Early hepatic insulin resistance in mice: a metabolomics analysis.
Early hepatic insulin resistance in mice: a metabolomics analysis.
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DOI：
10.1210/me.2009-0152
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发表时间：
2010-03-01
期刊：
影响因子：
--
通讯作者：
Coleman, Rosalind A
中科院分区：
文献类型：
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作者：
Li, Lei O;Hu, Yun-Fu;Coleman, Rosalind A
当喂食高脂红花油3wk时，野生型小鼠出现肝脏胰岛素抵抗，而缺乏甘油-3-磷酸酰基转移酶-1的小鼠保持胰岛素敏感性。我们通过肝脏和血浆代谢组分析来检测胰岛素抵抗发展的早期变化，这些分析比较了用低脂肪或红花油饮食喂养3wk的野生型和甘油-3-磷酸酰基转移酶缺陷小鼠。我们推断，饮食诱导的代谢产物的变化只发生在野生型小鼠身上，这反映了那些与肝脏胰岛素抵抗特定相关的代谢产物。在肝脏中可识别的代谢物(来自322种代谢物)中，喂食高脂饮食的野生型小鼠尿素循环中间产物增加，这与用于糖异生的氨基酸脱氨基增加一致。硬脂酰甘油、葡萄糖酸盐、葡萄糖酸盐、2-脱氧尿苷和泛酸也有所增加。观察到S-腺苷-同型半胱氨酸、乳酸、胆汁酸牛磺胆酸盐和1，5-脱水葡萄糖醇--一种先前已确定的短期血糖控制标记物--的下降。在血浆中可识别的代谢物(来自258种代谢物)中，喂食高脂饮食的野生型小鼠血浆硬脂酸和两种与嘧啶相关的代谢物增加，而血浆缓激肽、α-酮戊二酸、牛磺胆酸盐和色氨酸代谢物犬尿氨酸减少。这项研究确定了以前未知的与胰岛素抵抗相关的代谢物，并指出代谢组学分析在确定未知的生化途径方面的作用，这可能对理解糖尿病的病理生理很重要。
When fed with a high-fat safflower oil diet for 3 wk, wild-type mice develop hepatic insulin resistance, whereas mice lacking glycerol-3-phosphate acyltransferase-1 retain insulin sensitivity. We examined early changes in the development of insulin resistance via liver and plasma metabolome analyses that compared wild-type and glycerol-3-phosphate acyltransferase-deficient mice fed with either a low-fat or the safflower oil diet for 3 wk. We reasoned that diet-induced changes in metabolites that occurred only in the wild-type mice would reflect those metabolites that were specifically related to hepatic insulin resistance. Of the identifiable metabolites (from 322 metabolites) in liver, wild-type mice fed with the high-fat diet had increases in urea cycle intermediates, consistent with increased deamination of amino acids used for gluconeogenesis. Also increased were stearoylglycerol, gluconate, glucarate, 2-deoxyuridine, and pantothenate. Decreases were observed in S-adenosylhomocysteine, lactate, the bile acid taurocholate, and 1,5-anhydroglucitol, a previously identified marker of short-term glycemic control. Of the identifiable metabolites (from 258 metabolites) in plasma, wild-type mice fed with the high-fat diet had increases in plasma stearate and two pyrimidine-related metabolites, whereas decreases were found in plasma bradykinin, alpha-ketoglutarate, taurocholate, and the tryptophan metabolite, kynurenine. This study identified metabolites previously not known to be associated with insulin resistance and points to the utility of metabolomics analysis in identifying unrecognized biochemical pathways that may be important in understanding the pathophysiology of diabetes.