| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Department of Physiology (J.A.E., V.R.C., T.D., J.A.P., K.D.W., R.A.P., C.H.S.M.), Faculty of Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada; and Probiodrug Research (H.-U.D.), Biocenter, Weinbergweg 22, D-06120 Halle (Saale), Germany
Address all correspondence and requests for reprints to: Dr. C. H. S. McIntosh, Department of Physiology, Faculty of Medicine, University of British Columbia, 2146 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3. E-mail: mcintoch{at}interchange.ubc.ca.
The incretin glucose-dependent insulinotropic polypeptide (GIP) is a major regulator of postprandial insulin secretion in mammals. Recent studies in our laboratory, and others have suggested that GIP is a potent stimulus for protein kinase activation, including the MAPK (ERK1/2) module. Based on these studies, we hypothesized that GIP could regulate cell fate and sought to examine the underlying mechanisms involved in GIP stimulation of cell survival. GIP potentiated glucose-induced ß-(INS-1)-cell growth to levels comparable with GH and GLP-1 while promoting cell survival in the face of serum and glucose-deprivation or treatment with wortmannin or streptozotocin. In the absence of GIP, 50% of cells died after 48 h of serum and glucose withdrawal, whereas 91 ± 10% of cells remained viable in the presence of GIP [n = 3, P < 0.05; EC50 of 1.24 ± 0.48 nM GIP (n = 4)]. Effects of GIP on cell survival and inhibition of caspase-3 were mimicked by forskolin, but pharmacological experiments excluded roles for MAPK kinase (Mek)1/2, phosphatidylinositol 3-kinase, protein kinase A, Epac, and Rap 1. Survival effects of GIP were ablated by the inhibitor SB202190, indicating a role for p38 MAPK. Furthermore, caspase-3 activity was also regulated by p38 MAPK, with a lesser role for Mek1/2, based on RNA interference studies. We propose that GIP is able to reverse caspase-3 activation via inhibition of long-term p38 MAPK phosphorylation in response to glucose deprivation (±wortmannin). Intriguingly, these findings contrasted with short-term phosphorylation of MKK3/6
p38 MAPKATF-2 by GIP. Thus, these data suggest that GIP is able to regulate INS-1 cell survival by dynamic control of p38 MAPK phosphorylation via cAMP signaling and lend further support to the notion that GIP regulation of MAPK signaling is critical for its regulation of cell fate.
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]
|
|
|
|
 |
|
 S.-J. Kim, C. Nian, D. J. Doudet, and C. H.S. McIntosh Inhibition of Dipeptidyl Peptidase IV With Sitagliptin (MK0431) Prolongs Islet Graft Survival in Streptozotocin-Induced Diabetic Mice Diabetes, May 1, 2008; 57(5): 1331 - 1339. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Hou, S. Torii, N. Saito, M. Hosaka, and T. Takeuchi Reactive Oxygen Species-Mediated Pancreatic {beta}-Cell Death Is Regulated by Interactions between Stress-Activated Protein Kinases, p38 and c-Jun N-Terminal Kinase, and Mitogen-Activated Protein Kinase Phosphatases Endocrinology, April 1, 2008; 149(4): 1654 - 1665. [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]
|
|
|
|
|
|
B. J. Lamont and D. J. Drucker Differential Antidiabetic Efficacy of Incretin Agonists Versus DPP-4 Inhibition in High Fat Fed Mice Diabetes, January 1, 2008; 57(1): 190 - 198. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. L. McClean, N. Irwin, R. S. Cassidy, J. J. Holst, V. A. Gault, and P. R. Flatt GIP receptor antagonism reverses obesity, insulin resistance, and associated metabolic disturbances induced in mice by prolonged consumption of high-fat diet Am J Physiol Endocrinol Metab, December 1, 2007; 293(6): E1746 - E1755. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-J. Kim, C. Nian, and C. H. S. McIntosh Activation of Lipoprotein Lipase by Glucose-dependent Insulinotropic Polypeptide in Adipocytes: A ROLE FOR A PROTEIN KINASE B, LKB1, AND AMP-ACTIVATED PROTEIN KINASE CASCADE J. Biol. Chem., March 23, 2007; 282(12): 8557 - 8567. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. Parker, K S Lavery, N Irwin, B D Green, B Greer, P Harriott, F P M O'Harte, V A Gault, and P R Flatt Effects of sub-chronic exposure to naturally occurring N-terminally truncated metabolites of glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), GIP(3-42) and GLP-1(9-36)amide, on insulin secretion and glucose homeostasis in ob/ob mice. J. Endocrinol., October 1, 2006; 191(1): 93 - 100. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A Reimer Meat hydrolysate and essential amino acid-induced glucagon-like peptide-1 secretion, in the human NCI-H716 enteroendocrine cell line, is regulated by extracellular signal-regulated kinase1/2 and p38 mitogen-activated protein kinases. J. Endocrinol., October 1, 2006; 191(1): 159 - 170. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Lampron, I. Bourdeau, P. Hamet, J. Tremblay, and A. Lacroix Whole Genome Expression Profiling of Glucose-Dependent Insulinotropic Peptide (GIP)- and Adrenocorticotropin-Dependent Adrenal Hyperplasias Reveals Novel Targets for the Study of GIP-Dependent Cushing's Syndrome J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3611 - 3618. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Alana, J. C. Parker, V. A. Gault, P. R. Flatt, F. P. M. O'Harte, J. P. G. Malthouse, and C. M. Hewage NMR and Alanine Scan Studies of Glucose-dependent Insulinotropic Polypeptide in Water J. Biol. Chem., June 16, 2006; 281(24): 16370 - 16376. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. S. Narang and R. I. Mahato Biological and biomaterial approaches for improved islet transplantation. Pharmacol. Rev., June 1, 2006; 58(2): 194 - 243. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Mu, J. Woods, Y.-P. Zhou, R. S. Roy, Z. Li, E. Zycband, Y. Feng, L. Zhu, C. Li, A. D. Howard, et al. Chronic Inhibition of Dipeptidyl Peptidase-4 With a Sitagliptin Analog Preserves Pancreatic {beta}-Cell Mass and Function in a Rodent Model of Type 2 Diabetes Diabetes, June 1, 2006; 55(6): 1695 - 1704. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Liu, W. Zhen, Z. Yang, J. D. Carter, H. Si, and K. A. Reynolds Genistein Acutely Stimulates Insulin Secretion in Pancreatic {beta}-Cells Through a cAMP-Dependent Protein Kinase Pathway. Diabetes, April 1, 2006; 55(4): 1043 - 1050. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Irwin, B. D. Green, M. H. Mooney, B. Greer, P. Harriott, C. J. Bailey, V. A. Gault, F. P. M. O'Harte, and P. R. Flatt A Novel, Long-Acting Agonist of Glucose-Dependent Insulinotropic Polypeptide Suitable for Once-Daily Administration in Type 2 Diabetes J. Pharmacol. Exp. Ther., September 1, 2005; 314(3): 1187 - 1194. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. A. Gault, N. Irwin, B. D. Green, J. T. McCluskey, B. Greer, C. J. Bailey, P. Harriott, F. P.M. O'Harte, and P. R. Flatt Chemical Ablation of Gastric Inhibitory Polypeptide Receptor Action by Daily (Pro3)GIP Administration Improves Glucose Tolerance and Ameliorates Insulin Resistance and Abnormalities of Islet Structure in Obesity-Related Diabetes Diabetes, August 1, 2005; 54(8): 2436 - 2446. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-J. Kim, K. Winter, C. Nian, M. Tsuneoka, Y. Koda, and C. H. S. McIntosh Glucose-dependent Insulinotropic Polypeptide (GIP) Stimulation of Pancreatic {beta}-Cell Survival Is Dependent upon Phosphatidylinositol 3-Kinase (PI3K)/Protein Kinase B (PKB) Signaling, Inactivation of the Forkhead Transcription Factor Foxo1, and Down-regulation of bax Expression J. Biol. Chem., June 10, 2005; 280(23): 22297 - 22307. [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]
|
|
|
|
|
|
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]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
