A single major gene controls most of the difference in susceptibility to streptozotocin-induced diabetes between C57BL/6J and C3H/HeJ mice

Kaku, Kohei; McGill, Janet B.; Province, Michael A.; Permutt, M. A.

doi:10.1007/bf00274530

Cited by 11 publications

(8 citation statements)

References 30 publications

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“…Indeed, in contrast to a previous study which claimed that a single major gene controlled the difference in susceptibility to HDS-diabetes between C57BL/6 J and C3H/Hej [18], our work indicates that NOD susceptibility to HDS-diabetes is controlled by many genes, only two of which were detected by our genome scan.…”

Section: Discussioncontrasting

confidence: 99%

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Genetic control of non obese diabetic mice susceptibility to high-dose streptozotocin-induced diabetes

et al. 2003

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Aims/hypothesis. Streptozotocin is a monofunctional alkylating agent that induces diabetes in a large variety of mammals. While multiple low doses of streptozotocin induce immune-mediated diabetes, a single high dose of streptozotocin causes a strictly toxic diabetes. Among mouse strains, non-obese diabetic (NOD) mice are characterized by an extreme susceptibility to high dose of streptozotocin-induced diabetes whereas C3H/Or mice are particularly resistant. We hypothesized that NOD genes involved in high dose streptozotocin-induced diabetes could be also involved in the autoimmune destruction of pancreatic beta cells that characterizes this mouse strain which is a model of Type 1 diabetes. Methods. We carried out a whole genome linkage scan on a population of (C3H/Or × NOD) × NOD backcross 1 mice in order to identify the genetic loci involved in NOD susceptibility to high dose of streptozotocin-induced diabetes.Results. Two loci, in chromosome 9 (D9Mit135 marker, 48 cM) and in chromosome 11 (D11Mit286 marker, 52 cM), were associated with NOD susceptibility to high dose streptozotocin-induced diabetes, the latter being co-localized with the autoimmune diabetes-predisposing idd4 locus. Moreover, we report here that C57BL/6 mice deficient in Nitric Oxide Synthase 2 were as sensitive as wild-type C57BL/6 mice to high dose streptozotocin-induced diabetes. Conclusion/interpretation. Although the Nitric Oxide Synthase 2 (Nos2) gene, localized at 45.6 cM in chromosome 11, is a good candidate gene, our results suggest that Nitric Oxide Synthase 2 activation might not be a crucial event for streptozotocin-induced destruction of pancreatic beta cells. [Diabetologia (2003[Diabetologia ( ) 46:1291[Diabetologia ( -1295 Keywords Non-obese diabetic mouse, diabetes, autoimmune, streptozotocin, pancreatic beta cells, genetic susceptibility, nitric-oxide synthase, C3H, C57BL/6, idd4, genome scan.

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Section: Discussioncontrasting

confidence: 99%

“…Moreover, we expected that the genetics of the susceptibility of the NOD mouse to toxic HDS-diabetes would be less complex than that of the spontaneous disease. A previous study suggested that a single major gene could determine the susceptibility of C57BL/6 mouse to HDS-diabetes [18].…”

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confidence: 99%

Genetic control of non obese diabetic mice susceptibility to high-dose streptozotocin-induced diabetes

et al. 2003

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“…A single high dose of STZ (80 -200 mg/kg) is thought to produce a combination of apoptosis and necrotic damage of ␤ cells (30,31). Interestingly, a role for an immune response in the single high dose of STZ model is suggested from studies using TLR4-deficient C3H mice (32) and those demonstrating activation of islet Ag-specific T cells in PDLN after a single STZ dosing (11,31,33,34).…”

Section: Elevated Expression Of Hsc70 Increases Diabetes Following Ismentioning

confidence: 99%

Transgenic Expression of Hsc70 in Pancreatic Islets Enhances Autoimmune Diabetes in Response to β Cell Damage

Alam

Harken

Knorn

et al. 2009

The Journal of Immunology

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Inflammation following tissue damage promotes lymphocyte recruitment, tissue remodelling, and wound healing while maintaining self tolerance. Endogenous signals associated with tissue damage and cell death have been proposed to initiate and instruct immune responses following injury. Here we have examined the effects of elevated levels of a candidate endogenous danger signal, heat shock cognate protein 70 (Hsc70), on stimulation of inflammation and autoimmunity following cell damage. We find that damage to pancreatic β-cells expressing additional cytosolic Hsc70 leads to an increased incidence of diabetes in a transgenic mouse model. Steady-state levels of activated APC and T cell populations in the draining lymph node were enhanced, which further increased following streptozotocin-induced β-cell death. In addition, pro-inflammatory serum cytokines, and lymphocyte recruitment were increased in Hsc70 transgenic mice. Islet-antigen-specific T cells underwent a greater extent of proliferation in the lymph nodes of mice expressing Hsc70 following β-cell damage, suggesting elevated antigen presentation following release of antigen in the presence of Hsc70. These findings suggest that an elevated content of Hsc70 in cells undergoing necrotic or apoptotic cell death can increase the extent of sterile inflammation and increase the susceptibility to autoimmunity.

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“…Our results in this study showed that B6 demonstrated relatively low GHR mRNA levels in liver, but the opposite trend was observed in skeletal muscle. The relatively increased GH action in skeletal muscle may be one of the explanations for the susceptibility to the development of diabetes in B6 compared with C3H (Kaku et al 1989). Normal GHR and IGF-I receptor signaling in skeletal muscle may also explain the normal growth in B6 compared with C3H.…”

Section: Figurementioning

confidence: 99%

“…C3H mice with higher serum IGF-I levels have increased BMD compared with B6. B6 mice have higher glycosylated hemoglobin levels (Kaku et al 1989) and demonstrated poor glucose tolerance with a lower insulin response to i.p. glucose administration compared with C3H (Kayo et al 2000).…”

Section: Introductionmentioning

confidence: 99%

Genetic differences in the IGF-I gene among inbred strains of mice with different serum IGF-I levels

Iida¹,

Rosen²,

Ackert‐Bicknell³

et al. 2005

Journal of Endocrinology

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There is significant heterogeneity in serum IGF-I concentrations among normal healthy individuals across all ages and among inbred strains of mice. C3H/HeJ (C3H) mice have 30% higher serum IGF-I concentrations over a lifetime than C57BL/6J (B6), even though body size and length are identical. The underlying mechanism for this disparity remains unknown although several possibilities exist including altered GH secretion, resistance to GH action, or impaired IGF-I secretion from the liver or peripheral tissues. To study this further, we evaluated mRNA levels of pituitary GH, and of IGF-I, GH receptor (GHR) and acid-labile subunit (ALS) in liver and skeletal muscle of male C3H and B6 strains. mRNA levels of hepatic IGF-I paralleled serum IGF-I levels, whereas pituitary GH mRNA expression was significantly lower in C3H than B6. In addition, reduced hepatic mRNA levels of ALS and GHR in B6 suggests hepatic GH resistance in B6. In contrast, mRNA levels of IGF-I and GHR in skeletal muscle were not different between B6 and C3H. There was a single sequence repeat polymorphism (SSR) in the promoter region of both GHR and IGF-I genes in mice; the SSR in the IGF-I gene was significantly different between the two strains. The SSR in the IGF-I gene corresponds to the E2F binding site, which is critical for regulating IGF-I gene expression. These results suggest that the SSR in the promoter region of the IGF-I gene may be partially responsible for differences in serum IGF-I levels between B6 and C3H strains.

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A single major gene controls most of the difference in susceptibility to streptozotocin-induced diabetes between C57BL/6J and C3H/HeJ mice

Cited by 11 publications

References 30 publications

Genetic control of non obese diabetic mice susceptibility to high-dose streptozotocin-induced diabetes

Genetic control of non obese diabetic mice susceptibility to high-dose streptozotocin-induced diabetes

Transgenic Expression of Hsc70 in Pancreatic Islets Enhances Autoimmune Diabetes in Response to β Cell Damage

Genetic differences in the IGF-I gene among inbred strains of mice with different serum IGF-I levels

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