Increased Plasma Levels of Xanthurenic and Kynurenic Acids in Type 2 Diabetes.
Increased Plasma Levels of Xanthurenic and Kynurenic Acids in Type 2 Diabetes.
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DOI：
10.1007/s12035-015-9232-0
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发表时间：
2015-10
影响因子：
5.1
通讯作者：
Oxenkrug GF
中科院分区：
文献类型：
--
作者：
Oxenkrug GF
全球约有3.5亿人患有2型糖尿病（T2D）。T2D的主要危险因素是糖耐量受损（糖尿病前期），每年有10%的糖尿病前期受试者发生T2D。了解糖尿病前期发展为T2D的机制对预防和治疗T2D具有重要意义。慢性应激和慢性低度炎症是糖尿病前期受试者发生T2D的重要危险因素。然而，应激和炎症介导糖尿病前期T2D发展的分子机制尚不清楚。其中一种机制可能涉及色氨酸（TRP）代谢的犬尿氨酸（KYN）途径（KP）。我们认为，慢性应激或慢性低级别炎症诱导的上游KTP代谢物KYN和3-羟基KYN的形成上调，加上慢性应激或慢性低级别炎症诱导的KTP下游酶的辅助因子pyridoxal 5'-磷酸缺乏，会引发致糖尿病的下游KYN代谢物kynurenic酸（KYNA）和3-羟基KYNA（也称为黄嘌呤酸（XA））的过量产生。作为我们工作假设的初步评估，我们评估了相同T2D患者样本中KP的血浆上下游代谢物水平。t2dm患者血浆样品中KYN、XA和KYNA水平高于非糖尿病患者。我们的研究结果进一步支持了“胰岛素抵抗及其发展为T2D的犬尿氨酸假说”，该假说表明，慢性应激或慢性低度炎症诱导的糖尿病性KP代谢物的过量产生是促进糖尿病前期发展为T2D的机制之一。KP的下游代谢物可能作为T2D的生物标志物和临床干预的靶点。
About 350 million people worldwide have type 2 diabetes (T2D). The major risk factor of T2D is impaired glucose tolerance (pre-diabetes) with 10% of pre-diabetes subjects develop T2D every year. Understanding of mechanisms of development of T2D from pre-diabetes is important for prevention and treatment of T2D. Chronic stress and chronic low grade inflammation are prominent risk factors for T2D development in pre-diabetic subjects. However, molecular mechanisms mediating effect of stress and inflammation on development of T2D from pre-diabetes remain unknown. One of such mechanisms might involve kynurenine (KYN) pathway (KP) of tryptophan (TRP) metabolism. We suggested that chronic stress- or chronic low grade inflammation-induced upregulation of formation of upstream KTP metabolites, KYN and 3-hydroxyKYN, combined with chronic stress or chronic low grade inflammation-induced deficiency of pyridoxal 5'-phosphate, a cofactor of downstream enzymes of KTP, triggers overproduction of diabetogenic downstream KYN metabolites, kynurenic acid (KYNA) and 3-hydroxyKYNA (also known as xanthurenic acid (XA)). As the initial assessment of our working hypothesis, we evaluated plasma levels of up- and down-stream KP metabolites in the same samples of T2D patients. KYN, XA and KYNA levels in plasma samples of T2D patients were higher than in samples of non-diabetic subjects. Our results provide further support of “kynurenine hypothesis of insulin resistance and its progression to T2D” that suggested that overproduction of diabetogenic KP metabolites, induced by chronic stress- or chronic low grade inflammation, is one of the mechanisms promoting development of T2D from pre-diabetes. Downstream metabolites of KP might serve as biomarkers of T2D and targets for clinical intervention.