An emerging theme in experimental therapeutics concerns the use of glucagon-like peptide-1-(7-36)- amide (GLP-1) and its synthetic peptide analogs (the """"""""incretin mimetics"""""""") to lower levels of blood glucose in Type 2 diabetic subjects. This action of GLP-1 results, at least in part, from its ability to stimulate the secretion of insulin from pancreatic beta cells located in the islets of Langerhans. Given the established importance of GLP-1 for the treatment of diabetes, our laboratory is interested in defining the signal transduction properties of the beta cell GLP-1 receptor (GLP-1-R). To this end, we have focused on a newly-discovered signaling mechanism that uses the second messenger cAMP to activate cAMP- regulated guanine nucleotide exchange factors designated as Epad and Epac2 (the Exchange Proteins directly Activated by Cyclic AMP). Our studies lead us to Hypothesize that GLP-1, a cAMP-elevating hormone, stimulates Ca2+-dependent insulin secretion, and that this insulinotropic action is mediated not simply by protein kinase A (PKA), but also by Epac. To test our Hypothesis concerning the putative role of Epac in GLP-1-R-mediated signal transduction, the Specific Aims of this project are to: 1) determine if GLP-1 uses Epad and/or Epac2 to mobilize intracellular Ca2+ via a process of Ca2+-induced Ca2+ release (CICR) that originates at the endoplasmic reticulum (ER) and which may involve IP3 receptors or ryanodine receptors, 2) assess what role Rap family GTPases play in the process of ER Ca2""""""""1"""""""" mobilization, with special emphasis on the potential role of Rap1 as an intermediary linking activation of Epac to the stimulation of phospholipase C-epsilon, and 3) determine the nature of a novel signaling mechanism by which beta cell growth factors and receptor tyrosine kinases utilize the Ras GTPases to recruit Epac2 to the plasma membrane where an interaction of Epac2 with its putative effector molecule the sulfonylurea receptor-1 (SUR1) occurs. The Relevance of this line of investigation is fully apparent. We wish to establish the molecular basis for """"""""antidiabetogenic"""""""" properties of a new class of blood glucose-lowering agents that activate the GLP-1-R and which stimulate pancreatic insulin secretion.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Appel, Michael C
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Upstate Medical University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Wang, Dawei; Meng, Qinghe; Leech, Colin A et al. (2018) ?7 Nicotinic Acetylcholine Receptor Regulates the Function and Viability of L Cells. Endocrinology 159:3132-3142
Veluthakal, Rajakrishnan; Chepurny, Oleg G; Leech, Colin A et al. (2018) Restoration of Glucose-Stimulated Cdc42-Pak1 Activation and Insulin Secretion by a Selective Epac Activator in Type 2 Diabetic Human Islets. Diabetes 67:1999-2011
Mietlicki-Baase, Elizabeth G; Liberini, Claudia G; Workinger, Jayme L et al. (2018) A vitamin B12 conjugate of exendin-4 improves glucose tolerance without associated nausea or hypophagia in rodents. Diabetes Obes Metab 20:1223-1234
Chepurny, Oleg G; Bonaccorso, Ron L; Leech, Colin A et al. (2018) Chimeric peptide EP45 as a dual agonist at GLP-1 and NPY2R receptors. Sci Rep 8:3749
Henry, Kelly E; Kerwood, Deborah J; Allis, Damian G et al. (2016) Solution Structure and Constrained Molecular Dynamics Study of Vitamin B12 Conjugates of the Anorectic Peptide PYY(3-36). ChemMedChem 11:1015-21
Chepurny, Oleg G; Leech, Colin A; Tomanik, Martin et al. (2016) Synthetic small molecule GLP-1 secretagogues prepared by means of a three-component indole annulation strategy. Sci Rep 6:28934
Kolic, Jelena; Manning Fox, Jocelyn E; Chepurny, Oleg G et al. (2016) PI3 kinases p110? and PI3K-C2? negatively regulate cAMP via PDE3/8 to control insulin secretion in mouse and human islets. Mol Metab 5:459-471
Chepurny, Oleg G; Holz, George G; Roe, Michael W et al. (2016) GPR119 Agonist AS1269574 Activates TRPA1 Cation Channels to Stimulate GLP-1 Secretion. Mol Endocrinol 30:614-29
Takeda, Yukari; Shimayoshi, Takao; Holz, George G et al. (2016) Modeling analysis of inositol 1,4,5-trisphosphate receptor-mediated Ca2+ mobilization under the control of glucagon-like peptide-1 in mouse pancreatic ?-cells. Am J Physiol Cell Physiol 310:C337-47
Schwede, Frank; Chepurny, Oleg G; Kaufholz, Melanie et al. (2015) Rp-cAMPS Prodrugs Reveal the cAMP Dependence of First-Phase Glucose-Stimulated Insulin Secretion. Mol Endocrinol 29:988-1005

Showing the most recent 10 out of 36 publications