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Nonobese diabetic mice express aspects of both type 1 and type 2 diabetes.

ABSTRACT: Before the onset of autoimmune destruction, type 1 diabetic patients and an animal model, the nonobese diabetic (NOD) mouse, show morphological and functional abnormalities in target organs, which may act as inciting events for leukocyte infiltration. To better understand these abnormalities, but without the complications associated with lymphocytic infiltrates, we examined genes expressed in autoimmune target tissues of NOD/severe combined immunodeficient (scid) mice and of autoimmune-resistant C57BL/6/scid mice. Our results suggest that the NOD genetic background may predispose them to diabetic complications, including insulin resistance in the absence of high circulating glucose levels and without autoimmune destruction of their beta cells. Several of these genes lie within known type 1 and 2 diabetes loci. These data suggest that the NOD mouse may be a good candidate to study an interface between type 1 and type 2 diabetes.

SUBMITTER: Chaparro RJ

PROVIDER: S-EPMC1832259 | biostudies-literature | 2006 Aug

REPOSITORIES: biostudies-literature

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Nonobese diabetic mice express aspects of both type 1 and type 2 diabetes.

Chaparro Rodolfo José RJ Konigshofer Yves Y Beilhack Georg F GF Shizuru Judith A JA McDevitt Hugh O HO Chien Yueh-Hsiu YH

Proceedings of the National Academy of Sciences of the United States of America 20060808 33

Before the onset of autoimmune destruction, type 1 diabetic patients and an animal model, the nonobese diabetic (NOD) mouse, show morphological and functional abnormalities in target organs, which may act as inciting events for leukocyte infiltration. To better understand these abnormalities, but without the complications associated with lymphocytic infiltrates, we examined genes expressed in autoimmune target tissues of NOD/severe combined immunodeficient (scid) mice and of autoimmune-resistant ...[more]

PMID: 16895987

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Project description:Background: Epigenetic alteration of the genome has been shown to provide palliative effects in mouse models of certain human autoimmune disorders. We have investigated whether chromatin remodeling could provide protection against autoimmune diabetes in nonobese diabetic (NOD) mice. Treatment of female mice during the transition from prediabetic to diabetic stage (18-24 weeks of age) with the well-characterized histone deacetylase inhibitor, Trichostatin A (TSA) effectively reduced the incidence of diabetes and abrogated the ability of splenocytes to adoptively transfer the disease into immunodeficient NOD.scid mice. Protection against diabetes was accompanied by histone hyperacetylation in pancreas and spleen, increased frequency of CD4+ CD62L+ cells in the spleen, reduction in cellular infiltration of islets, restoration of normoglycemia and glucose-induced insulin release by beta cells. In vitro activation of splenic T lymphocytes derived from protected mice resulted in enhanced expression of IFN-gamma mRNA and protein without altering the expression of Il4, Il17, Il18, Inos, and Tnfa genes nor the secretion of IL-2, IL-4, IL-17 and TNF-alpha proteins. Consistently, expression of the transcription factor involved in Ifng transcription, Tbet/Tbx21 but not Gata3 and Rorgt, respectively required for the transcription of Il4 and Il17, was upregulated in activated splenocytes of protected mice. These data indicate that abrogation of autoimmune diabetes is associated with the selective upregulation of certain inducible genes in T lymphocytes. Microarray analysis was performed to determine the changes in global gene expression underlying abrogation of autoimmune diabetes by TSA-mediated epigenetic modulation and identified a distinct group of genes down-regulated during this process. Female NOD mice were treated subcutaneously with TSA (500 µg/Kg body weight) during the transition from prediabetic to diabetic stage (18-24 weeks of age), at weekly intervals. Since we sought to determine the modulation of global gene expression associated with long-term protection against diabetes, TSA treated mice were killed between 32 and 36 weeks of age and total RNA was extracted from uninduced splenocytes. RNA was also extracted from splenocytes of untreated mice that became diabetic and those that did not develop diabetes till 36 weeks of age. Blood glucose levels were determined weekly to monitor the glycemic condition in untreated and TSA-treated mice. To minimize the variability in gene expression among individual mice, RNA was extracted from splenocytes of 3 to 5 mice per group and pooled. Each sample was hybridized to microchips in duplicate. Female NOD mice were treated with Trichostatin A (500 µg/Kg body weight) between 18-24 weeks of age or left untreated.

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Nonobese diabetic mice express aspects of both type 1 and type 2 diabetes.

Publications

Nonobese diabetic mice express aspects of both type 1 and type 2 diabetes.

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