title: Tungstate promotes β-cell survival in Irs2-/- mice.
abstract: Pancreatic β-cells play a central role in type 2 diabetes (T2D) development, which is characterized by the progressive decline of the functional β-cell mass that is associated mainly with increased β-cell apoptosis. Thus, understanding how to enhance survival of β-cells is key for the management of T2D. The insulin receptor substrate-2 (IRS-2) protein is pivotal in mediating the insulin/IGF signaling pathway in β-cells. In fact, IRS-2 is critically required for β-cell compensation in conditions of increased insulin demand and for β-cell survival. Tungstate is a powerful antidiabetic agent that has been shown to promote β-cell recovery in toxin-induced diabetic rodent models. In this study, we investigated whether tungstate could prevent the onset of diabetes in a scenario of dysregulated insulin/IGF signaling and massive β-cell death. To this end, we treated mice deficient in IRS2 (Irs2(-/-)), which exhibit severe β-cell loss, with tungstate for 3 wk. Tungstate normalized glucose tolerance in Irs2(-/-) mice in correlation with increased β-cell mass, increased β-cell replication, and a striking threefold reduction in β-cell apoptosis. Islets from treated Irs2(-/-) exhibited increased phosphorylated Erk1/2. Interestingly, tungstate repressed apoptosis-related genes in Irs2(-/-) islets in vitro, and ERK1/2 blockade abolished some of these effects. Gene expression profiling showed evidence of a broad impact of tungstate on cell death pathways in islets from Irs2(-/-) mice, consistent with reduced apoptotic rates. Our results support the finding that β-cell death can be arrested in the absence of IRS2 and that therapies aimed at reversing β-cell mass decline are potential strategies to prevent the progression to T2D.
authors.affiliation: Diabetes and Obesity Research Laboratory, Institut d'Investigations Biomediques August Pi i Sunyer, Barcelona, Spain;
authors.forename: Joana Moitinho
authors.initials: JM
authors.lastname: Oliveira
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Rebuffat
authors.forename: Rosa
authors.initials: R
authors.lastname: Gasa
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Burks
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Garcia
authors.forename: Susana G
authors.initials: SG
authors.lastname: Kalko
authors.forename: Delia
authors.initials: D
authors.lastname: Zafra
authors.forename: Joan J
authors.initials: JJ
authors.lastname: Guinovart
authors.forename: Ramon
authors.initials: R
authors.lastname: Gomis
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000517:prevention & control; D015536:Down-Regulation / Q000187:drug effects; D018149:Glucose Intolerance / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D055504:Insulin Receptor Substrate Proteins / Q000172:deficiency* / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology; D008099:Liver / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction; D017973:Tungsten Compounds / Q000008:administration & dosage*
chemical_list: D007004:Hypoglycemic Agents; D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; D017973:Tungsten Compounds; C045951:tungstate
keywords: apoptosis; extracellular signal-regulated kinase 1/2; insulin receptor substrate -2; islet; tungstate; type 2 diabetes; β-cell loss