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)
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Cellular Aspects of Diabetes and Obesity Study Section (CADO)
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Appel, Michael C
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Upstate Medical University
Internal Medicine/Medicine
Schools of Medicine
United States
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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
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 5:459-71
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Henry, Kelly E; Elfers, Clinton T; Burke, Rachael M et al. (2015) Vitamin B12 conjugation of peptide-YY(3-36) decreases food intake compared to native peptide-YY(3-36) upon subcutaneous administration in male rats. Endocrinology 156:1739-49
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
Nadkarni, Prashant; Chepurny, Oleg G; Holz, George G (2014) Regulation of glucose homeostasis by GLP-1. Prog Mol Biol Transl Sci 121:23-65
Holz, George G; Leech, Colin A; Chepurny, Oleg G (2014) New insights concerning the molecular basis for defective glucoregulation in soluble adenylyl cyclase knockout mice. Biochim Biophys Acta 1842:2593-600

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