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A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents.
Finan, Brian; Yang, Bin; Ottaway, Nickki; Smiley, David L; Ma, Tao; Clemmensen, Christoffer; Chabenne, Joe; Zhang, Lianshan; Habegger, Kirk M; Fischer, Katrin; Campbell, Jonathan E; Sandoval, Darleen; Seeley, Randy J; Bleicher, Konrad; Uhles, Sabine; Riboulet, William; Funk, Jürgen; Hertel, Cornelia; Belli, Sara; Sebokova, Elena; Conde-Knape, Karin; Konkar, Anish; Drucker, Daniel J; Gelfanov, Vasily; Pfluger, Paul T; Müller, Timo D; Perez-Tilve, Diego; DiMarchi, Richard D; Tschöp, Matthias H.
Afiliación
  • Finan B; 1] Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. [2] Department of Medicine, Division of Metabolic Diseases,Technische Universität München, Munich, Germany. [3] Department of Chemistry, Indiana University, Bloomin
  • Yang B; 1] Department of Chemistry, Indiana University, Bloomington, Indiana, USA. [2] Marcadia Biotech, Carmel, Indiana, USA.
  • Ottaway N; Metabolic Diseases Institute, Division of Endocrinology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
  • Smiley DL; Department of Chemistry, Indiana University, Bloomington, Indiana, USA.
  • Ma T; 1] Department of Chemistry, Indiana University, Bloomington, Indiana, USA. [2] Research Center, Beijing Hanmi Pharm., Beijing, China.
  • Clemmensen C; 1] Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. [2] Department of Medicine, Division of Metabolic Diseases,Technische Universität München, Munich, Germany.
  • Chabenne J; 1] Department of Chemistry, Indiana University, Bloomington, Indiana, USA. [2] AIT Laboratories, Indianapolis, Indiana, USA.
  • Zhang L; Marcadia Biotech, Carmel, Indiana, USA.
  • Habegger KM; Comprehensive Diabetes Center, Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama, USA.
  • Fischer K; 1] Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. [2] Department of Medicine, Division of Metabolic Diseases,Technische Universität München, Munich, Germany.
  • Campbell JE; Department of Medicine, Lunenfeld Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
  • Sandoval D; Metabolic Diseases Institute, Division of Endocrinology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
  • Seeley RJ; Metabolic Diseases Institute, Division of Endocrinology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
  • Bleicher K; Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
  • Uhles S; Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
  • Riboulet W; Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
  • Funk J; Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
  • Hertel C; Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
  • Belli S; Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
  • Sebokova E; Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
  • Conde-Knape K; Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
  • Konkar A; Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
  • Drucker DJ; Department of Medicine, Lunenfeld Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
  • Gelfanov V; Department of Chemistry, Indiana University, Bloomington, Indiana, USA.
  • Pfluger PT; 1] Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. [2] Department of Medicine, Division of Metabolic Diseases,Technische Universität München, Munich, Germany.
  • Müller TD; 1] Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. [2] Department of Medicine, Division of Metabolic Diseases,Technische Universität München, Munich, Germany.
  • Perez-Tilve D; Metabolic Diseases Institute, Division of Endocrinology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
  • DiMarchi RD; Department of Chemistry, Indiana University, Bloomington, Indiana, USA.
  • Tschöp MH; 1] Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. [2] Department of Medicine, Division of Metabolic Diseases,Technische Universität München, Munich, Germany.
Nat Med ; 21(1): 27-36, 2015 Jan.
Article en En | MEDLINE | ID: mdl-25485909
We report the discovery of a new monomeric peptide that reduces body weight and diabetic complications in rodent models of obesity by acting as an agonist at three key metabolically-related peptide hormone receptors: glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon receptors. This triple agonist demonstrates supraphysiological potency and equally aligned constituent activities at each receptor, all without cross-reactivity at other related receptors. Such balanced unimolecular triple agonism proved superior to any existing dual coagonists and best-in-class monoagonists to reduce body weight, enhance glycemic control and reverse hepatic steatosis in relevant rodent models. Various loss-of-function models, including genetic knockout, pharmacological blockade and selective chemical knockout, confirmed contributions of each constituent activity in vivo. We demonstrate that these individual constituent activities harmonize to govern the overall metabolic efficacy, which predominantly results from synergistic glucagon action to increase energy expenditure, GLP-1 action to reduce caloric intake and improve glucose control, and GIP action to potentiate the incretin effect and buffer against the diabetogenic effect of inherent glucagon activity. These preclinical studies suggest that, so far, this unimolecular, polypharmaceutical strategy has potential to be the most effective pharmacological approach to reversing obesity and related metabolic disorders.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Péptidos / Complicaciones de la Diabetes / Diabetes Mellitus Tipo 2 / Obesidad Límite: Animals / Humans Idioma: En Revista: Nat Med Asunto de la revista: BIOLOGIA MOLECULAR / MEDICINA Año: 2015 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Péptidos / Complicaciones de la Diabetes / Diabetes Mellitus Tipo 2 / Obesidad Límite: Animals / Humans Idioma: En Revista: Nat Med Asunto de la revista: BIOLOGIA MOLECULAR / MEDICINA Año: 2015 Tipo del documento: Article Pais de publicación: Estados Unidos