Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
41
pubmed:dateCreated
2009-10-5
pubmed:abstractText
Obesity and type 2 diabetes present partially overlapping phenotypes with systemic inflammation as a common feature, raising the hypothesis that elevated cytokine levels may contribute to peripheral insulin resistance as well as the decreased beta cell functional mass observed in type 2 diabetes. In healthy humans, TNF-alpha infusion induces skeletal muscle insulin resistance. We now explore the impact of TNF-alpha on primary beta cell function and the underlying signaling pathways. Human and rat primary beta cells were sorted by FACS and cultured for 24 h +/- 20 ng/ml TNF-alpha to explore the impact on apoptosis, proliferation, and short-term insulin secretion (1 h, 2.8 mm glucose followed by 1 h, 16.7 mm glucose at the end of the 24-h culture period) as well as key signaling protein phosphorylation and expression. Prior exposure to TNF-alpha for 24 h inhibits glucose-stimulated insulin secretion from primary beta cells. This is associated with a decrease in glucose-stimulated phosphorylation of key proteins in the insulin signaling pathway including Akt, AS160, and other Akt substrates, ERK as well as the insulin receptor. Strikingly, TNF-alpha treatment decreased IRS-2 protein level by 46 +/- 7% versus control, although mRNA expression was unchanged. While TNF-alpha treatment increased MAP4K4 mRNA expression by 33 +/- 5%, knockdown of MAP4K4 by siRNA-protected beta cells against the detrimental effects of TNF-alpha on both insulin secretion and signaling. We thus identify MAP4K4 as a key upstream mediator of TNF-alpha action on the beta cell, making it a potential therapeutic target for preservation of beta cell function in type 2 diabetes.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Glucose, http://linkedlifedata.com/resource/pubmed/chemical/IRS1 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/IRS2 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Insulin, http://linkedlifedata.com/resource/pubmed/chemical/Insulin Receptor Substrate Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Intracellular Signaling Peptides..., http://linkedlifedata.com/resource/pubmed/chemical/MAP4K4 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinases, http://linkedlifedata.com/resource/pubmed/chemical/NF-kappa B, http://linkedlifedata.com/resource/pubmed/chemical/Nitric Oxide Synthase, http://linkedlifedata.com/resource/pubmed/chemical/Protein-Serine-Threonine Kinases, http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-akt, http://linkedlifedata.com/resource/pubmed/chemical/Tumor Necrosis Factor-alpha, http://linkedlifedata.com/resource/pubmed/chemical/Tyrosine
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
1083-351X
pubmed:author
pubmed:issnType
Electronic
pubmed:day
9
pubmed:volume
284
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
27892-8
pubmed:dateRevised
2011-11-17
pubmed:meshHeading
pubmed-meshheading:19690174-Animals, pubmed-meshheading:19690174-Cell Death, pubmed-meshheading:19690174-Cell Proliferation, pubmed-meshheading:19690174-Cells, Cultured, pubmed-meshheading:19690174-Diabetes Mellitus, Type 2, pubmed-meshheading:19690174-Glucose, pubmed-meshheading:19690174-Humans, pubmed-meshheading:19690174-Insulin, pubmed-meshheading:19690174-Insulin Receptor Substrate Proteins, pubmed-meshheading:19690174-Insulin-Secreting Cells, pubmed-meshheading:19690174-Intracellular Signaling Peptides and Proteins, pubmed-meshheading:19690174-Male, pubmed-meshheading:19690174-Mitogen-Activated Protein Kinases, pubmed-meshheading:19690174-NF-kappa B, pubmed-meshheading:19690174-Nitric Oxide Synthase, pubmed-meshheading:19690174-Protein-Serine-Threonine Kinases, pubmed-meshheading:19690174-Proto-Oncogene Proteins c-akt, pubmed-meshheading:19690174-Rats, pubmed-meshheading:19690174-Rats, Wistar, pubmed-meshheading:19690174-Signal Transduction, pubmed-meshheading:19690174-Tumor Necrosis Factor-alpha, pubmed-meshheading:19690174-Tyrosine
pubmed:year
2009
pubmed:articleTitle
Silencing mitogen-activated protein 4 kinase 4 (MAP4K4) protects beta cells from tumor necrosis factor-alpha-induced decrease of IRS-2 and inhibition of glucose-stimulated insulin secretion.
pubmed:affiliation
Department of Genetic Medicine and Development, University Medical Center, University of Geneva, CH-1211 Geneva 4, Switzerland. karim.bouzakri@unige.ch
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't