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

To assess genetic factors determining sensitivity to streptozotocin-induced diabetes in inbred strains of mice, a genetic analysis of streptozotocin-sensitive C57BL/6J and streptozotocin-resistant C3H/HeJ mice was performed. One week after a single dose of streptozotocin (200 mg/kg body weight), differences in plasma glucose concentration were marked between male mice of the C57BL/6J and C3H/HeJ strains (p<0.001). To determine the number of genes responsible for the difference, F₁ male progeny of a cross between parental strains were produced, and found to be streptozotocin resistant like C3H/HeJ parents. F₁ mice were, therefore, backcrossed with streptozotocin-sensitive C57BL/6J mice (Backcross: F₁♂ ♂ X C57BL/6J ♀ ♀). The plasma glucoses of backcrossed male mice (n=41) following streptozotocin treatment appeared to segregate into two populations, half like the C57BL/6J parent, and half like the F₁ parent. Statistical analysis of the data revealed that the data fit a model with two distributions better than one with a single distribution, suggesting a single major gene responsible for the difference in streptozotocin susceptibility. This hypothesis was also supported by the observation that streptozotocin sensitivity in 12 recombinant inbred strains of C57BL/6J and C3H/HeJ mice appeared to segregate into two classes. Resistance to streptozotocin induced diabetes in F₁ mice suggested that the expression of this gene is recessive, although X-chromosome linked inheritance could not be excluded. Efforts to map the streptozotocin-sensitivity gene revealed lack of right linkage to several loci including the H-2 locus. If inherited differences in the ability to resist a B-cell toxin play a role in genetic susceptibility to diabetes in man, then mapping the streptozotocin-susceptibility gene in mice may provide a means to evaluate the role of a putative homologous locus in the aetiology of diabetes in man.