The expression of the mouse mutation, diabetes (db), was examined on eight different inbred genetic backgrounds. The influence of H-2 haplotype and sex was examined. Mice of both sexes in two diabetes (db) strains (C57BL/6J, 129/J) having the H-2b haplotype were resistant to the diabetogenic action of the mutant gene. On the contrary, two H-2d congenic diabetes stocks (C57BL/KsJ, DBA/2J) exhibited severe diabetes associated with beta-cell necrosis. However, diabetes resistance was not restricted to mice with H-2b haplotype since the congenic diabetes MA/J stock (H-2k) was also resistant. Similarly, diabetes susceptibility was not restricted to mice with the H-2d haplotype, since males, but generally not females, in the congenic CBA/Lt-db/db and C3HeB/FeJ-db/db stocks (both H-2k) also exhibited a severe diabetes. Males of the congenic SWR/J-db stock (H-2q) had a diabetes of intermediate severity. Female diabetes mice with H-2k and H-2q haplotypes exhibited a sustained hypertrophy and hyperplasia of beta-cells and were able to control hyperglycemia better than males. Thus, while the H-2b haplotype remains associated with resistance, and the H-2d haplotype with susceptibility to induction of genetic diabetes, the diabetes stocks with H-2k haplotype clearly illustrate the importance of non-H-2, but sex-associated, genetic modifiers.

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