title: Incretin-like effects of small molecule trace amine-associated receptor 1 agonists.
abstract: OBJECTIVE
  Type 2 diabetes and obesity are emerging pandemics in the 21st century creating worldwide urgency for the development of novel and safe therapies. We investigated trace amine-associated receptor 1 (TAAR1) as a novel target contributing to the control of glucose homeostasis and body weight.
  
  
  METHODS
  We investigated the peripheral human tissue distribution of TAAR1 by immunohistochemistry and tested the effect of a small molecule TAAR1 agonist on insulin secretion in vitro using INS1E cells and human islets and on glucose tolerance in C57Bl6, and db/db mice. Body weight effects were investigated in obese DIO mice.
  
  
  RESULTS
  TAAR1 activation by a selective small molecule agonist increased glucose-dependent insulin secretion in INS1E cells and human islets and elevated plasma PYY and GLP-1 levels in mice. In diabetic db/db mice, the TAAR1 agonist normalized glucose excursion during an oral glucose tolerance test. Sub-chronic treatment of diet-induced obese (DIO) mice with the TAAR1 agonist resulted in reduced food intake and body weight. Furthermore insulin sensitivity was improved and plasma triglyceride levels and liver triglyceride content were lower than in controls.
  
  
  CONCLUSIONS
  We have identified TAAR1 as a novel integrator of metabolic control, which acts on gastrointestinal and pancreatic islet hormone secretion. Thus TAAR1 qualifies as a novel and promising target for the treatment of type 2 diabetes and obesity.
authors: Roche Pharma Research & Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland.
authors: Susanne
authors: S
authors: Raab
authors: Roche Pharma Research & Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland.
authors: Haiyan
authors: H
authors: Wang
authors: Roche Pharma Research & Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland.
authors: Sabine
authors: S
authors: Uhles
authors: Roche Pharma Research & Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland.
authors: Nadine
authors: N
authors: Cole
authors: Roche Pharma Research & Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland.
authors: Ruben
authors: R
authors: Alvarez-Sanchez
authors: Roche Pharma Research & Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland.
authors: Basil
authors: B
authors: Künnecke
authors: Roche Pharma Research & Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland.
authors: Christoph
authors: C
authors: Ullmer
authors: Roche Pharma Research & Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland.
authors: Hugues
authors: H
authors: Matile
authors: Roche Pharma Research & Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland.
authors: Marc
authors: M
authors: Bedoucha
authors: Roche Pharma Research & Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland.
authors: Roger D
authors: RD
authors: Norcross
authors: Department of Internal Medicine, Metabolic Disease Institute, University of Cincinnati, Cincinnati, OH 45237, USA.
authors: Nickki
authors: N
authors: Ottaway-Parker
authors: Department of Internal Medicine, Metabolic Disease Institute, University of Cincinnati, Cincinnati, OH 45237, USA.
authors: Diego
authors: D
authors: Perez-Tilve
authors: Roche Pharma Research & Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland.
authors: Karin
authors: K
authors: Conde Knape
authors: Helmholtz Diabetes Center, Helmholtz Zentrum München and Division of Metabolic Diseases, Technische Universität München, Germany.
authors: Matthias H
authors: MH
authors: Tschöp
authors: Roche Pharma Research & Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland.
authors: Marius C
authors: MC
authors: Hoener
authors: Roche Pharma Research & Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland.
authors: Sabine
authors: S
authors: Sewing
keywords: Incretin hormones; Insulin secretion; Obesity; Pancreatic β-cell; Type 2 diabetes