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Title

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

Authors
Ribaux, Pascale
Published in Journal of Biological Chemistry. 2009, vol. 284, no. 41, p. 27892-27898
Abstract 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.
Keywords AnimalsCell Death/drug effectsCell Proliferation/drug effectsCells, CulturedDiabetes Mellitus, Type 2/metabolismGlucose/ metabolismHumansInsulin/ secretionInsulin Receptor Substrate Proteins/genetics/ metabolismInsulin-Secreting Cells/cytology/ drug effects/ metabolismIntracellular Signaling Peptides and Proteins/genetics/ metabolismMaleMitogen-Activated Protein Kinases/metabolismNF-kappa B/metabolismNitric Oxide Synthase/metabolismProtein-Serine-Threonine Kinases/genetics/ metabolismProto-Oncogene Proteins c-akt/metabolismRatsRats, WistarSignal Transduction/drug effectsTumor Necrosis Factor-alpha/ pharmacologyTyrosine/metabolism
Identifiers
PMID: 19690174
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Other version: http://www.jbc.org/content/284/41/27892.full.pdf
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BOUZAKRI, Karim, RIBAUX, Pascale, HALBAN, Philippe A. 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. In: Journal of Biological Chemistry, 2009, vol. 284, n° 41, p. 27892-27898. https://archive-ouverte.unige.ch/unige:8655

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Deposited on : 2010-07-12

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