Di Fulvio Mauricio, Rathod Yakshkumar Dilipbhai, Khader Shorooq
Department of Pharmacology and Toxicology, School of Medicine, Wright State University, Dayton, OH, United States.
Front Pharmacol. 2025 Mar 28;16:1513125. doi: 10.3389/fphar.2025.1513125. eCollection 2025.
Thiazides, thiazide-like and loop diuretics are commonly prescribed to manage hypertension and heart failure. The main mechanism of action of these diuretics involve inhibition of Na reabsorption in the kidneys, leading to increased urine production. While effective, diuretics, particularly hydrochlorothiazide, have been linked to altered glucose metabolism and other metabolic issues. These disruptions in fuel homeostasis are not clearly related to their primary action of fluid management, raising concerns for patients with metabolic syndrome, in which high blood pressure coexists with obesity, insulin resistance, glucose intolerance and dyslipidemia. In this review, we conducted an extensive examination of existing literature on these classes of diuretics, covering publications from the late 1950s to the present. Our objective was to investigate the origins, development and current understanding of the widely recognized association between the use of diuretics in general and their potential negative impact on glucose homeostasis. We focused on the clinical and experimental evidence of the most commonly prescribed diuretics: hydrochlorothiazide, chlorthalidone, bumetanide and furosemide. On one hand, the clinical evidence supports the hypothesis that the metabolic effects on glucose homeostasis are primarily linked to hydrochlorothiazide, with little, if any impact observed in other diuretics. In addition, these metabolic effects do not appear to be related to their diuretic action or intended pharmacological targets, raising concerns about the long-term metabolic impact of specific diuretics, particularly in vulnerable populations, including those with metabolic syndrome. On the other hand, the experimental evidence using animal models suggest variable effects of diuretics in insulin secretion and general glucose metabolism. Although the mechanisms involved are not clearly understood, further research is needed to uncover the molecular mechanisms by which certain diuretics disrupt fuel metabolism and contribute to metabolic disturbances.
噻嗪类、噻嗪样和袢利尿剂常用于治疗高血压和心力衰竭。这些利尿剂的主要作用机制包括抑制肾脏对钠的重吸收，从而导致尿量增加。虽然利尿剂有效，但特别是氢氯噻嗪，已与葡萄糖代谢改变和其他代谢问题有关。这些能量稳态的破坏与它们在液体管理方面的主要作用并无明显关联，这引起了代谢综合征患者的担忧，因为代谢综合征患者中高血压与肥胖、胰岛素抵抗、葡萄糖不耐受和血脂异常并存。在本综述中，我们广泛查阅了关于这些类利尿剂的现有文献，涵盖了从20世纪50年代末至今的出版物。我们的目的是研究普遍使用利尿剂与其对葡萄糖稳态潜在负面影响之间广泛认可的关联的起源、发展和当前认识。我们重点关注了最常用的利尿剂：氢氯噻嗪、氯噻酮、布美他尼和呋塞米的临床和实验证据。一方面，临床证据支持这样的假设，即对葡萄糖稳态的代谢影响主要与氢氯噻嗪有关，而在其他利尿剂中观察到的影响很小，如果有的话。此外，这些代谢影响似乎与它们的利尿作用或预期的药理学靶点无关，这引发了对特定利尿剂长期代谢影响的担忧，特别是在包括代谢综合征患者在内的易感人群中。另一方面，使用动物模型的实验证据表明利尿剂对胰岛素分泌和总体葡萄糖代谢有不同的影响。尽管其中涉及的机制尚不清楚，但需要进一步研究以揭示某些利尿剂破坏能量代谢并导致代谢紊乱的分子机制。
