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Deletion of the G6pc2 gene encoding the islet-specific glucose-6-phosphatase catalytic subunit-related protein does not affect the progression or incidence of type 1 diabetes in NOD/ShiLtJ mice.

Oeser JK, Parekh VV, Wang Y, Jegadeesh NK, Sarkar SA, Wong R, Lee CE, Pound LD, Hutton JC, Van Kaer L, O'Brien RM - Diabetes (2011)

Bottom Line: Insulitis was prominent in both groups, but whereas NOD/ShiLtJ G6pc2(+/+) islets contained CD8(+) T cells reactive to the G6pc2 NRP peptide, G6pc2 NRP-reactive T cells were absent in NOD/ShiLtJ G6pc2(-/-) islets.These results demonstrate that G6pc2 is an important driver for the selection and expansion of islet-reactive CD8(+) T cells infiltrating NOD/ShiLtJ islets.However, autoreactivity to G6pc2 is not essential for the emergence of autoimmune diabetes.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

ABSTRACT

Objective: Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), now known as G6PC2, is a major target of autoreactive T cells implicated in the pathogenesis of type 1 diabetes in both mice and humans. This study aimed to determine whether suppression of G6p2 gene expression might therefore prevent or delay disease progression.

Research design and methods: G6pc2(-/-) mice were generated on the NOD/ShiLtJ genetic background, and glycemia was monitored weekly up to 35 weeks of age to determine the onset and incidence of diabetes. The antigen specificity of CD8(+) T cells infiltrating islets from NOD/ShiLtJ G6pc2(+/+) and G6pc2(-/-) mice at 12 weeks was determined in parallel.

Results: The absence of G6pc2 did not affect the time of onset, incidence, or sex bias of type 1 diabetes in NOD/ShiLtJ mice. Insulitis was prominent in both groups, but whereas NOD/ShiLtJ G6pc2(+/+) islets contained CD8(+) T cells reactive to the G6pc2 NRP peptide, G6pc2 NRP-reactive T cells were absent in NOD/ShiLtJ G6pc2(-/-) islets.

Conclusions: These results demonstrate that G6pc2 is an important driver for the selection and expansion of islet-reactive CD8(+) T cells infiltrating NOD/ShiLtJ islets. However, autoreactivity to G6pc2 is not essential for the emergence of autoimmune diabetes. The results remain consistent with previous studies indicating that insulin may be the primary autoimmune target, at least in NOD/ShiLtJ mice.

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Insulitis in normoglycemic wild-type and G6pc2-deficient NOD/ShiLtJ mice. Paraffin sections of pancreata removed from 25-week-old normoglycemic male animals were stained by immunoperoxidase methods for the presence of insulin (gray) and glucagon (brown). Varying degrees of peri-islet mononuclear cell infiltration were evident, as visualized by the methyl green counter stain. Representative images (scale bar = 50 μm) are shown in A, whereas insulitis scores from five wild-type and five NOD/ShiLtJ G6pc2−/− mice are shown in B, based on the examination of a total of 127 wild-type and 151 G6pc2−/− islets. KO, knockout; WT, wild-type. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 3: Insulitis in normoglycemic wild-type and G6pc2-deficient NOD/ShiLtJ mice. Paraffin sections of pancreata removed from 25-week-old normoglycemic male animals were stained by immunoperoxidase methods for the presence of insulin (gray) and glucagon (brown). Varying degrees of peri-islet mononuclear cell infiltration were evident, as visualized by the methyl green counter stain. Representative images (scale bar = 50 μm) are shown in A, whereas insulitis scores from five wild-type and five NOD/ShiLtJ G6pc2−/− mice are shown in B, based on the examination of a total of 127 wild-type and 151 G6pc2−/− islets. KO, knockout; WT, wild-type. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: Histological analyses performed on a series of male G6pc2+/+ and G6pc2−/− mice at 25 weeks of age that exhibited no glycosuria revealed insulitis in both groups, which ranged from apparent normal islets, islets with pronounced peri-insulitis yet strong insulin immunoreactivity, and islets with reduced insulin immunoreactivity and invasive mononuclear cell infiltrates (Fig. 3A and B). Such histopathological lesions typify the presence of autoimmune diabetes in NOD/ShiLtJ animals from as early as 8 weeks of age (16,17). No major differences were observed between G6pc2+/+ and G6pc2−/− mice (Fig. 3B).


Deletion of the G6pc2 gene encoding the islet-specific glucose-6-phosphatase catalytic subunit-related protein does not affect the progression or incidence of type 1 diabetes in NOD/ShiLtJ mice.

Oeser JK, Parekh VV, Wang Y, Jegadeesh NK, Sarkar SA, Wong R, Lee CE, Pound LD, Hutton JC, Van Kaer L, O'Brien RM - Diabetes (2011)

Insulitis in normoglycemic wild-type and G6pc2-deficient NOD/ShiLtJ mice. Paraffin sections of pancreata removed from 25-week-old normoglycemic male animals were stained by immunoperoxidase methods for the presence of insulin (gray) and glucagon (brown). Varying degrees of peri-islet mononuclear cell infiltration were evident, as visualized by the methyl green counter stain. Representative images (scale bar = 50 μm) are shown in A, whereas insulitis scores from five wild-type and five NOD/ShiLtJ G6pc2−/− mice are shown in B, based on the examination of a total of 127 wild-type and 151 G6pc2−/− islets. KO, knockout; WT, wild-type. (A high-quality digital representation of this figure is available in the online issue.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3198073&req=5

Figure 3: Insulitis in normoglycemic wild-type and G6pc2-deficient NOD/ShiLtJ mice. Paraffin sections of pancreata removed from 25-week-old normoglycemic male animals were stained by immunoperoxidase methods for the presence of insulin (gray) and glucagon (brown). Varying degrees of peri-islet mononuclear cell infiltration were evident, as visualized by the methyl green counter stain. Representative images (scale bar = 50 μm) are shown in A, whereas insulitis scores from five wild-type and five NOD/ShiLtJ G6pc2−/− mice are shown in B, based on the examination of a total of 127 wild-type and 151 G6pc2−/− islets. KO, knockout; WT, wild-type. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: Histological analyses performed on a series of male G6pc2+/+ and G6pc2−/− mice at 25 weeks of age that exhibited no glycosuria revealed insulitis in both groups, which ranged from apparent normal islets, islets with pronounced peri-insulitis yet strong insulin immunoreactivity, and islets with reduced insulin immunoreactivity and invasive mononuclear cell infiltrates (Fig. 3A and B). Such histopathological lesions typify the presence of autoimmune diabetes in NOD/ShiLtJ animals from as early as 8 weeks of age (16,17). No major differences were observed between G6pc2+/+ and G6pc2−/− mice (Fig. 3B).

Bottom Line: Insulitis was prominent in both groups, but whereas NOD/ShiLtJ G6pc2(+/+) islets contained CD8(+) T cells reactive to the G6pc2 NRP peptide, G6pc2 NRP-reactive T cells were absent in NOD/ShiLtJ G6pc2(-/-) islets.These results demonstrate that G6pc2 is an important driver for the selection and expansion of islet-reactive CD8(+) T cells infiltrating NOD/ShiLtJ islets.However, autoreactivity to G6pc2 is not essential for the emergence of autoimmune diabetes.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

ABSTRACT

Objective: Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), now known as G6PC2, is a major target of autoreactive T cells implicated in the pathogenesis of type 1 diabetes in both mice and humans. This study aimed to determine whether suppression of G6p2 gene expression might therefore prevent or delay disease progression.

Research design and methods: G6pc2(-/-) mice were generated on the NOD/ShiLtJ genetic background, and glycemia was monitored weekly up to 35 weeks of age to determine the onset and incidence of diabetes. The antigen specificity of CD8(+) T cells infiltrating islets from NOD/ShiLtJ G6pc2(+/+) and G6pc2(-/-) mice at 12 weeks was determined in parallel.

Results: The absence of G6pc2 did not affect the time of onset, incidence, or sex bias of type 1 diabetes in NOD/ShiLtJ mice. Insulitis was prominent in both groups, but whereas NOD/ShiLtJ G6pc2(+/+) islets contained CD8(+) T cells reactive to the G6pc2 NRP peptide, G6pc2 NRP-reactive T cells were absent in NOD/ShiLtJ G6pc2(-/-) islets.

Conclusions: These results demonstrate that G6pc2 is an important driver for the selection and expansion of islet-reactive CD8(+) T cells infiltrating NOD/ShiLtJ islets. However, autoreactivity to G6pc2 is not essential for the emergence of autoimmune diabetes. The results remain consistent with previous studies indicating that insulin may be the primary autoimmune target, at least in NOD/ShiLtJ mice.

Show MeSH
Related in: MedlinePlus