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      Glycation of human serum albumin impairs binding to the glucagon-like peptide-1 analogue liraglutide

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          Abstract

          The long-acting glucagon-like peptide-1 analogue liraglutide has proven efficiency in the management of type 2 diabetes and also has beneficial effects on cardiovascular diseases. Liraglutide's protracted action highly depends on its capacity to bind to albumin via its palmitic acid part. However, in diabetes, albumin can undergo glycation, resulting in impaired drug binding. Our objective in this study was to assess the impact of human serum albumin (HSA) glycation on liraglutide affinity. Using fluorine labeling of the drug and 19F NMR, we determined HSA affinity for liraglutide in two glycated albumin models. We either glycated HSA in vitro by incubation with glucose (G25- or G100-HSA) or methylglyoxal (MGO-HSA) or purified in vivo glycated HSA from the plasma of diabetic patients with poor glycemic control. Nonglycated commercial HSA (G0-HSA) and HSA purified from plasma of healthy individuals served as controls. We found that glycation decreases affinity for liraglutide by 7-fold for G100-HSA and by 5-fold for MGO-HSA compared with G0-HSA. A similarly reduced affinity was observed for HSA purified from diabetic individuals compared with HSA from healthy individuals. Our results reveal that glycation significantly impairs HSA affinity to liraglutide and confirm that glycation contributes to liraglutide's variable therapeutic efficiency, depending on diabetes stage. Because diabetes is a progressive disease, the effect of glycated albumin on liraglutide affinity found here is important to consider when diabetes is managed with this drug.

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          Author and article information

          Journal
          J Biol Chem
          J. Biol. Chem
          jbc
          jbc
          JBC
          The Journal of Biological Chemistry
          American Society for Biochemistry and Molecular Biology (11200 Rockville Pike, Suite 302, Rockville, MD 20852-3110, U.S.A. )
          0021-9258
          1083-351X
          30 March 2018
          2 February 2018
          : 293
          : 13
          : 4778-4791
          Affiliations
          From the []Université de La Réunion, INSERM, UMR 1188 Diabète Athérothrombose Thérapie Réunion Océan Indien (DéTROI), 97490 Saint-Denis de La Réunion, France,
          the [§ ]Services de Cardiologie et de Biologie, Centre Hospitalier Gabriel Martin, 97866 Saint-Paul, France,
          the []Service d'Endocrinologie, Nutrition, et Diabétologie, CHU de La Réunion, 97400 Saint-Denis de La Réunion, France,
          []CIC1410 INSERM, 97448 Saint-Pierre, Réunion, France,
          the [** ]Proteomic Unit and Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Hospital Clínico Universitario de Santiago, 15706 Santiago de Compostela, Spain,
          [‡‡ ]CIBERCV, Av. Monforte de Lemos, 3–5, Pabellón 11, Planta 0 28029 Madrid, Spain, and
          the [§§ ]Centre d'Investigation Clinique, CHU de La Réunion, 97448 Saint-Pierre, Réunion, France
          Author notes
          [2 ] To whom correspondence may be addressed: UMR DéTROI INSERM 1188, Université de La Réunion Plateforme CYROI, 2 Rue Maxime Rivière, 97490 Sainte-Clotilde, France. E-mail: rophil@ 123456univ-reunion.fr .
          [3 ] To whom correspondence may be addressed: UMR DéTROI INSERM 1188, Université de La Réunion Plateforme CYROI, 2 Rue Maxime Rivière, 97490 Sainte-Clotilde, France. E-mail: joel.couprie@ 123456univ-reunion.fr .
          [1]

          Supported by a fellowship from the regional council of La Réunion et l'Europe.

          Edited by Wolfgang Peti

          Article
          PMC5880132 PMC5880132 5880132 M117.815274
          10.1074/jbc.M117.815274
          5880132
          29414771
          cc200354-d699-4828-b0c6-70caffb36029
          © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.
          History
          : 5 September 2017
          : 17 January 2018
          Categories
          Molecular Biophysics

          spectroscopy,albumin,protein drug interaction,liraglutide,nuclear magnetic resonance (NMR),glycation,diabetes

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