Genetic control of non obese diabetic mice susceptibility to high-dose streptozotocin-induced diabetes.
OBJECTIVE
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 x NOD) x 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.


CONCLUSIONS
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.
Gonzalez
C
C
Institut National de la Santé et de la Recherche Médicale, Hôpital Necker, Paris, France.
Cuvellier
S
S
Hue-Beauvais
C
C
Lévi-Strauss
M
M
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D003921:Diabetes Mellitus, Experimental / Q000235:genetics*; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D016678:Genome; D005838:Genotype; D007700:Kinetics; D051379:Mice; D008809:Mice, Inbred C3H / Q000235:genetics; D016688:Mice, Inbred NOD / Q000235:genetics*; D013045:Species Specificity; D013997:Time Factors
D001786:Blood Glucose; D005819:Genetic Markers