disruption of mitochondrial bioenergetics: (1) advanced glycation end-products (AGEs)/and their cognate receptor for advanced glycation end-products (RAGEs), and (2) the hexosamine biosynthetic pathway (HBP). In preclinical models, cultured vascular endothelial cells exposed to hyperglycemic glucose concentrations were observed to produce enhanced levels of reactive oxygen species (ROS) functionally linked to increased formation of AGEs and expression of their cognate RAGEs. Importantly, inhibitors of AGEs formation, mitochondrial complex II, or un-couplers of oxidative phosphorylation, were observed to significantly reduce the effects of hyperglycemia on ROS production and cellular damage, thereby establishing a critical linkage to multiple levels of mitochondrial functioning. Hyperglycemia-mediated enhancement of mitochondrial ROS/superoxide production in vascular endothelial cells has been functionally linked to the shunting of glucose into the HBP with resultant long-term activation of pro-inflammatory signaling processes. Additionally, exposure of cultured cells to hyperglycemic conditions resulted in enhanced HBP-mediated inhibition of protein subunits of mitochondrial respiratory complexes I, III, and IV, intimately associated with normative cellular bioenergetics and ATP production. Convergent lines of evidence link chronic hyperglycemic conditions to aberrant expression of AGEs/RAGEs and HBP signaling pathways in relation to the pathophysiological formation of ROS and pro-inflammatory processes on the functional dysregulation of mitochondrial bioenergetics.
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影响因子：
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通讯作者：
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