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.
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.
Bouzakri
Karim
K
Department of Genetic Medicine and Development, University Medical Center, University of Geneva, CH-1211 Geneva 4, Switzerland. Electronic address: karim.bouzakri@unige.ch.
Ribaux
Pascale
P
Department of Genetic Medicine and Development, University Medical Center, University of Geneva, CH-1211 Geneva 4, Switzerland.
Halban
Philippe A
PA
Department of Genetic Medicine and Development, University Medical Center, University of Geneva, CH-1211 Geneva 4, Switzerland.
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism
C526292:IRS1 protein, human; C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine; D019001:Nitric Oxide Synthase; C117090:MAP4K4 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D005947:Glucose
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