Recently published studies of islet cell function reveal unexpected features of glucagon-like peptide-1 (GLP-1) receptor-mediated signal transduction in the pancreatic a-cell. Although GLP-1 is established to be a cAMP-elevating agent, these studies demonstrate that protein kinase A (PKA) is not the only cAMP-binding protein by which GLP-1 acts. Instead, an alternative cAMP signaling mechanism has been described, one in which GLP-1 activates cAMP-binding proteins designated as cAMP-regulated guanine nucleotide exchange factors (cAMPGEFs, also known as Epac). Two variants of Epac are expressed in a-cells, and down regulation of Epac function diminishes stimulatory actions of GLP-1 on Ca2+ signaling and insulin secretion. Of particular note are new reports demonstrating that Epac couples a-cell cAMP production to the stimulation of fast Ca2+-dependent exocytosis. It is also reported that Epac mediates the cAMP-dependent mobilization of Ca2+ from intracellular Ca2+ stores. This is a process of Ca2+-induced Ca2+ release (CICR) and it generates an increase of [Ca2+]i that may serve as a direct stimulus for mitochondrial ATP production and secretory granule exocytosis. Such findings lead us to advance the Hypothesis that activation of Epac might explain how GLP-1 acts as a a -cell glucose-sensitizer. By facilitating a-cell glucose signaling, GLP-1 may increase the efficacy and potency of glucose as an insulinotropic stimulus. To test this Hypothesis, we will perform studies of human or rodent a-cells in which the glucose-dependent actions of GLP-1 are assessed in assays of mitochondrial ATP production, K-ATP ion channel regulation, and secretory granule exocytosis. Our long term goal is to elucidate the complex signal transduction properties of GLP-1 that explain its effectiveness as a blood glucose lowering agent when used for the treatment of type 2 diabetes mellitus.

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Metabolism Study Section (MET)
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Blondel, Olivier
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New York University
Schools of Medicine
New York
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Nadkarni, Prashant; Chepurny, Oleg G; Holz, George G (2014) Regulation of glucose homeostasis by GLP-1. Prog Mol Biol Transl Sci 121:23-65
Smrcka, Alan V; Brown, Joan Heller; Holz, George G (2012) Role of phospholipase Cýý in physiological phosphoinositide signaling networks. Cell Signal 24:1333-43
Leech, Colin A; Dzhura, Igor; Chepurny, Oleg G et al. (2011) Molecular physiology of glucagon-like peptide-1 insulin secretagogue action in pancreatic ? cells. Prog Biophys Mol Biol 107:236-47
Dzhura, Igor; Chepurny, Oleg G; Leech, Colin A et al. (2011) Phospholipase C-? links Epac2 activation to the potentiation of glucose-stimulated insulin secretion from mouse islets of Langerhans. Islets 3:121-8
Leech, Colin A; Dzhura, Igor; Chepurny, Oleg G et al. (2010) Facilitation of ß-cell K(ATP) channel sulfonylurea sensitivity by a cAMP analog selective for the cAMP-regulated guanine nucleotide exchange factor Epac. Islets 2:72-81
Chepurny, Oleg G; Kelley, Grant G; Dzhura, Igor et al. (2010) PKA-dependent potentiation of glucose-stimulated insulin secretion by Epac activator 8-pCPT-2'-O-Me-cAMP-AM in human islets of Langerhans. Am J Physiol Endocrinol Metab 298:E622-33
Leech, Colin A; Chepurny, Oleg G; Holz, George G (2010) Epac2-dependent rap1 activation and the control of islet insulin secretion by glucagon-like peptide-1. Vitam Horm 84:279-302
Dzhura, Igor; Chepurny, Oleg G; Kelley, Grant G et al. (2010) Epac2-dependent mobilization of intracellular Ca²+ by glucagon-like peptide-1 receptor agonist exendin-4 is disrupted in ?-cells of phospholipase C-? knockout mice. J Physiol 588:4871-89
Chepurny, Oleg G; Leech, Colin A; Kelley, Grant G et al. (2009) Enhanced Rap1 activation and insulin secretagogue properties of an acetoxymethyl ester of an Epac-selective cyclic AMP analog in rat INS-1 cells: studies with 8-pCPT-2'-O-Me-cAMP-AM. J Biol Chem 284:10728-36
Peyot, Marie-Line; Gray, Joshua P; Lamontagne, Julien et al. (2009) Glucagon-like peptide-1 induced signaling and insulin secretion do not drive fuel and energy metabolism in primary rodent pancreatic beta-cells. PLoS One 4:e6221

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