Targeted disruption of the Chop gene delays endoplasmic reticulum stress–mediated diabetes
Seiichi Oyadomari, … , Eiichi Araki, Masataka Mori
Seiichi Oyadomari, … , Eiichi Araki, Masataka Mori
Published February 15, 2002
Citation Information: J Clin Invest. 2002;109(4):525-532. https://doi.org/10.1172/JCI14550.
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Targeted disruption of the Chop gene delays endoplasmic reticulum stress–mediated diabetes

Abstract

Overload of pancreatic β cells in conditions such as hyperglycemia, obesity, and long-term treatment with sulfonylureas leads to β cell exhaustion and type 2 diabetes. Because β cell mass declines under these conditions, apparently as a result of apoptosis, we speculated that overload kills β cells as a result of endoplasmic reticulum (ER) stress. The Akita mouse, which carries a conformation-altering missense mutation (Cys96Tyr) in Insulin 2, likewise exhibits hyperglycemia and a reduced β cell mass. In the development of diabetes in Akita mice, mRNAs for the ER chaperone Bip and the ER stress–associated apoptosis factor Chop were induced in the pancreas. Overexpression of the mutant insulin in mouse MIN6 β cells induced Chop expression and led to apoptosis. Targeted disruption of the Chop gene delayed the onset of diabetes in heterozygous Akita mice by 8–10 weeks. We conclude that ER overload in β cells causes ER stress and leads to apoptosis via Chop induction. Our findings suggest a new therapeutic approach for preventing the onset of diabetes by inhibiting Chop induction or by increasing chaperone capacity in the ER.

Authors

Seiichi Oyadomari, Akio Koizumi, Kiyoshi Takeda, Tomomi Gotoh, Shizuo Akira, Eiichi Araki, Masataka Mori

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Figure 4

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Characteristics of the double-mutant mice with Ins2 mutation and Chop di...
Characteristics of the double-mutant mice with Ins2 mutation and Chop disruption. (a) Genotyping of double-mutant mice. Representative genotyping of the Ins2 gene by RFLP; the Chop gene from nine mutant lines is shown by PCR. Ins2 exon 3 was amplified by PCR using genomic DNA. The Ins2C96Y mutation in Akita mice disrupts an Fnu4HI site in exon 3 of Ins2. Digestion with Fnu4HI did not change the size of the PCR product from the mutated allele (280 bp), but it decreased that of the wild-type allele to 140 bp. Primers for wild-type and mutated Chop mice are described in Methods. The left lane shows 100-bp DNA ladder markers (top panel) and λDNA/Hind III + φ×174DNA/Hae III fragment markers (middle and bottom panels). (b–d) Phenotypic characterization of double-mutant mice at 8 weeks of age. (b) Body weight. (c) Morning blood glucose. (d) Pancreatic insulin content. Data are shown as mean ± SD. Significant differences among the genotype of the CHOP gene were evaluated by the Student t test: *P < 0.001 versus Chop+/+. ‡Ins2C96Y/C96YChop+/+ mice died within days of birth. Therefore, †data are shown as only one mouse and ‡data are shown as means ± ranges (n = 2).