PDF(Pubmed)
Abstract：
Diabetes and obesity are risk factors for kidney disease. Whereas renal glucose production increases in diabetes, recent data suggest that gluconeogenic and oxidative capacity decline in kidney disease. Thus, metabolic dysregulation caused by diet-induced insulin resistance may sensitize the kidney for a loss in function. Here, we examined how diet-induced insulin resistance disrupts mitochondrial metabolic fluxes in the renal cortex in vivo. C57BL/6J mice were rendered insulin resistant through high-fat (HF) feeding; anaplerotic, cataplerotic, and oxidative metabolic fluxes in the cortex were quantified through 13C-isotope tracing during a hyperinsulinemic-euglycemic clamp. As expected, HF-fed mice exhibited increased body weight, gluconeogenesis, and systemic insulin resistance compared with chow-fed mice. Relative to the citric acid cycle, HF feeding increased metabolic flux through pyruvate carboxylation (anaplerosis) and phosphoenolpyruvate carboxykinase (cataplerosis) and decreased flux through the pyruvate dehydrogenase complex in the cortex. Furthermore, the relative flux from nonpyruvate sources of acetyl-CoA profoundly increased in the cortex of HF-fed mice, correlating with a marker of oxidative stress. The data demonstrate that HF feeding spares pyruvate from dehydrogenation at the expense of increasing cataplerosis, which may underpin renal gluconeogenesis during insulin resistance; the results also support the hypothesis that dysregulated oxidative metabolism in the kidney contributes to metabolic disease.
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摘要：
糖尿病和肥胖是肾病的危险因素。而糖尿病患者肾脏葡萄糖产生增加，最近的数据表明肾脏疾病的糖异生和氧化能力下降。因此，饮食诱导的胰岛素抵抗引起的代谢失调可能会使肾脏对功能丧失敏感.这里,我们研究了饮食诱导的胰岛素抵抗如何破坏体内肾皮质线粒体代谢通量.C57BL/6J小鼠通过高脂肪（HF）喂养使胰岛素抵抗；Cataplerotic,在高胰岛素-正常血糖钳夹期间，通过13C同位素示踪对皮质中的氧化代谢通量进行了定量。不出所料,HF喂养的小鼠表现出体重增加，糖异生,与喂食小鼠相比，全身胰岛素抵抗。相对于柠檬酸循环，HF喂养通过丙酮酸羧化（回补）和磷酸烯醇丙酮酸羧激酶（回补）增加了代谢通量，并减少了皮质中丙酮酸脱氢酶复合物的通量。此外，来自乙酰辅酶A的非丙酮酸来源的相对通量在HF喂养小鼠的皮质中急剧增加，与氧化应激标志物相关。数据表明，HF进料可以避免丙酮酸从脱氢中以增加转化率为代价，这可能是胰岛素抵抗期间肾脏糖异生的基础;结果也支持肾脏氧化代谢失调导致代谢性疾病的假设。
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