Compensatory responses in mice carrying a null mutation for Ins1 or Ins2.

Leroux, Loïc; Desbois, Pierrette; Lamotte, Luciane; Duvillié, Bertrand; Cordonnier, Nathalie; Jackerott, Malene; Jami, Jacques; Bucchini, Danielle; Joshi, Rajiv L.

doi:10.2337/diabetes.50.2007.s150

Cited by 133 publications

(130 citation statements)

References 22 publications

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“…Heterozygous mutant Akita mice also show a significant decrease of the relative insulinpositive area, and homozygous Akita mice show an additional decrease of the relative islet area and an increase of the glucagon-positive area in the islets (18,23). In contrast to mice exhibiting a point mutation in the proinsulin gene, mice lacking the Ins1 and/or Ins2 gene show enlarged islets (13,24,25). This finding further underlines the dominant-negative phenotype of mice expressing mutant insulin.…”

Section: C95s Mutant Micementioning

confidence: 69%

“…Homozygous Munich Ins2 C95S mutant mice show an even more pronounced diabetic phenotype and die within 2 months after weaning. Since Ins2 knockout mice do not develop diabetes or hypoinsulinemia (13), the production of mutant insulin is thought to cause the ␤-cell dysfunction observed in Munich Ins2 C95S mutant mice by a dominantnegative mechanism. Several dominant-negative mechanisms may be postulated, such as downregulation of the synthesis of wild-type insulin, cross-linkage of mutant and wild-type proinsulin/insulin, and cytotoxicity by mutant insulin leading to ␤-cell loss (14).…”

Section: Discussionmentioning

confidence: 99%

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Dominant-Negative Effects of a Novel Mutated Ins2 Allele Causes Early-Onset Diabetes and Severe β-Cell Loss in Munich Ins2C95S Mutant Mice

et al. 2007

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The novel diabetic mouse model Munich Ins2C95S was discovered within the Munich N-ethyl-N-nitrosourea mouse mutagenesis screen. These mice exhibit a T3 A transversion in the insulin 2 (Ins2) gene at nucleotide position 1903 in exon 3, which leads to the amino acid exchange C95S and loss of the A6-A11 intrachain disulfide bond. From 1 month of age onwards, blood glucose levels of heterozygous Munich Ins2 C95S mutant mice were significantly increased compared with controls. The fasted and postprandial serum insulin levels of the heterozygous mutants were indistinguishable from those of wild-type littermates. However, serum insulin levels after glucose challenge, pancreatic insulin content, and homeostasis model assessment (HOMA) ␤-cell indices of heterozygous mutants were significantly lower than those of wild-type littermates. The initial blood glucose decrease during an insulin tolerance test was lower and HOMA insulin resistance indices were significantly higher in mutant mice, indicating the development of insulin resistance in mutant mice. The total islet volume, the volume density of ␤-cells in the islets, and the total ␤-cell volume of heterozygous male mutants was significantly reduced compared with wild-type mice. Electron microscopy of the ␤-cells of male mutants showed virtually no secretory insulin granules, the endoplasmic reticulum was severely enlarged, and mitochondria appeared swollen. Thus, Munich Ins2 C95S mutant mice are considered a valuable model to study the mechanisms of ␤-cell dysfunction and death during the development of diabetes.

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Section: C95s Mutant Micementioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Dominant-Negative Effects of a Novel Mutated Ins2 Allele Causes Early-Onset Diabetes and Severe β-Cell Loss in Munich Ins2C95S Mutant Mice

et al. 2007

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“…It has been reported that Ins1-KO and Ins2-KO, when on a C57BL/6 strain background and with two copies of each gene encoding insulin, have insulin content in the pancreas similar to wild-type mice, in addition to normal glucose tolerance, because of the compensatory response of insulin transcription [7,8]. In contrast to these studies, our NOD Ins1+/+,Ins2−/− mice have lower insulin content compared with wild-type NOD mice.…”

Section: Discussionmentioning

confidence: 99%

A new model of insulin-deficient diabetes: male NOD mice with a single copy of Ins1 and no Ins2

Babaya¹,

Nakayama²,

Moriyama

et al. 2006

Diabetologia

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“…Protein aggregation in the ER after focal brain ischemia and reperfusion was observed using electron microscopy analysis. 90 These aggregates persist in vulnerable neurons but not in resistant ones. Global translational attenuation, a key response in the pathogenesis of neuronal cell injury, is caused by phosphorylation of eIF2a via the activation of PERK.…”

Section: Brain Ischemiamentioning

confidence: 99%

Roles of CHOP/GADD153 in endoplasmic reticulum stress

2003

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Endoplasmic reticulum (ER) is the site of synthesis and folding of secretory proteins. Perturbations of ER homeostasis affect protein folding and cause ER stress. ER can sense the stress and respond to it through translational attenuation, upregulation of the genes for ER chaperones and related proteins, and degradation of unfolded proteins by a quality-control system. However, when the ER function is severely impaired, the organelle elicits apoptotic signals. ER stress has been implicated in a variety of common diseases such as diabetes, ischemia and neurodegenerative disorders. One of the components of the ER stress-mediated apoptosis pathway is C/EBP homologous protein (CHOP), also known as growth arrestand DNA damage-inducible gene 153 (GADD153). Here, we summarize the current understanding of the roles of CHOP/ GADD153 in ER stress-mediated apoptosis and in diseases including diabetes, brain ischemia and neurodegenerative disease.

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Compensatory responses in mice carrying a null mutation for Ins1 or Ins2.

Cited by 133 publications

References 22 publications

Dominant-Negative Effects of a Novel Mutated Ins2 Allele Causes Early-Onset Diabetes and Severe β-Cell Loss in Munich Ins2C95S Mutant Mice

Dominant-Negative Effects of a Novel Mutated Ins2 Allele Causes Early-Onset Diabetes and Severe β-Cell Loss in Munich Ins2C95S Mutant Mice

A new model of insulin-deficient diabetes: male NOD mice with a single copy of Ins1 and no Ins2

Roles of CHOP/GADD153 in endoplasmic reticulum stress

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