This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hui, H. Articles by Perfetti, R. Search for Related Content PubMed PubMed Citation Articles by Hui, H. Articles by Perfetti, R.

Glucagon-Like Peptide-1 Inhibits Apoptosis of Insulin-Secreting Cells via a Cyclic 5'-Adenosine Monophosphate-Dependent Protein Kinase A- and a Phosphatidylinositol 3-Kinase-Dependent Pathway

Division of Endocrinology and Metabolism (H.H., A.N., R.P.), and Division of Cardiology (X.Z.), Cedars-Sinai Medical Center, Los Angeles, California 90048; and University of California Los Angeles (H.H., R.P.), Los Angeles, California 90024

Address all correspondence and requests for reprints to: Riccardo Perfetti, M.D., Ph.D., Division of Endocrinology, Diabetes, and Metabolism, 8723 Alden Drive, SSB 290, Los Angeles, California 90048. E-mail: perfettir{at}cshs.org.

The activation of the glucagon-like peptide-1 (GLP-1) receptor has been shown to have an important role in the functional activity of islet ß-cells and in the expansion of the islet cell mass. Constant remodeling of islet cell mass is mediated in vivo by proliferative and apoptotic stimuli to ensure a dynamic response to a changing demand for insulin. The present study was undertaken to investigate the biological activity of GLP-1 when cells were challenged by a proapoptotic stimulus. We have shown that activation of the GLP-1 receptor inhibits H₂O₂-induced apoptosis in a cultured mouse insulinoma cell line, termed MIN6. GLP-1 reduced DNA fragmentation and improved cell survival. This was mediated by an increased expression of the antiapoptotic proteins Bcl-2 and Bcl-xL. GLP-1 also prevented the H₂O₂-dependent cleavage of poly-(ADP-ribose)-polymerase. Inhibition of the GLP-1-dependent increase of cAMP by Rp-cAMP blocked the antiapoptotic action of GLP-1, as determined by DNA fragmentation and poly-(ADP-ribose)-polymerase assays and by detection of Bcl-2 and Bcl-xL protein levels. Investigation of the role of the protein kinases, PI-3 kinase (PI3K) and MAPK, by use of the inhibitors PD098059 and LY294002 demonstrated that the activation of PI3K, but not MAPK, was required to prevent proapoptotic events in cells exposed to H₂O₂. The present study provides evidence that GLP-1 has an antiapoptotic action mediated by a cAMP- and PI3K-dependent signaling pathway.

This article has been cited by other articles:

				M. Salehi, B. A. Aulinger, and D. A. D'Alessio Targeting {beta}-Cell Mass in Type 2 Diabetes: Promise and Limitations of New Drugs Based on Incretins Endocr. Rev., May 1, 2008; 29(3): 367 - 379. [Abstract] [Full Text] [PDF]

				M. Ferdaoussi, S. Abdelli, J.-Y. Yang, M. Cornu, G. Niederhauser, D. Favre, C. Widmann, R. Regazzi, B. Thorens, G. Waeber, et al. Exendin-4 Protects {beta}-Cells From Interleukin-1{beta}-Induced Apoptosis by Interfering With the c-Jun NH2-Terminal Kinase Pathway Diabetes, May 1, 2008; 57(5): 1205 - 1215. [Abstract] [Full Text] [PDF]

				R. Granata, F. Settanni, D. Gallo, L. Trovato, L. Biancone, V. Cantaluppi, R. Nano, M. Annunziata, P. Campiglia, E. Arnoletti, et al. Obestatin Promotes Survival of Pancreatic {beta}-Cells and Human Islets and Induces Expression of Genes Involved in the Regulation of {beta}-Cell Mass and Function Diabetes, April 1, 2008; 57(4): 967 - 979. [Abstract] [Full Text] [PDF]

				S.-J. Kim, C. Nian, S. Widenmaier, and C. H. S. McIntosh Glucose-Dependent Insulinotropic Polypeptide-Mediated Up-Regulation of {beta}-Cell Antiapoptotic Bcl-2 Gene Expression Is Coordinated by Cyclic AMP (cAMP) Response Element Binding Protein (CREB) and cAMP-Responsive CREB Coactivator 2 Mol. Cell. Biol., March 1, 2008; 28(5): 1644 - 1656. [Abstract] [Full Text] [PDF]

				M. S. Winzell and B. Ahren Durable islet effects on insulin secretion and protein kinase A expression following exendin-4 treatment of high-fat diet-fed mice J. Mol. Endocrinol., February 1, 2008; 40(2): 93 - 100. [Abstract] [Full Text] [PDF]

				J. E. Ayala, D. P. Bracy, T. Hansotia, G. Flock, Y. Seino, D. H. Wasserman, and D. J. Drucker Insulin Action in the Double Incretin Receptor Knockout Mouse Diabetes, February 1, 2008; 57(2): 288 - 297. [Abstract] [Full Text] [PDF]

				M. Korner, M. Stockli, B. Waser, and J. C. Reubi GLP-1 Receptor Expression in Human Tumors and Human Normal Tissues: Potential for In Vivo Targeting J. Nucl. Med., May 1, 2007; 48(5): 736 - 743. [Abstract] [Full Text] [PDF]

				B. L. Wajchenberg {beta}-Cell Failure in Diabetes and Preservation by Clinical Treatment Endocr. Rev., April 1, 2007; 28(2): 187 - 218. [Abstract] [Full Text] [PDF]

				Y.-C. Hsieh, H.-P. Yu, M. Frink, T. Suzuki, M. A. Choudhry, M. G. Schwacha, and I. H. Chaudry G Protein-Coupled Receptor 30-Dependent Protein Kinase A Pathway Is Critical in Nongenomic Effects of Estrogen in Attenuating Liver Injury after Trauma-Hemorrhage Am. J. Pathol., April 1, 2007; 170(4): 1210 - 1218. [Abstract] [Full Text] [PDF]

				C. Verga Falzacappa, E. Petrucci, V. Patriarca, S. Michienzi, A. Stigliano, E. Brunetti, V. Toscano, and S. Misiti Thyroid hormone receptor TR{beta}1 mediates Akt activation by T3 in pancreatic {beta} cells J. Mol. Endocrinol., February 1, 2007; 38(2): 221 - 233. [Abstract] [Full Text] [PDF]

				R. Granata, F. Settanni, L. Biancone, L. Trovato, R. Nano, F. Bertuzzi, S. Destefanis, M. Annunziata, M. Martinetti, F. Catapano, et al. Acylated and Unacylated Ghrelin Promote Proliferation and Inhibit Apoptosis of Pancreatic {beta}-Cells and Human Islets: Involvement of 3',5'-Cyclic Adenosine Monophosphate/Protein Kinase A, Extracellular Signal-Regulated Kinase 1/2, and Phosphatidyl Inositol 3-Kinase/Akt Signaling Endocrinology, February 1, 2007; 148(2): 512 - 529. [Abstract] [Full Text] [PDF]

				J. Buteau, A. Shlien, S. Foisy, and D. Accili Metabolic Diapause in Pancreatic beta-Cells Expressing a Gain-of-function Mutant of the Forkhead Protein Foxo1 J. Biol. Chem., January 5, 2007; 282(1): 287 - 293. [Abstract] [Full Text] [PDF]

				C. Santangelo, P. Matarrese, R. Masella, M. C. Di Carlo, A. Di Lillo, B. Scazzocchio, E. Vecci, W. Malorni, R. Perfetti, and E. Anastasi Hepatocyte growth factor protects rat RINm5F cell line against free fatty acid-induced apoptosis by counteracting oxidative stress J. Mol. Endocrinol., January 1, 2007; 38(1): 147 - 158. [Abstract] [Full Text] [PDF]

				R K. Campbell Rationale for Dipeptidyl Peptidase 4 Inhibitors: A New Class of Oral Agents for the Treatment of Type 2 Diabetes Mellitus Ann. Pharmacother., January 1, 2007; 41(1): 51 - 60. [Abstract] [Full Text] [PDF]

				H. A Walz, L. Harndahl, N. Wierup, E. Zmuda-Trzebiatowska, F. Svennelid, V. C Manganiello, T. Ploug, F. Sundler, E. Degerman, B. Ahren, et al. Early and rapid development of insulin resistance, islet dysfunction and glucose intolerance after high-fat feeding in mice overexpressing phosphodiesterase 3B. J. Endocrinol., June 1, 2006; 189(3): 629 - 641. [Abstract] [Full Text] [PDF]

				J. A. Koehler and D. J. Drucker Activation of glucagon-like Peptide-1 receptor signaling does not modify the growth or apoptosis of human pancreatic cancer cells. Diabetes, May 1, 2006; 55(5): 1369 - 1379. [Abstract] [Full Text] [PDF]

				F. Ranta, D. Avram, S. Berchtold, M. Dufer, G. Drews, F. Lang, and S. Ullrich Dexamethasone induces cell death in insulin-secreting cells, an effect reversed by exendin-4. Diabetes, May 1, 2006; 55(5): 1380 - 1390. [Abstract] [Full Text] [PDF]

				B. N Friedrichsen, N. Neubauer, Y. C Lee, V. K Gram, N. Blume, J. S Petersen, J. H Nielsen, and A. Moldrup Stimulation of pancreatic {beta}-cell replication by incretins involves transcriptional induction of cyclin D1 via multiple signalling pathways. J. Endocrinol., March 1, 2006; 188(3): 481 - 492. [Abstract] [Full Text] [PDF]

				S. Park, X. Dong, T. L. Fisher, S. Dunn, A. K. Omer, G. Weir, and M. F. White Exendin-4 Uses Irs2 Signaling to Mediate Pancreatic beta Cell Growth and Function J. Biol. Chem., January 13, 2006; 281(2): 1159 - 1168. [Abstract] [Full Text] [PDF]

				K. Masur, E. C. Tibaduiza, C. Chen, B. Ligon, and M. Beinborn Basal Receptor Activation by Locally Produced Glucagon-Like Peptide-1 Contributes to Maintaining {beta}-Cell Function Mol. Endocrinol., May 1, 2005; 19(5): 1373 - 1382. [Abstract] [Full Text] [PDF]

				E. D'Amico, H. Hui, N. Khoury, U. Di Mario, and R. Perfetti Pancreatic {beta}-cells expressing GLP-1 are resistant to the toxic effects of immunosuppressive drugs J. Mol. Endocrinol., April 1, 2005; 34(2): 377 - 390. [Abstract] [Full Text] [PDF]

				A. K. Bose, M. M. Mocanu, R. D. Carr, C. L. Brand, and D. M. Yellon Glucagon-like Peptide 1 Can Directly Protect the Heart Against Ischemia/Reperfusion Injury Diabetes, January 1, 2005; 54(1): 146 - 151. [Abstract] [Full Text] [PDF]

				P. E. MacDonald, J. W. Joseph, D. Yau, J. Diao, Z. Asghar, F. Dai, G. Y. Oudit, M. M. Patel, P. H. Backx, and M. B. Wheeler Impaired Glucose-Stimulated Insulin Secretion, Enhanced Intraperitoneal Insulin Tolerance, and Increased {beta}-Cell Mass in Mice Lacking the p110{gamma} Isoform of Phosphoinositide 3-Kinase Endocrinology, September 1, 2004; 145(9): 4078 - 4083. [Abstract] [Full Text] [PDF]

				K. A. Cullen, J. McCool, M. S. Anwer, and C. R. L. Webster Activation of cAMP-guanine exchange factor confers PKA-independent protection from hepatocyte apoptosis Am J Physiol Gastrointest Liver Physiol, August 1, 2004; 287(2): G334 - G343. [Abstract] [Full Text] [PDF]

				J. F. List and J. F. Habener Glucagon-like peptide 1 agonists and the development and growth of pancreatic {beta}-cells Am J Physiol Endocrinol Metab, June 1, 2004; 286(6): E875 - E881. [Abstract] [Full Text] [PDF]

				P. L. Brubaker and D. J. Drucker Minireview: Glucagon-Like Peptides Regulate Cell Proliferation and Apoptosis in the Pancreas, Gut, and Central Nervous System Endocrinology, June 1, 2004; 145(6): 2653 - 2659. [Abstract] [Full Text] [PDF]

				I. Cozar-Castellano, K. K. Takane, R. Bottino, A.N. Balamurugan, and A. F. Stewart Induction of {beta}-Cell Proliferation and Retinoblastoma Protein Phosphorylation in Rat and Human Islets Using Adenovirus-Mediated Transfer of Cyclin-Dependent Kinase-4 and Cyclin D1 Diabetes, January 1, 2004; 53(1): 149 - 159. [Abstract] [Full Text] [PDF]

				P. E. MacDonald, X. Wang, F. Xia, W. El-kholy, E. D. Targonsky, R. G. Tsushima, and M. B. Wheeler Antagonism of Rat {beta}-Cell Voltage-dependent K+ Currents by Exendin 4 Requires Dual Activation of the cAMP/Protein Kinase A and Phosphatidylinositol 3-Kinase Signaling Pathways J. Biol. Chem., December 26, 2003; 278(52): 52446 - 52453. [Abstract] [Full Text] [PDF]

				D. J. Drucker Glucagon-Like Peptide-1 and the Islet {beta}-Cell: Augmentation of Cell Proliferation and Inhibition of Apoptosis Endocrinology, December 1, 2003; 144(12): 5145 - 5148. [Full Text] [PDF]

				L. Farilla, A. Bulotta, B. Hirshberg, S. Li Calzi, N. Khoury, H. Noushmehr, C. Bertolotto, U. Di Mario, D. M. Harlan, and R. Perfetti Glucagon-Like Peptide 1 Inhibits Cell Apoptosis and Improves Glucose Responsiveness of Freshly Isolated Human Islets Endocrinology, December 1, 2003; 144(12): 5149 - 5158. [Abstract] [Full Text] [PDF]

				D. J. Drucker Enhancing Incretin Action for the Treatment of Type 2 Diabetes Diabetes Care, October 1, 2003; 26(10): 2929 - 2940. [Abstract] [Full Text] [PDF]

				U. S. Jhala, G. Canettieri, R. A. Screaton, R. N. Kulkarni, S. Krajewski, J. Reed, J. Walker, X. Lin, M. White, and M. Montminy cAMP promotes pancreatic {beta}-cell survival via CREB-mediated induction of IRS2 Genes & Dev., July 1, 2003; 17(13): 1575 - 1580. [Abstract] [Full Text] [PDF]