Glucose-Dependent Insulinotropic Polypeptide Promotes β-(INS-1) Cell Survival via Cyclic Adenosine Monophosphate-Mediated Caspase-3 Inhibition and Regulation of p38 Mitogen-Activated Protein Kinase

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 the...

Full description

Saved in:

Bibliographic Details
Published in:	Endocrinology (Philadelphia) Vol. 144; no. 10; pp. 4433 - 4445
Main Authors:	Ehses, Jan A, Casilla, Vanbric R, Doty, Tim, Pospisilik, J. Andrew, Winter, Kyle D, Demuth, Hans-Ulrich, Pederson, Raymond A, McIntosh, Christopher H. S
Format:	Journal Article
Language:	English
Published:	Bethesda, MD Endocrine Society 01-10-2003 Oxford University Press
Subjects:	1-Phosphatidylinositol 3-kinase Ablation Activating transcription factor 2 Activation analysis Adenosine monophosphate Animals Biological and medical sciences Caspase 3 Caspase Inhibitors Caspases - metabolism Cell fate Cell Line Cell survival Cell Survival - drug effects Cyclic AMP Cyclic AMP - physiology Deprivation Dynamic control Extracellular signal-regulated kinase Forskolin Fundamental and applied biological sciences. Psychology Gastric Inhibitory Polypeptide - pharmacology GIP protein Glucose Growth hormones Insulin secretion Islets of Langerhans - physiology Kinases MAP kinase Mitogen-Activated Protein Kinases - metabolism Mitogen-Activated Protein Kinases - physiology MKK3 protein p38 Mitogen-Activated Protein Kinases Phosphorylation Polypeptides Protein kinase A Proteins Receptors, Gastrointestinal Hormone - metabolism Receptors, Gastrointestinal Hormone - physiology RNA-mediated interference Streptozocin Survival Vertebrates: endocrinology Wortmannin Peptidases Purine nucleoside Adenosine Enzyme Polypeptide Cysteine endopeptidases Caspase Hydrolases β Cell Glucose Inhibition Survival
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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 β-(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 MAPK→ATF-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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0013-7227 1945-7170
DOI:	10.1210/en.2002-0068