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Nitric Oxide. 2020 Apr 1;97:48-56. doi: 10.1016/j.niox.2020.01.013. Epub 2020 Feb 4.

Head-to-head comparison of inorganic nitrate and metformin in a mouse model of cardiometabolic disease.

Author information

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 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.

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, metformin or a combination of nitrate and metformin 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 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.

PMID:
32032718
DOI:
10.1016/j.niox.2020.01.013
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Conflict of interest statement

Declaration of competing interest J.O.L and E.W. are co-inventors on patent applications related to the therapeutic use of inorganic nitrate. The other authors have no conflicts of interest.

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