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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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Comparison of the incidence and time of onset of type 1 diabetes in wild-type NOD/ShiLtJ and NOD/ShiLtJ G6pc2−/− mice: the effect of sex. The incidence and time of onset of type 1 diabetes in male and female wild-type NOD/ShiLtJ, NOD/ShiLtJ G6pc2−/+, and NOD/ShiLtJ G6pc2−/− mice was compared starting at the age of 10 weeks. Clear differences were observed between male and female wild-type NOD/ShiLtJ mice (A), between male and female NOD/ShiLtJ G6pc2−/− mice (B), and between male and female NOD/ShiLtJ G6pc2−/+ mice (C). The number of animals studied is indicated in parentheses. Statistical significance between curves was determined by the log-rank (Mantel-Cox) test. Het, heterozygous; KO, knockout; WT, wild-type.
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Figure 1: Comparison of the incidence and time of onset of type 1 diabetes in wild-type NOD/ShiLtJ and NOD/ShiLtJ G6pc2−/− mice: the effect of sex. The incidence and time of onset of type 1 diabetes in male and female wild-type NOD/ShiLtJ, NOD/ShiLtJ G6pc2−/+, and NOD/ShiLtJ G6pc2−/− mice was compared starting at the age of 10 weeks. Clear differences were observed between male and female wild-type NOD/ShiLtJ mice (A), between male and female NOD/ShiLtJ G6pc2−/− mice (B), and between male and female NOD/ShiLtJ G6pc2−/+ mice (C). The number of animals studied is indicated in parentheses. Statistical significance between curves was determined by the log-rank (Mantel-Cox) test. Het, heterozygous; KO, knockout; WT, wild-type.

Mentions: Monitoring for diabetes in this mouse colony began at 10 weeks of age. Figures 1 and 2 show survival analysis data. A clear sex difference was evident between female and male mice in the median onset of disease in G6pc2+/+ (18 vs. 26 weeks, P = 0.0002), G6pc2−/+ (19 vs. 29 weeks, P < 0.0001), and G6pc2−/− (21 vs. 28 weeks, P = 0.0021) animals (Fig. 1), which was in accord with reported studies on wild-type NOD/ShiLtJ mice (15). However, the key observation was that neither the absence of G6pc2 nor G6pc2 gene dosage affected the median onset of diabetes or final incidence at 35 weeks. Post hoc analysis of data up to 24 weeks indicated a weak trend (P = 0.0924) toward retarded onset of diabetes in male G6pc2−/− animals versus wild-type animals; however, this was not apparent in females (P = 0.6470).


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)

Comparison of the incidence and time of onset of type 1 diabetes in wild-type NOD/ShiLtJ and NOD/ShiLtJ G6pc2−/− mice: the effect of sex. The incidence and time of onset of type 1 diabetes in male and female wild-type NOD/ShiLtJ, NOD/ShiLtJ G6pc2−/+, and NOD/ShiLtJ G6pc2−/− mice was compared starting at the age of 10 weeks. Clear differences were observed between male and female wild-type NOD/ShiLtJ mice (A), between male and female NOD/ShiLtJ G6pc2−/− mice (B), and between male and female NOD/ShiLtJ G6pc2−/+ mice (C). The number of animals studied is indicated in parentheses. Statistical significance between curves was determined by the log-rank (Mantel-Cox) test. Het, heterozygous; KO, knockout; WT, wild-type.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 1: Comparison of the incidence and time of onset of type 1 diabetes in wild-type NOD/ShiLtJ and NOD/ShiLtJ G6pc2−/− mice: the effect of sex. The incidence and time of onset of type 1 diabetes in male and female wild-type NOD/ShiLtJ, NOD/ShiLtJ G6pc2−/+, and NOD/ShiLtJ G6pc2−/− mice was compared starting at the age of 10 weeks. Clear differences were observed between male and female wild-type NOD/ShiLtJ mice (A), between male and female NOD/ShiLtJ G6pc2−/− mice (B), and between male and female NOD/ShiLtJ G6pc2−/+ mice (C). The number of animals studied is indicated in parentheses. Statistical significance between curves was determined by the log-rank (Mantel-Cox) test. Het, heterozygous; KO, knockout; WT, wild-type.
Mentions: Monitoring for diabetes in this mouse colony began at 10 weeks of age. Figures 1 and 2 show survival analysis data. A clear sex difference was evident between female and male mice in the median onset of disease in G6pc2+/+ (18 vs. 26 weeks, P = 0.0002), G6pc2−/+ (19 vs. 29 weeks, P < 0.0001), and G6pc2−/− (21 vs. 28 weeks, P = 0.0021) animals (Fig. 1), which was in accord with reported studies on wild-type NOD/ShiLtJ mice (15). However, the key observation was that neither the absence of G6pc2 nor G6pc2 gene dosage affected the median onset of diabetes or final incidence at 35 weeks. Post hoc analysis of data up to 24 weeks indicated a weak trend (P = 0.0924) toward retarded onset of diabetes in male G6pc2−/− animals versus wild-type animals; however, this was not apparent in females (P = 0.6470).

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