Translational Cardiology Group, Health Research Institute of Santiago de Compostela, Spain.
Cardiovascular Area and Coronary Unit, University Clinical Hospital of Santiago de Compostela, Spain; CIBERCV, Madrid, Spain; Cardiology Group, Health Research Institute of Santiago de Compostela, Spain.
Atherosclerosis. 2020 Jan;292:60-69. doi: 10.1016/j.atherosclerosis.2019.11.016. Epub 2019 Nov 15.
Dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, improves glucose uptake by epicardial adipose tissue (EAT). However, its metabolism might raise the lactate production and acidosis under hypoxia conditions, i.e. coronary artery disease (CAD), or lipogenesis and, in consequence, expand adipose tissue. Since lactate secreted by adipose tissue is correlated with tissue stress and inflammation, our aim was to study glucose metabolism by epicardial fat in CAD and its regulation by dapagliflozin.
Paired EAT and subcutaneous adipose tissue (SAT) biopsies from 49 patients who underwent open-heart surgery were cultured and split into three equal pieces, some treated with and others without dapagliflozin at 10 or 100 μM for 6 h. Anaerobic glucose metabolites were measured in supernatants of fat pads, and acidosis on adipogenesis-induced primary culture cells was analysed by colorimetric or fluorescence assays. Gene expression levels were assessed by real-time polymerase chain reaction.
Our results showed that dapagliflozin reduced the released lactate and acidosis in epicardial fat (p < 0.05) without changes in lipid storage-involved genes. In addition, this drug induced gene expression levels of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α), a mitochondrial biogenesis-involved gene in both EAT and SAT (p < 0.05). After splitting the population regarding the presence of CAD, we observed higher lactate production in EAT from these patients (2.46 [1.75-3.47] mM), which was reduced after treatment with dapagliflozin 100 μM (1.99 [1.08-2.99] mM, p < 0.01).
Dapagliflozin improved glucose metabolism without lipogenesis-involved gene regulation or lactate production, mainly in patients with CAD. These results suggest an improvement of glucose oxidation metabolism that can contribute to cardiovascular benefits.
达格列净是一种钠-葡萄糖协同转运蛋白 2 抑制剂，可提高心外膜脂肪组织（EAT）的葡萄糖摄取量。然而，它的代谢可能会在缺氧条件下（即冠状动脉疾病（CAD））增加乳酸的产生和酸中毒，或者增加脂肪生成，从而扩大脂肪组织。由于脂肪组织分泌的乳酸与组织应激和炎症有关，我们的目的是研究 CAD 中心外膜脂肪的葡萄糖代谢及其受达格列净的调节。
对 49 例行心脏直视手术的患者进行心外膜脂肪和皮下脂肪（SAT）活检，培养并分成 3 等份，部分用达格列净 10 或 100μM 处理 6 小时，另一部分不处理。测量脂肪垫上清液中的无氧葡萄糖代谢物，通过比色法或荧光法分析诱导脂肪生成的原代细胞的酸中毒。通过实时聚合酶链反应评估基因表达水平。
我们的结果表明，达格列净降低了心外膜脂肪中释放的乳酸和酸中毒（p<0.05），而不改变与脂质储存相关的基因。此外，该药物诱导了两种脂肪组织（EAT 和 SAT）中与线粒体生物发生相关的基因过氧化物酶体增殖物激活受体γ共激活因子 1α（PGC1α）的基因表达水平（p<0.05）。在根据 CAD 的存在对人群进行分组后，我们观察到这些患者的心外膜脂肪中乳酸的产生更高（2.46 [1.75-3.47] mM），用达格列净 100μM 治疗后降低（1.99 [1.08-2.99] mM，p<0.01）。
达格列净改善了葡萄糖代谢，而不涉及脂生成相关基因调节或乳酸产生，主要在 CAD 患者中。这些结果表明，葡萄糖氧化代谢得到改善，这可能有助于心血管获益。
