Incretin-like effects of small molecule trace amine-associated receptor 1 agonists
| Autor: | Basil Künnecke, Marius C. Hoener, Roger David Norcross, Haiyan Wang, Rubén Alvarez-Sánchez, Christoph Ullmer, Susanne Raab, Diego Perez-Tilve, Matthias H. Tschöp, Sabine Sewing, Marc Bedoucha, Hugues Matile, Nadine Cole, Karin Conde Knape, Nickki Ottaway-Parker, Sabine Uhles |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty endocrine system lcsh:Internal medicine Incretin Type 2 diabetes Biology Body weight Trace amine associated receptor 1 03 medical and health sciences Internal medicine TAAR1 medicine Glucose homeostasis Obesity Receptor Pancreatic β-cell lcsh:RC31-1245 Molecular Biology Insulin secretion Cell Biology medicine.disease Small molecule ddc Incretin hormones 030104 developmental biology Endocrinology Original Article Incretin Hormones Insulin Secretion Type 2 Diabetes |
| Zdroj: | Molecular Metabolism, Vol 5, Iss 1, Pp 47-56 (2016) Molecular Metabolism Mol. Metab. 5, 47-56 (2016) |
| ISSN: | 2212-8778 |
| Popis: | 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. Graphical abstract Highlights • TAAR1 is a novel key player in metabolic control. • TAAR1 is expressed in β-cells and intestinal enteroendocrine cells in mice and humans. • TAAR1 agonist improved glucose tolerance and reduced body weight in mouse disease models. |
| Databáze: | OpenAIRE |
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