Glucagon-Like Peptide-1 Induced Signaling and Insulin Secretion Do Not Drive Fuel and Energy Metabolism in Primary Rodent Pancreatic b-Cells

Background: Glucagon like peptide-1 (GLP-1) and its analogue exendin-4 (Ex-4) enhance glucose stimulated insulin secretion (GSIS) and activate various signaling pathways in pancreatic b-cells, in particular cAMP, Ca and protein kinase-B (PKB/Akt). In many cells these signals activate intermediary metabolism. However, it is not clear whether the acute amplification of GSIS by GLP-1 involves in part metabolic alterations and the production of metabolic coupling factors. Methodology/Prinicipal Findings: GLP-1 or Ex-4 at high glucose caused release (,20%) of the total rat islet insulin content over 1 h. While both GLP-1 and Ex-4 markedly potentiated GSIS in isolated rat and mouse islets, neither had an effect on bcell fuel and energy metabolism over a 5 min to 3 h time period. GLP-1 activated PKB without changing glucose usage and oxidation, fatty acid oxidation, lipolysis or esterification into various lipids in rat islets. Ex-4 caused a rise in [Ca]i and cAMP but did not enhance energy utilization, as neither oxygen consumption nor mitochondrial ATP levels were altered. Conclusions/Significance: The results indicate that GLP-1 barely affects b-cell intermediary metabolism and that metabolic signaling does not significantly contribute to GLP-1 potentiation of GSIS. The data also indicate that insulin secretion is a minor energy consuming process in the b-cell, and that the b-cell is different from most cell types in that its metabolic activation appears to be primarily governed by a ‘‘push’’ (fuel substrate driven) process, rather than a ‘‘pull’’ mechanism secondary to enhanced insulin release as well as to Ca, cAMP and PKB signaling. Citation: Peyot M-L, Gray JP, Lamontagne J, Smith PJS, Holz GG, et al. (2009) Glucagon-Like Peptide-1 Induced Signaling and Insulin Secretion Do Not Drive Fuel and Energy Metabolism in Primary Rodent Pancreatic b-Cells. PLoS ONE 4(7): e6221. doi:10.1371/journal.pone. 0006221 Editor: Kathrin Maedler, University of Bremen, Germany Received April 14, 2009; Accepted June 15, 2009; Published July 13, 2009 This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. Funding: MP is funded by Merck-Frosst and the Canadian Institute of Health Research. MP is recipient of Canadian chair in diabetes and metabolism. GGH is funded by the National Institutes of Health (DK045817), EH by the American Diabetes Association (7-08-JF-18) and PJSS by the National Science Foundation (P41RR-001395. JL is a recipient of a fellowship from Fonds de la Recherche en Sante du Quebec. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: marc.prentki@umontreal.ca . These authors contributed equally to this work.