Yamaguchi Hiroko, Nagai Ryoji
Laboratory of Food and Regulation Biology, Graduate School of Bioscience, Tokai University, Kumamoto, Japan.
Laboratory of Food and Regulation Biology, Department of Food and Life Science, School of Agriculture, Tokai University, Kumamoto, Japan.
J Diabetes Investig. 2025 Apr;16(4):569-577. doi: 10.1111/jdi.70000. Epub 2025 Feb 1.
Advanced glycation end-products (AGEs) have been extensively studied because of their close association with the onset and progression of diabetic complications. However, owing to their formation through diverse metabolic pathways, AGEs often reflect a wide range of pathological conditions rather than being specific to diabetic complications. Consequently, identifying an AGE that directly correlates only with diabetic complications remains a challenge. Chronic hyperglycemia not only saturates the glycolytic pathway but also upregulates the polyol pathway, leading to the excessive production of fructose, a highly reactive reducing sugar. Although it has long been understood that fructose-derived AGEs contribute to diabetic complications, their chemical structures remain unidentified. Recent breakthroughs have revealed that glucoselysine (GL) is a primary fructose-specific AGE. Unlike other AGEs, GL is exclusively formed from fructose and not from other reducing sugars, such as glucose or galactose. This specificity provides GL with a distinct advantage in that its production pathway can be traced, making it a reliable indicator of polyol pathway activity. Furthermore, emerging evidence suggests that GL levels correlate with the progression of diabetic complications, including both micro- and macrovascular complications, making it a promising biomarker. GL's potential extends beyond diagnostics, as it may serve as a therapeutic target for managing complications associated with prolonged hyperglycemia and enhanced of polyol pathway. This review focuses on the enhanced polyol pathway and the formation of GL and discusses its biochemical characteristics, clinical significance, and potential as a novel diagnostic marker and therapeutic target in diabetic care.
晚期糖基化终产物（AGEs）因其与糖尿病并发症的发生和发展密切相关而受到广泛研究。然而，由于它们通过多种代谢途径形成，AGEs往往反映了广泛的病理状况，而不是特异性地针对糖尿病并发症。因此，鉴定仅与糖尿病并发症直接相关的AGE仍然是一项挑战。慢性高血糖不仅使糖酵解途径饱和，还上调多元醇途径，导致高反应性还原糖果糖的过量产生。虽然长期以来人们都知道果糖衍生的AGEs会导致糖尿病并发症，但其化学结构仍未明确。最近的突破表明，葡萄糖赖氨酸（GL）是一种主要的果糖特异性AGE。与其他AGEs不同，GL仅由果糖形成，而非由其他还原糖（如葡萄糖或半乳糖）形成。这种特异性赋予了GL明显的优势，即其产生途径可以被追踪，使其成为多元醇途径活性的可靠指标。此外，新出现的证据表明，GL水平与糖尿病并发症的进展相关，包括微血管和大血管并发症，使其成为一种有前景的生物标志物。GL的潜力不仅限于诊断，因为它可能成为治疗与长期高血糖和多元醇途径增强相关并发症的治疗靶点。本综述重点关注增强的多元醇途径和GL的形成，并讨论其生化特性、临床意义以及作为糖尿病护理中新型诊断标志物和治疗靶点的潜力。
