Head-to-head comparison of inorganic nitrate (beetroot) and metF
Nitric Oxide. 2020 Feb 4.
Head-to-head comparison of inorganic nitrate and MetF in a mouse model of cardiometabolic disease.
Cordero-Herrera I1, Guimarães DD1, Moretti C1, Zhuge Z1, Han H1, McCann Haworth S1, Uribe Gonzalez AE1, Andersson DC2, Weitzberg E3, Lundberg JO4, Carlström M5.
1 Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
2 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.
3 Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Department of Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden.
4 Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. Electronic address: jon.lundberg@ki.se.
5 Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. Electronic address: mattias.carlstrom@ki.se.
Abstract
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 MetF 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 MetF alone and their combination in a model of cardiometabolic disease.
EXPERIMENTAL APPROACH:
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, MetF or a combination of nitrate and MetF in (drinking water). Cardiometabolic functions were assessed in vivo and tissues were collected/processed for analyses.
KEY RESULTS:
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 MetF improved insulin/glucose homeostasis, whereas only nitrate had favourable effects on cardiovascular function and steatosis. Mechanistically, MetF and nitrate improved AMPK signalling, whereas only nitrate attenuated oxidative stress. Combination of nitrate and MetF reduced HbA1c and trended to further increase AMPK activation.
CONCLUSION / IMPLICATIONS:
Nitrate and MetF 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.
Copyright © 2020. Published by Elsevier Inc.
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