Islet β-Cell Endoplasmic Reticulum Stress Precedes the Onset of Type 1 Diabetes in the Nonobese Diabetic Mouse Model

Diabetes - Tập 61 Số 4 - Trang 818-827 - 2012
Ernesto Nakayasu1,2, Yurika Nishiki1,2, Andrew T. Templin3, Susanne M. Cabrera1,2, Natalie D. Stull1,2, Stephanie C. Colvin1,2, Carmella Evans‐Molina3,4,2, Jenna L. Rickus5,6,7, Bernhard Maier1,2, Raghavendra G. Mirmira3,4,1,2
1Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
2The Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana
3Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana
4Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
5Bindley Bioscience Center, Purdue University, West Lafayette, Indiana
6Birck Nanotechnology Center, Purdue University, West Lafayette, Indiana
7Department of Agricultural and Biological Engineering, Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana

Tóm tắt

Type 1 diabetes is preceded by islet β-cell dysfunction, but the mechanisms leading to β-cell dysfunction have not been rigorously studied. Because immune cell infiltration occurs prior to overt diabetes, we hypothesized that activation of inflammatory cascades and appearance of endoplasmic reticulum (ER) stress in β-cells contributes to insulin secretory defects. Prediabetic nonobese diabetic (NOD) mice and control diabetes-resistant NOD-SCID and CD1 strains were studied for metabolic control and islet function and gene regulation. Prediabetic NOD mice were relatively glucose intolerant and had defective insulin secretion with elevated proinsulin:insulin ratios compared with control strains. Isolated islets from NOD mice displayed age-dependent increases in parameters of ER stress, morphologic alterations in ER structure by electron microscopy, and activation of nuclear factor-κB (NF-κB) target genes. Upon exposure to a mixture of proinflammatory cytokines that mimics the microenvironment of type 1 diabetes, MIN6 β-cells displayed evidence for polyribosomal runoff, a finding consistent with the translational initiation blockade characteristic of ER stress. We conclude that β-cells of prediabetic NOD mice display dysfunction and overt ER stress that may be driven by NF-κB signaling, and strategies that attenuate pathways leading to ER stress may preserve β-cell function in type 1 diabetes.

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Tài liệu tham khảo

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Diabetes

Tập 61 Số 4

818-827

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