Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China.
Department of Pharmacology, Toxicology and Therapeutics, School of Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Acta Biochim Biophys Sin (Shanghai). 2022 Apr 25;54(4):415-451. doi: 10.3724/abbs.2022012.
Hyperglycemia in diabetic patients is associated with abnormally-elevated cellular glucose levels. It is hypothesized that increased cellular glucose will lead to increased formation of endogenous methanol and/or formaldehyde, both of which are then metabolically converted to formic acid. These one-carbon metabolites are known to be present naturally in humans, and their levels are increased under diabetic conditions. Mechanistically, while formaldehyde is a cross-linking agent capable of causing extensive cytotoxicity, formic acid is an inhibitor of mitochondrial cytochrome oxidase, capable of inducing histotoxic hypoxia, ATP deficiency and cytotoxicity. Chronic increase in the production and accumulation of these toxic one-carbon metabolites in diabetic patients can drive the pathogenesis of ocular as well as other diabetic complications. This hypothesis is supported by a large body of experimental and clinical observations scattered in the literature. For instance, methanol is known to have organ- and species-selective toxicities, including the characteristic ocular lesions commonly seen in humans and non-human primates, but not in rodents. Similarly, some of the diabetic complications (such as ocular lesions) also have a characteristic species-selective pattern, closely resembling methanol intoxication. Moreover, while alcohol consumption or combined use of folic acid plus vitamin B is beneficial for mitigating acute methanol toxicity in humans, their use also improves the outcomes of diabetic complications. In addition, there is also a large body of evidence from biochemical and cellular studies. Together, there is considerable experimental support for the proposed hypothesis that increased metabolic formation of toxic one-carbon metabolites in diabetic patients contributes importantly to the development of various clinical complications.
糖尿病患者的高血糖与细胞内葡萄糖水平异常升高有关。据推测，增加的细胞葡萄糖会导致内源性甲醇和/或甲醛的形成增加，这两者随后都被代谢转化为甲酸。这些一碳代谢物在人类中自然存在，并且在糖尿病条件下其水平增加。从机制上讲，虽然甲醛是一种能够引起广泛细胞毒性的交联剂，但甲酸是线粒体细胞色素氧化酶的抑制剂，能够诱导组织毒性缺氧、ATP 缺乏和细胞毒性。糖尿病患者中这些有毒一碳代谢物的产生和积累的慢性增加可导致眼部以及其他糖尿病并发症的发病机制。这一假说得到了大量实验和临床观察的支持，这些观察结果散见于文献中。例如，甲醇具有器官和物种选择性毒性，包括在人类和非人类灵长类动物中常见但在啮齿动物中不常见的特征性眼部病变。同样，一些糖尿病并发症（如眼部病变）也具有特征性的物种选择性模式，与甲醇中毒非常相似。此外，尽管饮酒或同时使用叶酸加维生素 B 有益于减轻人类急性甲醇毒性，但它们的使用也改善了糖尿病并发症的结局。此外，还有大量来自生化和细胞研究的证据。综上所述，有相当多的实验证据支持这样的假设，即糖尿病患者中有毒一碳代谢物的代谢形成增加，这对各种临床并发症的发展有重要贡献。
