Abstract
The failure of β-cells has a central role in the pathogenesis of type 2 diabetes, and the identification of novel approaches to improve functional β-cell mass is essential to prevent/revert the disease. Here we show a critical novel role for thrombospondin 1 (THBS1) in β-cell survival during lipotoxic stress in rat, mouse and human models. THBS1 acts from within the endoplasmic reticulum to activate PERK and NRF2 and induce a protective antioxidant defense response against palmitate. Prolonged palmitate exposure causes THBS1 degradation, oxidative stress, activation of JNK and upregulation of PUMA, culminating in β-cell death. These findings shed light on the mechanisms leading to β-cell failure during metabolic stress and point to THBS1 as an interesting therapeutic target to prevent oxidative stress in type 2 diabetes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antioxidants / metabolism
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Apoptosis Regulatory Proteins / metabolism
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Cell Survival / drug effects
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Cytoprotection / drug effects*
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Endoplasmic Reticulum / drug effects
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Endoplasmic Reticulum / metabolism
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Endoplasmic Reticulum Stress / drug effects
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Female
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Humans
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Insulin-Secreting Cells / drug effects
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Insulin-Secreting Cells / metabolism
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Insulin-Secreting Cells / pathology*
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JNK Mitogen-Activated Protein Kinases / metabolism
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Lipids / toxicity*
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Male
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Mice
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Middle Aged
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Models, Biological
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NF-E2-Related Factor 2 / metabolism*
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Oxidative Stress / drug effects
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Palmitic Acid / toxicity
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Proteolysis / drug effects
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Rats, Wistar
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Signal Transduction / drug effects*
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Thrombospondin 1 / metabolism*
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eIF-2 Kinase / metabolism*
Substances
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Antioxidants
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Apoptosis Regulatory Proteins
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Lipids
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NF-E2-Related Factor 2
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Thrombospondin 1
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Palmitic Acid
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PERK kinase
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eIF-2 Kinase
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JNK Mitogen-Activated Protein Kinases