Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, 80523, USA.
Cardiovasc Diabetol. 2018 Apr 27;17(1):62. doi: 10.1186/s12933-018-0708-x.
Type 2 diabetes (T2D) is associated with generalized vascular dysfunction characterized by increases in large artery stiffness, endothelial dysfunction, and vascular smooth muscle dysfunction. Sodium glucose cotransporter 2 inhibitors (SGLT2i) represent the most recently approved class of oral medications for the treatment of T2D, and have been shown to reduce cardiovascular and overall mortality. Although it is currently unclear how SGLT2i decrease cardiovascular risk, an improvement in vascular function is one potential mechanism. The aim of the current study was to examine if dapagliflozin, a widely prescribed STLT2i, improves generalized vascular dysfunction in type 2 diabetic mice. In light of several studies demonstrating a bi-directional relation between orally ingested medications and the gut microbiota, a secondary aim was to determine the effects of dapagliflozin on the gut microbiota.
Male diabetic mice (Db, n = 24) and control littermates (Con; n = 23) were randomized to receive either a standard diet or a standard diet containing dapagliflozin (60 mg dapagliflozin/kg diet; 0.006%) for 8 weeks. Arterial stiffness was assessed by aortic pulse wave velocity; endothelial function and vascular smooth muscle dysfunction were assessed by dilatory responses to acetylcholine and sodium nitroprusside, respectively.
Compared to untreated diabetic mice, diabetic mice treated with dapagliflozin displayed significantly lower arterial stiffness (Db = 469 cm/s vs. Db + dapa = 435 cm/s, p < 0.05), and improvements in endothelial dysfunction (area under the curve [AUC] Db = 57.2 vs. Db + dapa = 117.0, p < 0.05) and vascular smooth muscle dysfunction (AUC, Db = 201.7 vs. Db + dapa = 285.5, p < 0.05). These vascular improvements were accompanied by reductions in hyperglycemia and circulating markers of inflammation. The microbiota of Db and Con mice were distinctly different, and dapagliflozin treatment was associated with minor alterations in gut microbiota composition, particularly in Db mice, although these effects did not conclusively mediate the improvements in vascular function.
Dapagliflozin treatment improves arterial stiffness, endothelial dysfunction and vascular smooth muscle dysfunction, and subtly alters microbiota composition in type 2 diabetic mice. Collectively, the improvements in generalized vascular function may represent an important mechanism underlying the cardiovascular benefits of SGLT2i treatment.
2 型糖尿病（T2D）与大动脉僵硬、内皮功能障碍和血管平滑肌功能障碍等全身性血管功能障碍有关。钠-葡萄糖共转运蛋白 2 抑制剂（SGLT2i）是最近批准用于治疗 T2D 的一类口服药物，已被证明可降低心血管和总体死亡率。尽管目前尚不清楚 SGLT2i 如何降低心血管风险，但改善血管功能是一种潜在机制。本研究旨在探讨广泛应用的 SGLT2i 达格列净是否能改善 2 型糖尿病小鼠的全身性血管功能障碍。鉴于几项研究表明口服药物与肠道微生物群之间存在双向关系，次要目标是确定达格列净对肠道微生物群的影响。
雄性糖尿病小鼠（Db，n=24）和对照同窝仔（Con；n=23）随机分为标准饮食组或标准饮食加达格列净组（60mg 达格列净/kg 饮食；0.006%），治疗 8 周。通过主动脉脉搏波速度评估动脉僵硬；通过乙酰胆碱和硝普钠的扩张反应评估内皮功能和血管平滑肌功能障碍。
与未经治疗的糖尿病小鼠相比，用达格列净治疗的糖尿病小鼠的动脉僵硬明显降低（Db=469cm/s 与 Db+dapa=435cm/s，p<0.05），内皮功能障碍（曲线下面积[AUC]Db=57.2 与 Db+dapa=117.0，p<0.05）和血管平滑肌功能障碍（AUC，Db=201.7 与 Db+dapa=285.5，p<0.05）改善。这些血管改善伴随着高血糖和循环炎症标志物的减少。Db 和 Con 小鼠的微生物群明显不同，达格列净治疗与肠道微生物群组成的微小变化有关，特别是在 Db 小鼠中，尽管这些影响并未明确介导血管功能的改善。
达格列净治疗可改善 2 型糖尿病小鼠的动脉僵硬、内皮功能障碍和血管平滑肌功能障碍，并轻微改变肠道微生物群组成。总体而言，全身性血管功能的改善可能是 SGLT2i 治疗心血管获益的重要机制。
