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

Cordero-Herrera, Isabel; Guimarães, Drielle D.; Moretti, Chiara; Zhuge, Zhengbing; Han, Hongya; Haworth, Sarah McCann; González, Arturo; Andersson, Daniel; Weitzberg, Eddie; Lundberg, Jon O.; Carlström, Mattias

doi:10.1016/j.niox.2020.01.013

Cited by 20 publications

(13 citation statements)

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“…NO is a major signalling molecule in the human body and has a key role in maintaining vascular tone, smooth muscle cell proliferation, platelet activity and inflammation [46,47]. In animal models, dietary nitrate has been shown to attenuate endothelial dysfunction in animals fed a high-fat diet [48] or with diabetes [49], and has equivalent effects to those of metformin on glucose/insulin homeostasis and even larger effects regarding protection against cardiovascular dysfunction and liver steatosis [50]. We indeed find that nitrate content is also correlated with lower blood cell counts corresponding to lower cardiometabolic risk.…”

Section: Discussionmentioning

confidence: 99%

High intake of vegetables is linked to lower white blood cell profile and the effect is mediated by the gut microbiome

Menni

Louca

Berry

et al. 2021

BMC Med

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Background Chronic inflammation, which can be modulated by diet, is linked to high white blood cell counts and correlates with higher cardiometabolic risk and risk of more severe infections, as in the case of COVID-19. Methods Here, we assessed the association between white blood cell profile (lymphocytes, basophils, eosinophils, neutrophils, monocytes and total white blood cells) as markers of chronic inflammation, habitual diet and gut microbiome composition (determined by sequencing of the 16S RNA) in 986 healthy individuals from the PREDICT-1 nutritional intervention study. We then investigated whether the gut microbiome mediates part of the benefits of vegetable intake on lymphocyte counts. Results Higher levels of white blood cells, lymphocytes and basophils were all significantly correlated with lower habitual intake of vegetables, with vegetable intake explaining between 3.59 and 6.58% of variation in white blood cells after adjusting for covariates and multiple testing using false discovery rate (q < 0.1). No such association was seen with fruit intake. A mediation analysis found that 20.00% of the effect of vegetable intake on lymphocyte counts was mediated by one bacterial genus, Collinsella, known to increase with the intake of processed foods and previously associated with fatty liver disease. We further correlated white blood cells to other inflammatory markers including IL6 and GlycA, fasting and post-prandial glucose levels and found a significant relationship between inflammation and diet. Conclusion A habitual diet high in vegetables, but not fruits, is linked to a lower inflammatory profile for white blood cells, and a fifth of the effect is mediated by the genus Collinsella. Trial registration The ClinicalTrials.gov registration identifier is NCT03479866.

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Section: Discussionmentioning

confidence: 99%

High intake of vegetables is linked to lower white blood cell profile and the effect is mediated by the gut microbiome

Menni

Louca

Berry

et al. 2021

BMC Med

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“…The reason for this lack of effect in these two studies, which contrasts with substantial experimental evidence, might be the fact that almost all the participants were receiving metformin treatment, which is known to activate AMPK 190 . In a mouse model of cardiometabolic disease, no additional beneficial effects on cardiovascular and metabolic parameters were observed when dietary nitrate supplementation was given in combination with metformin 191 , suggesting similar mechanisms of action. A phase II study that investigated the cardiometabolic effects of nitrite therapy (40 mg, three times daily) for 12 weeks in adults with stage 1–2 hypertension, metabolic syndrome and normal kidney function who were not receiving any medications that affect glucose metabolism showed that nitrite gradually lowered blood pressure during the first 8 weeks of treatment (by approximately −10 mmHg), but blood pressure levels started to return to baseline after 10–12 weeks 192 .…”

Section: Approaches To Restoring No Bioactivitymentioning

confidence: 96%

Nitric oxide signalling in kidney regulation and cardiometabolic health

2021

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The prevalence of cardiovascular and metabolic disease coupled with kidney dysfunction is increasing worldwide. This triad of disorders is associated with considerable morbidity and mortality as well as a substantial economic burden. Further understanding of the underlying pathophysiological mechanisms is important to develop novel preventive or therapeutic approaches. Among the proposed mechanisms, compromised nitric oxide (NO) bioactivity associated with oxidative stress is considered to be important. NO is a short-lived diatomic signalling molecule that exerts numerous effects on the kidneys, heart and vasculature as well as on peripheral metabolically active organs. The enzymatic l -arginine-dependent NO synthase (NOS) pathway is classically viewed as the main source of endogenous NO formation. However, the function of the NOS system is often compromised in various pathologies including kidney, cardiovascular and metabolic diseases. An alternative pathway, the nitrate–nitrite–NO pathway, enables endogenous or dietary-derived inorganic nitrate and nitrite to be recycled via serial reduction to form bioactive nitrogen species, including NO, independent of the NOS system. Signalling via these nitrogen species is linked with cGMP-dependent and independent mechanisms. Novel approaches to restoring NO homeostasis during NOS deficiency and oxidative stress have potential therapeutic applications in kidney, cardiovascular and metabolic disorders.

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“…Mice fed with low nitrite diet also displayed IR, glucose intolerance and dyslipidemia [ 5 ]. Non-specific NOS inhibition led to enhanced circulating lipids and hepatic fat deposition in rats [ 35 , 36 ], and metabolic syndrome in mice [ 37 ]. Single (eNOS) [ 17 ], double (eNOS/nNOS) [ 38 ] and triple (eNOS, nNOS and iNOS) [ 39 ] NOS KO mice also displayed metabolic disruptions.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Insulin Resistance, Dyslipidemia and Serum Metabolome in iNOS Knockout Mice following Treatment with Nitrite, Metformin, Pioglitazone, and a Combination of Ampicillin and Neomycin

Aggarwal

Pathak

Kumar

et al. 2021

IJMS

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Oxidative and nitrosative stress plays a pivotal role in the incidence of metabolic disorders. Studies from this lab and others in iNOS-/- mice have demonstrated occurrence of insulin resistance (IR), hyperglycemia and dyslipidemia highlighting the importance of optimal redox balance. The present study evaluates role of nitrite, L-arginine, antidiabetics (metformin, pioglitazone) and antibiotics (ampicillin-neomycin combination, metronidazole) on metabolic perturbations observed in iNOS-/- mice. The animals were monitored for glucose tolerance (IPGTT), IR (insulin, HOMA-IR, QUICKI), circulating lipids and serum metabolomics (LC-MS). Hyperglycemia, hyperinsulinemia and IR were rescued by nitrite, antidiabetics, and antibiotics treatments in iNOS-/- mice. Glucose intolerance was improved with nitrite, metformin and pioglitazone treatment, while ampicillin-neomycin combination normalised the glucose utilization in iNOS-/- mice. Increased serum phosphatidylethanolamine lipids in iNOS-/- mice were reversed by metformin, pioglitazone and ampicillin-neomycin; dyslipidemia was however marginally improved by nitrite treatment. The metabolic improvements were associated with changes in selected serum metabolites-purines, ceramide, 10-hydroxydecanoate, glucosaminate, diosmetin, sebacic acid, 3-nitrotyrosine and cysteamine. Bacterial metabolites-hippurate, indole-3-ethanol; IR marker-aminoadipate and oxidative stress marker-ophthalmate were reduced by pioglitazone and ampicillin-neomycin, but not by nitrite and metformin treatment. Results obtained in the present study suggest a crucial role of gut microbiota in the metabolic perturbations observed in iNOS-/- mice.

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

Cited by 20 publications

References 37 publications

High intake of vegetables is linked to lower white blood cell profile and the effect is mediated by the gut microbiome

High intake of vegetables is linked to lower white blood cell profile and the effect is mediated by the gut microbiome

Nitric oxide signalling in kidney regulation and cardiometabolic health

Modulation of Insulin Resistance, Dyslipidemia and Serum Metabolome in iNOS Knockout Mice following Treatment with Nitrite, Metformin, Pioglitazone, and a Combination of Ampicillin and Neomycin

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