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The l-arginine/NO pathway, homoarginine, and nitrite-dependent renal carbonic anhydrase activity in young people with type 1 diabetes mellitus

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Abstract

High circulating levels of asymmetric dimethylarginine (ADMA) and low circulating levels of homoarginine (hArg) are known cardiovascular risk factors in adults. While in adults with type 1 diabetes mellitus (T1DM) circulating ADMA is significantly elevated, in children and adolescents the reported ADMA data are contradictory. In 102 children with T1DM and 95 healthy controls (HC) serving as controls, we investigated the l-arginine (Arg)/nitric oxide (NO) pathway. Children with T1DM were divided into two groups, i.e., in children with newly diagnosed diabetes mellitus [T1DM-ND; n = 10; age, 8.8 (4.4–11.2) years; HbA1c, 13 (8.9–13.9) %] and in those with long-term treatment [T1DM-T; n = 92; age, 12.5 (10.5–15.4) years; HbA1c, 8.0 (7.2–8.6) %]. The age of the HC was 11.3 (8–13.3) years. Amino acids and NO metabolites of the Arg/NO pathway, creatinine and the oxidative stress biomarker malondialdehyde (MDA) were measured by GC–MS or GC–MS/MS. Plasma hArg, ADMA and the hArg/ADMA molar ratio did not differ between the T1DM and HC groups. There was a significant difference between T1DM-T and HC with regard to plasma nitrite [0.53 (0.48–0.61) vs 2.05 (0.86–2.36) µM, P < 0.0001] as well as to urinary nitrite [0.09 (0.06–0.17) vs 0.22 (0.13–0.37) μmol/mmol creatinine, P < 0.0001]. Plasma, but not urinary nitrite, differed between T1DM-ND and HC [0.55 (0.50–0.66) vs 2.05 (0.86–2.36) µM, P < 0.0001]. Plasma MDA did not differ between the groups. The urinary nitrate-to-nitrite molar ratio (UNOXR), a measure of nitrite-dependent renal carbonic anhydrase (CA) activity, was higher in T1DM-T [1173 (738–1481), P < 0.0001] and T1DM-ND [1341 (1117–1615), P = 0.0007] compared to HC [540 (324–962)], but did not differ between T1DM-T and T1DM-ND (P = 0.272). The lower nitrite excretion in the children with T1DM may indicate enhanced renal CA-dependent nitrite reabsorption compared with healthy children. Yet, lower plasma nitrite concentration in the T1DM patients may have also contributed to the higher UNOXR. Patients’ age correlated positively with plasma hArg and hArg/ADMA and urinary DMA/ADMA. Plasma ADMA and urinary ADMA, DMA, nitrite and nitrate correlated negatively with age of the T1DM-T children. Significant correlations were found between plasma hArg and plasma Arg (r = 0.468, P < 0.0001), and urinary DMA (r = −0.426, P = 0.0001), ADMA (r = −0.266, P = 0.021) and nitrate (r = −0.234, P = 0.043). Plasma hArg correlated positively with age at diagnosis (r = +0.337, P = 0.002). ADMA, but not hArg, correlated with HbA1c in T1DM-T (r = −0.418, P < 0.0001) and T1DM-ND (r = +0.879, P = 0.0016). The greatest differences between T1DM-T and T1DM-ND were observed for urinary ADMA, DMA/ADMA ratio, nitrite and nitrate. The Arg/NO pathway is altered in T1DM in childhood and adolescence, yet the role and the importance of hArg and ADMA in T1DM remain to be elucidated. In young T1DM patients, oxidative stress (lipid peroxidation) is not elevated.

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Abbreviations

ADMA:

Asymmetric dimethylarginine

Arg:

l-Arginine

BMI:

Body mass index

CA:

Carbonic anhydrase

DDAH:

Dimethylarginine dimethylaminohydrolase

DMA:

Dimethylamine

GFR:

Glomerular filtration rate

hArg:

l-Homoarginine

HC:

Healthy controls

MDA:

Malondialdehyde

NO:

Nitric oxide

NOS:

Nitric oxide synthase

eNOS:

Endothelial NOS

iNOS:

Inducible NOS

nNOS:

Neuronal NOS

PNOxR:

Plasma nitrate-to-nitrite molar ratio

QC:

Quality control

T1DM:

Type 1 diabetes mellitus

T1DM-ND:

Newly diagnosed T1DM

T1DM-T:

Treated T1DM

UNOxR:

Urinary nitrate-to-nitrite molar ratio

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Acknowledgments

The authors thank A. Mitschke and M. T. Suchy for excellent laboratory assistance and F.-M. Gutzki for performing GC–MS and GC–MS/MS analyses. We are also thankful to the Deutsche Diabetes Gesellschaft for the travel support given to Christina Carmann for the presentation of the study results at the Deutscher Diabetes Kongress 2014 in Berlin.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standard

The study was designed as a prospective cross-sectional study and was approved by the Ethics Committee of the University of Bochum. The study was performed in accordance with the guidelines of the Declaration of Helsinki and of Good Clinical Practice. Written and informed consent was given by parents and children.

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Authors and Affiliations

  1. Department of Neuropaediatrics, University Children’s Hospital, Ruhr-University Bochum, Alexandrinenstraße 5, 44791, Bochum, Germany

    Christina Carmann, Katharina Weigt-Usinger, Irina Hörster & Thomas Lücke

  2. Section of Endocrinology, University Children’s Hospital, Ruhr-University Bochum, Bochum, Germany

    Eggert Lilienthal

  3. Department of Gastroenterology, University Children’s Hospital, Ruhr-University Bochum, Bochum, Germany

    Anjona Schmidt-Choudhury

  4. Centre of Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany

    Arslan Arinc Kayacelebi, Bibiana Beckmann & Dimitrios Tsikas

  5. Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany

    Kristine Chobanyan-Jürgens

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  1. Christina Carmann
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  2. Eggert Lilienthal
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Correspondence to Thomas Lücke.

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D. Tsikas and T. Lücke are both senior authors.

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Carmann, C., Lilienthal, E., Weigt-Usinger, K. et al. The l-arginine/NO pathway, homoarginine, and nitrite-dependent renal carbonic anhydrase activity in young people with type 1 diabetes mellitus. Amino Acids 47, 1865–1874 (2015). https://doi.org/10.1007/s00726-015-2027-9

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