Kynurenine pathway in type 2 diabetes: Role of metformin

IF 3.5 4区医学 Q2 CHEMISTRY, MEDICINAL Drug Development Research Pub Date : 2024-08-12 DOI:10.1002/ddr.22243

Zainah Al-Qahtani, Hayder M. Al-kuraishy, Naif H. Ali, Yaser Hosny Ali Elewa, Gaber El-Saber Batiha

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Abstract

The Kynurenine pathway (KP) which is involved in the synthesis of nicotinamide adenine dinucleotide (NAD) from tryptophan (Trp) is intricate in the development of insulin resistance (IR) and type 2 diabetes (T2D). Inflammatory reactions in response to cardiometabolic disorders can induce the development of IR through the augmentation of KP. However, kynurenine (KYN), a precursor of kynurenic acid (KA) is increased following physical exercise and involved in the reduction of IR. Consequently, KP metabolites KA and KYN have anti-diabetogenic effects while other metabolites have diabetogenic effects. KP modulators, either inhibitors or activators, affect glucose homeostasis and insulin sensitivity in T2D in a bidirectional way, either protective or detrimental, that is not related to the KP effect. However, metformin through inhibition of inflammatory signaling pathways can reduce the activation of KP in T2D. These findings indicated a strong controversy regarding the role of KP in T2D. Therefore, the objectives of this mini review were to clarify how KP induces the development of IR and T2D. In addition, this review aimed to find the mechanistic role of antidiabetic drug metformin on the KP, and how KP modulators affect the pathogenesis of T2D.

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2型糖尿病中的犬尿氨酸通路：二甲双胍的作用

参与从色氨酸（Trp）合成烟酰胺腺嘌呤二核苷酸（NAD）的犬尿氨酸途径（KP）在胰岛素抵抗（IR）和 2 型糖尿病（T2D）的发展过程中错综复杂。心血管代谢紊乱引起的炎症反应可通过增加 KP 诱导 IR 的发生。然而，犬尿氨酸（Kynurenine，KYN）是犬尿酸（Kynurenic acid，KA）的前体，在体育锻炼后会增加，并参与降低 IR。因此，KP 代谢物 KA 和 KYN 具有抗糖尿病作用，而其他代谢物则具有致糖尿病作用。KP 调节剂，无论是抑制剂还是激活剂，都会以双向的方式影响 T2D 患者的血糖稳态和胰岛素敏感性，要么是保护性的，要么是有害的，这与 KP 的作用无关。然而，二甲双胍通过抑制炎症信号通路可以减少 T2D 中 KP 的激活。这些研究结果表明，KP 在 T2D 中的作用还存在很大争议。因此，本微综述旨在阐明 KP 如何诱导 IR 和 T2D 的发生。此外，本综述还旨在探究抗糖尿病药物二甲双胍对 KP 的机理作用，以及 KP 调节剂如何影响 T2D 的发病机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drug Development Research 医学-药学

CiteScore

6.40

自引率

2.60%

发文量

104

审稿时长

6-12 weeks

期刊介绍： Drug Development Research focuses on research topics related to the discovery and development of new therapeutic entities. The journal publishes original research articles on medicinal chemistry, pharmacology, biotechnology and biopharmaceuticals, toxicology, and drug delivery, formulation, and pharmacokinetics. The journal welcomes manuscripts on new compounds and technologies in all areas focused on human therapeutics, as well as global management, health care policy, and regulatory issues involving the drug discovery and development process. In addition to full-length articles, Drug Development Research publishes Brief Reports on important and timely new research findings, as well as in-depth review articles. The journal also features periodic special thematic issues devoted to specific compound classes, new technologies, and broad aspects of drug discovery and development.