SGLT2 inhibition via dapagliflozin improves generalized vascular dysfunction and alters the gut microbiota in type 2 diabetic mice

Abstract

BackgroundType 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.MethodsMale 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.ResultsCompared 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.ConclusionsDapagliflozin 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.

<p>SGLT-2 inhibitors as promising therapeutics for non-alcoholic fatty liver disease: pathophysiology, clinical outcomes, and future directions</p>

“…In keeping with the possibility of additional mechanisms, it was recently shown that in obese mice with diabetes resulting from homozygous mutation of the leptin gene (lepr db /lepr db ), treatment with dapagliflozin resulted in improved glycemic control associated with improvement in arterial stiffness and alteration in their microbiome. 76 Whether similar effects will be observed in patients with T2DM remains to be determined. Future research could explore combination of therapeutics that have shown promising results in the treatment of NAFLD in patients with and without T2DM.…”

The gut microbiota and its interactions with cardiovascular disease

“…SCFAs could alter the metabolic state via activation of nuclear receptors such as PPARs (Hasan, et al, 2019) or specific GPRs such as GPR41 and GPR43 that are involved in the release of the entero hormone PYY (Samuel, et al, 2008), fat accumulation reduction, energy expenditure (Kimura, et al, 2013) and insulin secretion (Tolhurst, et al, 2012). Several molecules, including GLP-1, MyD88, dipeptidyl peptidase-4 (DPP-4) and sodium glucose cotransporter 2 (SGLT2), interact closely with the gut microbiota to modulate insulin secretion (Grasset, et al, 2017), diabetes-related metabolic effects (Duparc, et al, 2017;Liao, et al, 2019) and diabetes-induced vascular dysfunction (Lee, et al, 2018).…”

Corrigendum: The new views on the state of the gut microbiota in obesity and diabetes mellitus type 2 (Diabetes mellitus. 2019;22(3). doi: 10.14341/DM10194)

“…Помимо этого, было выявлено, что сниженное в группе животных с ожирением и СД2 количество Lactobacillus, Bifidobacterium, как основных продуцентов КЦЖК, нивелировалось в группе Bifidobacterium и оставалось без изменений в группе Lactobacillus [47]. получавших дапаглифлозин, относительно группы контроля, что, вероятно, связано с увеличением продукции КЦЖК, сохранением целостности муцинового слоя и улучшением метаболических результатов [49]. В другом исследовании было показано, что двойной ингибитор НГЛТ-1, -2 снижает уровень глюкозы в крови и уровень HbA 1c и приводит к увеличению содержания ГПП-1 у животных, получающих богатую углеводами пищу.…”