Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Heart and Vascular Theme, Section for Heart Failure, Arrhythmia and GUCH, Karolinska University Hospital, Stockholm, Sweden.
Nitric Oxide. 2020 Apr 1;97:48-56. doi: 10.1016/j.niox.2020.01.013. Epub 2020 Feb 4.
BACKGROUND/PURPOSE: Unhealthy dietary habits contribute to the increasing incidence of metabolic syndrome and type 2 diabetes (T2D), which is accompanied by oxidative stress, compromised nitric oxide (NO) bioavailability and increased cardiovascular risk. Apart from lifestyle changes, biguanides such as metformin are the first-line pharmacological treatment for T2D. Favourable cardiometabolic effects have been demonstrated following dietary nitrate supplementation to boost the nitrate-nitrite-NO pathway. Here we aim to compare the therapeutic value of inorganic nitrate and metformin alone and their combination in a model of cardiometabolic disease.
Mice were fed control or high fat diet (HFD) for 7 weeks in combination with the NO synthase (NOS) inhibitor l-NAME to induce metabolic syndrome. Simultaneously, the mice were treated with vehicle, inorganic nitrate, metformin or a combination of nitrate and metformin in (drinking water). Cardiometabolic functions were assessed in vivo and tissues were collected/processed for analyses.
HFD + L-NAME was associated with cardiometabolic dysfunction, compared with controls, as evident from elevated blood pressure, endothelial dysfunction, impaired insulin sensitivity and compromised glucose clearance as well as liver steatosis. Both nitrate and metformin improved insulin/glucose homeostasis, whereas only nitrate had favourable effects on cardiovascular function and steatosis. Mechanistically, metformin and nitrate improved AMPK signalling, whereas only nitrate attenuated oxidative stress. Combination of nitrate and metformin reduced HbA1c and trended to further increase AMPK activation.
CONCLUSION/IMPLICATIONS: Nitrate and metformin had equipotent metabolic effects, while nitrate was superior regarding protection against cardiovascular dysfunction and liver steatosis. If reproduced in future clinical trials, these findings may have implications for novel nutrition-based strategies against metabolic syndrome, T2D and associated complications.
背景/目的：不健康的饮食习惯导致代谢综合征和 2 型糖尿病（T2D）的发病率不断上升，这伴随着氧化应激、一氧化氮（NO）生物利用度降低和心血管风险增加。除了生活方式的改变外，二甲双胍等双胍类药物是 T2D 的一线药物治疗方法。补充膳食硝酸盐可促进硝酸盐-亚硝酸盐-NO 途径，从而显示出有利的代谢和心血管作用。在这里，我们旨在比较无机硝酸盐和二甲双胍单独使用及其组合在代谢疾病模型中的治疗价值。
将小鼠用对照或高脂肪饮食（HFD）喂养 7 周，同时用一氧化氮合酶（NOS）抑制剂 l-NAME 诱导代谢综合征。同时，将小鼠用载体、无机硝酸盐、二甲双胍或硝酸盐和二甲双胍的组合（饮用水）进行治疗。在体内评估代谢和心血管功能，并收集/处理组织进行分析。
HFD+L-NAME 与对照组相比，与代谢综合征相关的心脏代谢功能障碍，表现为血压升高、内皮功能障碍、胰岛素敏感性受损和葡萄糖清除受损以及肝脂肪变性。硝酸盐和二甲双胍均改善了胰岛素/葡萄糖稳态，而只有硝酸盐对心血管功能和脂肪变性有有利影响。在机制上，二甲双胍和硝酸盐改善了 AMPK 信号，而只有硝酸盐减轻了氧化应激。硝酸盐和二甲双胍的联合使用降低了 HbA1c 并趋势进一步增加了 AMPK 激活。
结论/意义：硝酸盐和二甲双胍具有等效的代谢作用，而硝酸盐在预防心血管功能障碍和肝脂肪变性方面具有优势。如果在未来的临床试验中得到证实，这些发现可能对针对代谢综合征、T2D 及其相关并发症的新型营养策略具有重要意义。
