SGLT2 inhibition via dapagliflozin improves generalized vascular dysfunction and alters the gut microbiota in type 2 diabetic mice.
SGLT2 inhibition via dapagliflozin improves generalized vascular dysfunction and alters the gut microbiota in type 2 diabetic mice.
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DOI：
10.1186/s12933-018-0708-x
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发表时间：
2018-04-27
影响因子：
9.3
通讯作者：
Gentile CL
中科院分区：
文献类型：
--
作者：
Lee DM;Battson ML;Jarrell DK;Hou S;Ecton KE;Weir TL;Gentile CL
2型糖尿病(T2D)与以大动脉僵硬增加、内皮功能障碍和血管平滑肌功能障碍为特征的全身性血管功能障碍有关。钠葡萄糖共转运体2抑制剂(SGLT2i)是最近批准的治疗T2D的口服药物类别，已被证明可降低心血管疾病和总死亡率。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个潜在的机制。目前这项研究的目的是检查广泛使用的STLT2i达帕格列酮是否能改善2型糖尿病小鼠的全身血管功能障碍。鉴于几项研究表明口服药物和肠道微生物区系之间存在双向关系，第二个目标是确定达格列酮对肠道微生物区系的影响。雄性糖尿病小鼠(DB，n = 24)和对照仔鼠(Con；n = 23)随机接受标准饲料或含有达格列酮的标准饲料(60 mg/kg饲料，0.006%)，为期8周。用主动脉脉搏波速度评价动脉僵硬，用乙酰胆碱和硝普钠的扩张反应评价血管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，服用达格列酮治疗的糖尿病小鼠动脉硬度显著降低(DB = 469 cm/S vs DB + Dapa = 435 cm/S，p <； 0.05)，内皮功能障碍(曲线下面积[AuC]DB = 57.2vs DB + Dapa = 117.0，p <； 0.05)和血管平滑肌功能障碍(AuC，DB = 201.7 vs DB + Dapa = 285.5，p <； 0.05)。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小鼠的微生物区系明显不同，达格列酮治疗与肠道微生物区系组成的轻微变化有关，特别是在DB小鼠，尽管这些影响并不能最终中介血管功能的改善。达格列夫秦治疗改善了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，并微妙地改变了微生物区系组成。总体而言，全身血管功能的改善可能代表了SGLT2i治疗心血管益处的一个重要机制。
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.
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DOI：
10.1038/ismej.2012.8
发表时间：
2012-08
期刊：
The ISME journal
影响因子：
--
作者：
通讯作者：
--
DOI：
10.2147/dmso.s61438
发表时间：
2014
期刊：
Diabetes, metabolic syndrome and obesity : targets and therapy
影响因子：
--
作者：
Lorber D
通讯作者：
Lorber D
影响因子：
48
作者：
Callahan BJ;McMurdie PJ;Rosen MJ;Han AW;Johnson AJ;Holmes SP
通讯作者：
Holmes SP
影响因子：
4.6
作者：
Leng W;Ouyang X;Lei X;Wu M;Chen L;Wu Q;Deng W;Liang Z
通讯作者：
Liang Z
DOI：
10.1152/ajplung.00167.2015
发表时间：
2015-11-01
影响因子：
4.9
作者：
Han, Ying;Cho, Young-Eun;Makino, Ayako
通讯作者：
Makino, Ayako