GLP-1 Based Multi-Agonists-Induced Signaling Includes Profound TRP Channel Involvement in Insulin Secretion

Presentation Number: SUN 603
Date of Presentation: April 2nd, 2017

Noushafarin Khajavi*1, Brian Finan2, Oliver Kluth3, Stefan Mergler4, Timo Müller2, Angela Schulz5, Peter s Reinach6, Gunnar Kleinau1, Annette Schürmann7, Richard D DiMarchi8, Matthias Hans Tschöp9, Heiko Krude1 and Heike Biebermann1
1Charité - Universitätsmedizin Berlin Campus Virchow, Berlin, Germany, 2Institute for Diabetes and Obesity, Helmholtz Zentrum München and Department of Medicine, Technische Universität München, Munich, Germany, Germany, 3Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, 4Klinik für Augenheilkunde CVK, Charité - Universitätsmedizin Berlin, 5Institute of Biochemistry, leipzig, 6School of Ophthalmology and Optometry, Wenzhou, China, 7German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany, 8University of Indiana, Bloomington, IN, 9Helmholtz Zentrum München and Technische Universität München, Garching, Germany

Abstract

Promiscuous multi-agonists that simultaneously activate two or three key receptors (incretin- and/or glucagon receptor) were recently shown to improve glycemic control in mice(1-3). Here we investigated the underlying molecular mechanisms of these multi-agonists to enhance insulin secretion in murine islets and human pancreatic β-cells. These mixed agonists induced a greater increase in cAMP signaling potency compared to the native incretins. However, such effects could only partially explain the increases in insulin secretion. Therefore, additional mechanisms independent from Gs signaling-coupled Ca2+ influx appear to mediate insulin secretion. We show here that multi-agonists evoked significant and rapid increases in Ca2+ influx through activation of both voltage-dependent Ca2+ channels (VDCCs) as well as transient receptor potential channels (TRPs). These responses were more rapid and larger after multi-agonist stimulation than those after a mono-agonist. Pharmacological blockade of TRP channels suppresses Ca2+ transients induced by the multi-agonists to a greater degree than exposure to a VDCC blocker. TRP blockers also blunted cAMP accumulation and completely abolished increases in whole cell currents that are evoked with the multi-agonists. The prompt rises in calcium influx as well as outward whole-cell currents induced by multi-agonists argues for a direct TRP channel activation by ligand-engaged incretin receptors. Taken together, a direct activation of adenylyl cyclase through GPCR/channel constellations and a concomitant rapid Ca2+ influx likely contribute to the increases in insulin secretion and sensitivity induced by these multi-agonists.

 

Disclosure: MHT: Scientific Advisory Board Member, Novo Nordisk. Nothing to Disclose: NK, BF, OK, SM, TM, AS, PSR, GK, AS, RDD, HK, HB