Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Vestec, Czech Republic.
J Physiol Pharmacol. 2020 Oct;71(5). doi: 10.26402/jpp.2020.5.04. Epub 2021 Jan 16.
The mechanisms behind the cardiovascular and renal benefits of empagliflozin is not fully understood. The positive impact of the medication on cardiovascular mortality can not be solely attributed to its antidiabetic effect, with a metabolic mechanism possibly involved. To investigate the metabolic effects of empagliflozin treatment (10 mg/kg/day for 6 weeks), we used an adult male rat model with serious vascular complications associated with metabolic syndrome and prediabetes. Impaired glucose tolerance, severe albuminuria and impaired insulin sensitivity were induced by intragastric administration of methylglyoxal and high sucrose diet feeding for four months. Although empagliflozin decreased body weight, non-fasting glucose and insulin, glucagon levels remained unchanged. In addition, empagliflozin increased adiponectin levels (+40%; p < 0.01) and improved skeletal muscle insulin sensitivity. Increased non-esterified fatty acids (NEFA) in empagliflozin-treated rats is understood to generate ketone bodies. Empagliflozin increased β-hydroxybutyrate levels in serum (+66%; p < 0.05) and the myocardium (30%; p < 0.01), suggesting its possible involvement as an alternative substrate for metabolism. Empagliflozin switched substrate utilisation in the myocardium, diverting glucose oxidation to fatty acid oxidation. Representing another favorable effect, empagliflozin also contributed to decreased uric acid plasma levels (-19%; p < 0.05). In the kidney cortex, empagliflozin improved oxidative and dicarbonyl stress parameters and increased gene expression of β-hydroxybutyrate dehydrogenase, an enzyme involved in ketone body utilisation. In addition, empagliflozin decreased microalbuminuria (-27%; p < 0.01) and urinary neutrophil gelatinase-associated lipocalin (NGAL) excretion (-29%; p < 0.01). Our results reveal the important systemic metabolic effect of empagliflozin on alterations in substrate utilisation and on increased ketone body use in prediabetic rats. Improved oxidative and dicarbonyl stress and decreased uric acid are also possibly involved in the cardio- and reno-protective effects of empagliflozin.
恩格列净发挥心血管和肾脏获益的作用机制尚未完全阐明。该药物对心血管死亡率的积极影响不能仅仅归因于其降糖作用，可能涉及代谢机制。为了研究恩格列净治疗（每天 10mg/kg，6 周）的代谢作用，我们使用成年雄性大鼠模型，该模型存在与代谢综合征和糖尿病前期相关的严重血管并发症。通过给予甲基乙二醛和高蔗糖饮食喂养 4 个月，诱导大鼠出现葡萄糖耐量受损、严重白蛋白尿和胰岛素敏感性受损。尽管恩格列净降低了体重、非空腹血糖和胰岛素水平，但胰高血糖素水平保持不变。此外，恩格列净增加了脂联素水平（增加 40%；p<0.01）并改善了骨骼肌胰岛素敏感性。在用恩格列净治疗的大鼠中，增加的非酯化脂肪酸（NEFA）被认为产生酮体。恩格列净增加了血清（增加 66%；p<0.05）和心肌（增加 30%；p<0.01）中的β-羟丁酸水平，表明其可能作为代谢的替代底物参与其中。恩格列净改变了心肌中的底物利用，将葡萄糖氧化转向脂肪酸氧化。另外，恩格列净还有助于降低尿酸的血浆水平（降低 19%；p<0.05），这是另一个有利的作用。在肾脏皮质中，恩格列净改善了氧化和二羰基应激参数，并增加了参与酮体利用的β-羟丁酸脱氢酶的基因表达。此外，恩格列净降低了微量白蛋白尿（降低 27%；p<0.01）和尿中性粒细胞明胶酶相关脂质运载蛋白（NGAL）排泄（降低 29%；p<0.01）。我们的研究结果揭示了恩格列净在改变底物利用和增加糖尿病前期大鼠酮体利用方面的重要全身代谢作用。改善氧化和二羰基应激以及降低尿酸也可能参与恩格列净的心脏和肾脏保护作用。
