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

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.

l ‐Homoarginine supplementation prevents diabetic kidney damage

“…In addition, supplementation of homoarginine to control mice did not alter any hemodynamic parameters or body weight despite increasing plasma homoarginine levels (Atzler et al 2017;Karetnikova et al 2019). Although reduced L-homoarginine levels are a marker for cardiovascular and kidney disease (Morris et al 2011;Jud et al 2018;Martens-Lobenhoffer et al 2018), the role of L-homoarginine in diabetes remains controversial (Carmann et al 2015;Krebs et al 2015). In a diet-induced obese mouse model, Stockebrand et al (2015) reported that L-homoarginine supplementation reduced blood glucose and stimulated insulin production, despite having no effect on body weight or glucose tolerance.…”

Homoarginine, arginine, and relatives: analysis, metabolism, transport, physiology, and pathology

“…The circulating concentration of ADMA in healthy children is more than two times higher than in healthy adults (Lücke et al 2007), suggesting that ADMA and presumably the whole Arg/NO pathway greatly differ between children/adolescents and adults, i.e., that children are not small adults. In the present work, emphasis was given to the Arg/NO pathway, including hArg in healthy children and adolescents, as well as in those suffering from type 1 diabetes mellitus, Duchenne muscular dystrophy, and growth hormone deficiency (GHD) (Carmann et al 2015;Hörster et al 2015;Langen et al 2015; see also Thum et al 2007).…”

Biophysical, Biochemical, and Cell Based Approaches Used to Decipher the Role of Carbonic Anhydrases in Cancer and to Evaluate the Potency of Targeted Inhibitors

“…These studies have led to the development of targeted therapy against CAs that are currently in clinical use for the treatment of diseases such as glaucoma, altitude sickness, and epileptic seizures. CA targeting inhibitors are now being tested in preclinical models for the treatment of diabetes and obesity, while others are currently in clinical trials as cancer therapies [ 4 – 11 ]. Combined, these studies show that CAs are important therapeutic targets for the treatment of an expanding array of human diseases.…”