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Circulating biomarkers of nitric oxide bioactivity and impaired muscle vasoreactivity to exercise in adults with uncomplicated type 1 diabetes

Circulating biomarkers of nitric oxide bioactivity and impaired muscle vasoreactivity to exercise in adults with uncomplicated type 1 diabetes
Circulating biomarkers of nitric oxide bioactivity and impaired muscle vasoreactivity to exercise in adults with uncomplicated type 1 diabetes

Aims/hypothesis: Early compromised endothelial function challenges the ability of individuals with type 1 diabetes to perform normal physical exercise. The exact mechanisms underlying this vascular limitation remain unknown, but may involve either formation or metabolism of nitric oxide (NO), a major vasodilator, whose activity is known to be compromised by oxidative stress. Methods: Muscle microvascular reactivity (near-infrared spectroscopy) to an incremental exhaustive bout of exercise was assessed in 22 adults with uncomplicated type 1 diabetes (HbA1c 64.5 ± 15.7 mmol/mol; 8.0 ± 1.4%) and in 21 healthy individuals (18–40 years of age). NO-related substrates/metabolites were also measured in the blood along with other vasoactive compounds and oxidative stress markers; measurements were taken at rest, at peak exercise and after 15 min of recovery. Demographic characteristics, body composition, smoking status and diet were comparable in both groups. Results: Maximal oxygen uptake was impaired in individuals with type 1 diabetes compared with in healthy participants (35.6 ± 7.7 vs 39.6 ± 6.8 ml min−1 kg−1, p < 0.01) despite comparable levels of habitual physical activity (moderate to vigorous physical activity by accelerometery, 234.9 ± 160.0 vs 280.1 ± 114.9 min/week). Compared with non-diabetic participants, individuals with type 1 diabetes also displayed a blunted exercise-induced vasoreactivity (muscle blood volume at peak exercise as reflected by ∆ total haemoglobin, 2.03 ± 5.82 vs 5.33 ± 5.54 μmol/l; interaction ‘exercise’ × ‘group’, p < 0.05); this was accompanied by lower K+ concentration (p < 0.05), reduced plasma l-arginine (p < 0.05)—in particular when HbA1c was high (mean estimation: −4.0, p < 0.05)—and lower plasma urate levels (p < 0.01). Nonetheless, exhaustive exercise did not worsen lipid peroxidation or other oxidative stress biomarkers, and erythrocytic enzymatic antioxidant resources were mobilised to a comparable extent in both groups. Nitrite and total nitrosation products, which are potential alternative NO sources, were similarly unaltered. [Figure not available: see fulltext.] Conclusions/interpretation: Participants with uncomplicated type 1 diabetes displayed reduced availability of l-arginine, the essential substrate for enzymatic nitric oxide synthesis, as well as lower levels of the major plasma antioxidant, urate. Lower urate levels may reflect a defect in the activity of xanthine oxidase, an enzyme capable of producing NO from nitrite under hypoxic conditions. Thus, both canonical and non-canonical NO production may be reduced. However, neither of these changes exacerbated exercise-induced oxidative stress. Trial registration: clinicaltrials.gov NCT02051504

Aerobic fitness, Antioxidant defences, l-arginine, Nitric oxide, Oxidative stress, Physical exercise, Skeletal muscle, Type 1 diabetes, Urate, Vasoreactivity
0012-186X
325-338
Lespagnol, Elodie
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Tagougui, Sémah
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Fernandez, Bernadette O.
9890aabc-1fe6-4530-a51e-31182e537131
Zerimech, Farid
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Matran, Régis
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Maboudou, Patrice
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Berthoin, Serge
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Descat, Amandine
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Kim, Isabelle
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Pawlak-Chaouch, Mehdi
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Boissière, Julien
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Boulanger, Eric
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Feelisch, Martin
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Fontaine, Pierre
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Heyman, Elsa
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Lespagnol, Elodie
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Tagougui, Sémah
439da70d-3f59-4a59-a338-4064ba24a706
Fernandez, Bernadette O.
9890aabc-1fe6-4530-a51e-31182e537131
Zerimech, Farid
8424a81f-62d6-4da7-89cf-d2315f512cd7
Matran, Régis
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Maboudou, Patrice
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Berthoin, Serge
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Descat, Amandine
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Kim, Isabelle
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Pawlak-Chaouch, Mehdi
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Boissière, Julien
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Boulanger, Eric
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Feelisch, Martin
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Fontaine, Pierre
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Heyman, Elsa
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Lespagnol, Elodie, Tagougui, Sémah, Fernandez, Bernadette O., Zerimech, Farid, Matran, Régis, Maboudou, Patrice, Berthoin, Serge, Descat, Amandine, Kim, Isabelle, Pawlak-Chaouch, Mehdi, Boissière, Julien, Boulanger, Eric, Feelisch, Martin, Fontaine, Pierre and Heyman, Elsa (2020) Circulating biomarkers of nitric oxide bioactivity and impaired muscle vasoreactivity to exercise in adults with uncomplicated type 1 diabetes. Diabetologia, 64, 325-338. (doi:10.1007/s00125-020-05329-8).

Record type: Article

Abstract

Aims/hypothesis: Early compromised endothelial function challenges the ability of individuals with type 1 diabetes to perform normal physical exercise. The exact mechanisms underlying this vascular limitation remain unknown, but may involve either formation or metabolism of nitric oxide (NO), a major vasodilator, whose activity is known to be compromised by oxidative stress. Methods: Muscle microvascular reactivity (near-infrared spectroscopy) to an incremental exhaustive bout of exercise was assessed in 22 adults with uncomplicated type 1 diabetes (HbA1c 64.5 ± 15.7 mmol/mol; 8.0 ± 1.4%) and in 21 healthy individuals (18–40 years of age). NO-related substrates/metabolites were also measured in the blood along with other vasoactive compounds and oxidative stress markers; measurements were taken at rest, at peak exercise and after 15 min of recovery. Demographic characteristics, body composition, smoking status and diet were comparable in both groups. Results: Maximal oxygen uptake was impaired in individuals with type 1 diabetes compared with in healthy participants (35.6 ± 7.7 vs 39.6 ± 6.8 ml min−1 kg−1, p < 0.01) despite comparable levels of habitual physical activity (moderate to vigorous physical activity by accelerometery, 234.9 ± 160.0 vs 280.1 ± 114.9 min/week). Compared with non-diabetic participants, individuals with type 1 diabetes also displayed a blunted exercise-induced vasoreactivity (muscle blood volume at peak exercise as reflected by ∆ total haemoglobin, 2.03 ± 5.82 vs 5.33 ± 5.54 μmol/l; interaction ‘exercise’ × ‘group’, p < 0.05); this was accompanied by lower K+ concentration (p < 0.05), reduced plasma l-arginine (p < 0.05)—in particular when HbA1c was high (mean estimation: −4.0, p < 0.05)—and lower plasma urate levels (p < 0.01). Nonetheless, exhaustive exercise did not worsen lipid peroxidation or other oxidative stress biomarkers, and erythrocytic enzymatic antioxidant resources were mobilised to a comparable extent in both groups. Nitrite and total nitrosation products, which are potential alternative NO sources, were similarly unaltered. [Figure not available: see fulltext.] Conclusions/interpretation: Participants with uncomplicated type 1 diabetes displayed reduced availability of l-arginine, the essential substrate for enzymatic nitric oxide synthesis, as well as lower levels of the major plasma antioxidant, urate. Lower urate levels may reflect a defect in the activity of xanthine oxidase, an enzyme capable of producing NO from nitrite under hypoxic conditions. Thus, both canonical and non-canonical NO production may be reduced. However, neither of these changes exacerbated exercise-induced oxidative stress. Trial registration: clinicaltrials.gov NCT02051504

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Accepted/In Press date: 29 September 2020
Published date: 21 November 2020
Keywords: Aerobic fitness, Antioxidant defences, l-arginine, Nitric oxide, Oxidative stress, Physical exercise, Skeletal muscle, Type 1 diabetes, Urate, Vasoreactivity

Identifiers

Local EPrints ID: 445912
URI: http://eprints.soton.ac.uk/id/eprint/445912
ISSN: 0012-186X
PURE UUID: 71fcc472-9950-4cb9-aa1c-478f9b18c12d
ORCID for Bernadette O. Fernandez: ORCID iD orcid.org/0000-0001-6337-0381
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158

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Date deposited: 13 Jan 2021 17:31
Last modified: 18 Mar 2024 05:26

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Contributors

Author: Elodie Lespagnol
Author: Sémah Tagougui
Author: Bernadette O. Fernandez ORCID iD
Author: Farid Zerimech
Author: Régis Matran
Author: Patrice Maboudou
Author: Serge Berthoin
Author: Amandine Descat
Author: Isabelle Kim
Author: Mehdi Pawlak-Chaouch
Author: Julien Boissière
Author: Eric Boulanger
Author: Martin Feelisch ORCID iD
Author: Pierre Fontaine
Author: Elsa Heyman

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