Miranda Edwin R, Haus Jacob M
School of Kinesiology, University of Michigan, Ann Arbor, MI, United States of America; Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, United States of America.
School of Kinesiology, University of Michigan, Ann Arbor, MI, United States of America.
Pharmacol Ther. 2023 Oct;250:108524. doi: 10.1016/j.pharmthera.2023.108524. Epub 2023 Sep 16.
Obesity prevalence in the US has nearly tripled since 1975 and a parallel increase in prevalence of type 2 diabetes (T2D). Obesity promotes a myriad of metabolic derangements with insulin resistance (IR) being perhaps the most responsible for the development of T2D and other related diseases such as cardiovascular disease. The precarious nature of IR development is such that it provides a valuable target for the prevention of further disease development. However, the mechanisms driving IR are numerous and complex making the development of viable interventions difficult. The development of metabolic derangement in the context of obesity promotes accumulation of reactive metabolites such as the reactive alpha-dicarbonyl methylglyoxal (MG). MG accumulation has long been appreciated as a marker of disease progression in patients with T2D as well as the development of diabetic complications. However, recent evidence suggests that the accumulation of MG occurs with obesity prior to T2D onset and may be a primary driving factor for the development of IR and T2D. Further, emerging evidence also suggests that this accumulation of MG with obesity may be a result in a loss of MG detoxifying capacity of glyoxalase I. In this review, we will discuss the evidence that posits MG accumulation because of GLO1 attenuation is a novel target mechanism of the development of metabolic derangement. In addition, we will also explore the regulation of GLO1 and the strategies that have been investigated so far to target GLO1 regulation for the prevention and treatment of metabolic derangement.
自1975年以来，美国的肥胖患病率几乎增长了两倍，2型糖尿病（T2D）的患病率也相应增加。肥胖会引发一系列代谢紊乱，其中胰岛素抵抗（IR）可能是导致T2D及其他相关疾病（如心血管疾病）发展的最主要原因。IR发展的不稳定性质使其成为预防疾病进一步发展的重要靶点。然而，驱动IR的机制众多且复杂，使得开发可行的干预措施变得困难。肥胖背景下代谢紊乱的发展促进了反应性代谢产物的积累，如反应性α-二羰基甲基乙二醛（MG）。长期以来，MG的积累一直被视为T2D患者疾病进展以及糖尿病并发症发生的标志。然而，最近的证据表明，MG的积累在T2D发病前就随着肥胖出现，并且可能是IR和T2D发展的主要驱动因素。此外，新出现的证据还表明，肥胖导致的MG积累可能是由于乙二醛酶I的MG解毒能力丧失所致。在本综述中，我们将讨论因GLO1衰减导致MG积累是代谢紊乱发展的一种新的靶点机制的证据。此外，我们还将探讨GLO1的调节以及迄今为止为针对GLO1调节以预防和治疗代谢紊乱而研究的策略。
