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Effect of Irbesartan treatment on plasma and urinary markers of protein damage in patients with type 2 diabetes and microalbuminuria

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Abstract

The aim of this study was to assess the effect of the angiotensin II receptor blocker Irbesartan on protein damage by glycation, oxidation and nitration in patients with type 2 diabetes and microalbuminuria. In a double-masked randomised crossover trial of 52 hypertensive type 2 diabetic patients, antihypertensive treatment was replaced with bendroflumethiazide. After 2-months wash-out, patients were treated randomly with Irbesartan 300, 600, and 900 mg o.d., each dose for 2 months in a three-way crossover study. Glycation, oxidation and nitration adduct residues in plasma protein and related urinary free adducts were determined by stable isotopic dilution analysis liquid chromatography–tandem mass spectrometry. Treatment with Irbesartan decreased urinary excretion of advanced glycation endproducts (AGEs)—methylglyoxal- and glyoxal-derived hydroimidazolones, MG-H1 and G-H1. Urinary AGEs were decreased by 30–32%. In plasma protein, treatment with Irbesartan increased content of glycation adducts N ε-fructosyl-lysine, AGEs N ε-carboxymethyl-lysine, N ε-carboxyethyl-lysine and pentosidine, and also increased content of oxidation markers N-formylkynurenine and dityrosine. This was attributed to decreased clearance of plasma protein modified by N ε-fructosyl-lysine and oxidative markers through the glomerular filter tightened by Irbesartan treatment. Treatment of patients with type 2 diabetes with Irbesartan decreased urinary excretion of MG-H1, G-H1 and 3-NT, which may result from decreased exposure to these AGEs. This is likely achieved by blocking angiotensin II signalling and related down-regulation of glyoxalase 1 and may contribute to health benefits of Irbesartan therapy.

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Acknowledgments

This study was supported by 6th Framework Programme Priority 1, Life Sciences, Genomics and Biotechnology for Health, LSHM-CT-2005-018733, acronym PREDICTIONS (PREvention of DIabetic ComplicaTIONS) and by an unrestricted study grant from Sanofi-Aventis, who also provided the study medication. Peter Rossing has received research support from Novartis, and speakers honorarium from Novartis, Sanofi-Aventis, Boehringer Ingelheim, and MSD.

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Authors and Affiliations

  1. Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, University Hospital, Coventry, CV2 2DX, UK

    Naila Rabbani, Antonysunil Adaikalakoteswari & Paul J. Thornalley

  2. Steno Diabetes Center, 2820, Gentofte, Denmark

    Kasper Rossing, Peter Rossing & Lise Tarnow

  3. Department of Medical Endocrinology, University of Copenhagen Hospital, Rigshospitalet, 2100, Copenhagen, Denmark

    Hans-Henrik Parving

Authors
  1. Naila Rabbani
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  2. Antonysunil Adaikalakoteswari
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  3. Kasper Rossing
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  4. Peter Rossing
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  5. Lise Tarnow
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  6. Hans-Henrik Parving
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  7. Paul J. Thornalley
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Correspondence to Paul J. Thornalley.

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Rabbani, N., Adaikalakoteswari, A., Rossing, K. et al. Effect of Irbesartan treatment on plasma and urinary markers of protein damage in patients with type 2 diabetes and microalbuminuria. Amino Acids 42, 1627–1639 (2012). https://doi.org/10.1007/s00726-011-0857-7

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  • DOI: https://doi.org/10.1007/s00726-011-0857-7

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