Lost-in-Translation of Metabolic Effects of Inorganic Nitrate in Type 2 Diabetes: Is Ascorbic Acid the Answer?

Bahadoran, Zahra; Mirmiran, Parvin; Kashfi, Khosrow; Ghasemi, Asghar

doi:10.3390/ijms22094735

Cited by 16 publications

(8 citation statements)

References 138 publications

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“…Its concentration was reported to be between 14.8 and 89.4 ppm after potassium nitrate (KNO 3 ) ingestion [ 98 ]. Taking the presence of nitrite in saliva fluid into account, one can expect that ascorbate secreted into gastric juice facilitates the efficient chemical reduction of salivary nitrite to generate a ppm level of NO in the stomach [ 119 ]. A strong acidity (approx.…”

Section: Ascorbate-dependent No Productionmentioning

confidence: 99%

Pleiotropic Functions of Nitric Oxide Produced by Ascorbate for the Prevention and Mitigation of COVID-19: A Revaluation of Pauling’s Vitamin C Therapy

et al. 2023

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Linus Pauling, who was awarded the Nobel Prize in Chemistry, suggested that a high dose of vitamin C (L-ascorbic acid) might work as a prevention or treatment for the common cold. Vitamin C therapy was tested in clinical trials, but clear evidence was not found at that time. Although Pauling’s proposal has been strongly criticized for a long time, vitamin C therapy has continued to be tested as a treatment for a variety of diseases, including coronavirus infectious disease 2019 (COVID-19). The pathogen of COVID-19, SARS-CoV-2, belongs to the β-coronavirus lineage, which includes human coronavirus, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS). This review intends to shed new light on vitamin C antiviral activity that may prevent SARS-CoV-2 infection through the chemical production of nitric oxide (NO). NO is a gaseous free radical that is largely produced by the enzyme NO synthase (NOS) in cells. NO produced by upper epidermal cells contributes to the inactivation of viruses and bacteria contained in air or aerosols. In addition to enzymatic production, NO can be generated by the chemical reduction of inorganic nitrite (NO2−), an alternative mechanism for NO production in living organisms. Dietary vitamin C, largely contained in fruits and vegetables, can reduce the nitrite in saliva to produce NO in the oral cavity when chewing foods. In the stomach, salivary nitrite can also be reduced to NO by vitamin C secreted from the epidermal cells of the stomach. The strong acidic pH of gastric juice facilitates the chemical reduction of salivary nitrite to produce NO. Vitamin C contributes in multiple ways to the host innate immune system as a first-line defense mechanism against pathogens. Highlighting chemical NO production by vitamin C, we suggest that controversies on the therapeutic effects of vitamin C in previous clinical trials may partly be due to less appreciation of the pleiotropic functions of vitamin C as a universal bioreductant.

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Section: Ascorbate-dependent No Productionmentioning

confidence: 99%

Pleiotropic Functions of Nitric Oxide Produced by Ascorbate for the Prevention and Mitigation of COVID-19: A Revaluation of Pauling’s Vitamin C Therapy

et al. 2023

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“…[44][45][46][47][48] However, this has not been the case in human studies where nitrate or nitrite was ineffective in improving metabolic disorders 49,50 ; for details, see a recent review. 51 In addition, a high intake of nitrate and nitrite may increase the risk of βcell autoimmunity and type 1 diabetes. 52 Cit, a precursor of Arg de novo synthesis and NO production, 53 has a highly efficient intestinal absorption rate, low first-pass metabolism, and high renal reabsorption.…”

Section: Introductionmentioning

confidence: 99%

“…These anions increase insulin secretion from the β cells 15,42,43 and improve glucose utilization at the periphery 44–48 . However, this has not been the case in human studies where nitrate or nitrite was ineffective in improving metabolic disorders 49,50 ; for details, see a recent review 51 . In addition, a high intake of nitrate and nitrite may increase the risk of β‐cell autoimmunity and type 1 diabetes 52 …”

Section: Introductionmentioning

confidence: 99%

Metabolic effects of L‐citrulline in type 2 diabetes

et al. 2023

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The prevalence of type 2 diabetes (T2D) is increasing worldwide. Decreased nitric oxide (NO) bioavailability is involved in the pathophysiology of T2D and its complications. L‐citrulline (Cit), a precursor of NO production, has been suggested as a novel therapeutic agent for T2D. Available data from human and animal studies indicate that Cit supplementation in T2D increases circulating levels of Cit and L‐arginine while decreasing circulating glucose and free fatty acids and improving dyslipidemia. The underlying mechanisms for these beneficial effects of Cit include increased insulin secretion from the pancreatic β cells, increased glucose uptake by the skeletal muscle, as well as increased lipolysis and β‐oxidation, and decreased glyceroneogenesis in the adipose tissue. Thus, Cit has antihyperglycemic, antidyslipidemic, and antioxidant effects and has the potential to be used as a new therapeutic agent in the management of T2D. This review summarizes available literature from human and animal studies to explore the effects of Cit on metabolic parameters in T2D. It also discusses the possible mechanisms underlying Cit‐induced improved metabolic parameters in T2D.

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“…Like Arg, hArg is a potential substrate for NO synthase. Another possibility to increase NO production independent of NO synthase (NOS) is supplementation of inorganic nitrate (NO 3 − , O=N(O)O − ) [19][20][21][22], presumably via its reduction to nitrite (NO 2 − , O=NO − ). Surprisingly, inorganic nitrate was found to enhance the activity of dimethylarginine dimethylaminohydrolase (DDAH; EC 3.5.3.1) [23].…”

Section: Introductionmentioning

confidence: 99%

Short-Term Supplementation of Sodium Nitrate vs. Sodium Chloride Increases Homoarginine Synthesis in Young Men Independent of Exercise

Tsikas

Maassen

Thorns

et al. 2022

IJMS

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The aim of the study was to investigate the effects of short-term oral administration of inorganic nitrate (NaNO3; n = 8) or placebo (NaCl; n = 9) (each 0.1 mmol/kg body weight/d for 9 days) on plasma amino acids, creatinine, and oxidative stress in healthy young men. At baseline, the plasma concentrations of amino acids did not differ between the groups. At the end of the study, the plasma concentrations of homoarginine (hArg; by 24%, p = 0.0001), citrulline and ornithine (Cit/Orn; by 16%, p = 0.015), and glutamine/glutamate (Gln/Glu; by 6%, p = 0.0003) were higher in the NaNO3 group compared to the NaCl group. The plasma concentrations of sarcosine (Sarc; by 28%, p < 0.0001), tyrosine (by 14%, p = 0.0051), phenylalanine (by 8%, p = 0.0026), and tryptophan (by 8%, p = 0.0047) were lower in the NaNO3 group compared to the NaCl group. These results suggest that nitrate administration affects amino-acid metabolism. The arginine/glycine amidinotransferase (AGAT) catalyzes two reactions: (1) the formation of l-homoarginine (hArg) and l-ornithine (Orn) from l-arginine (Arg) and l-lysine (Lys): Arg + Lys <−> hArg + Orn, with equilibrium constant Kharg; (2) the formation of guanidinoacetate (GAA) and Orn from Arg and glycine (Gly): Arg + Gly <−> GAA + Orn, with equilibrium constant Kgaa. The plasma Kgaa/KhArg ratio was lower in the NaNO3 group compared to the NaCl group (1.57 vs. 2.02, p = 0.0034). Our study suggests that supplementation of inorganic nitrate increases the AGAT-catalyzed synthesis of hArg and decreases the N-methyltransferase-catalyzed synthesis of GAA, the precursor of creatine. To our knowledge, this is the first study to demonstrate elevation of hArg synthesis by inorganic nitrate supplementation. Remarkably, an increase of 24% corresponds to the synthesis capacity of one kidney in healthy humans. Differences in the association between plasma concentrations of amino acids in the NaNO3 and NaCl groups suggest changes in amino-acid homeostasis. Plasma concentrations of the oxidative stress marker malondialdehyde (MDA) did not change after supplementation of NaNO3 or NaCl over the whole exercise time range. Plasma nitrite concentration turned out to be a more discriminant marker of NaNO3 ingestion than plasma nitrate (area under the receiver operating characteristic curve: 0.951 vs. 0.866, p < 0.0001 each).

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Lost-in-Translation of Metabolic Effects of Inorganic Nitrate in Type 2 Diabetes: Is Ascorbic Acid the Answer?

Cited by 16 publications

References 138 publications

Pleiotropic Functions of Nitric Oxide Produced by Ascorbate for the Prevention and Mitigation of COVID-19: A Revaluation of Pauling’s Vitamin C Therapy

Pleiotropic Functions of Nitric Oxide Produced by Ascorbate for the Prevention and Mitigation of COVID-19: A Revaluation of Pauling’s Vitamin C Therapy

Metabolic effects of L‐citrulline in type 2 diabetes

Short-Term Supplementation of Sodium Nitrate vs. Sodium Chloride Increases Homoarginine Synthesis in Young Men Independent of Exercise

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