Genetic Control of Pathogenesis of Diabetes in C3H Mice: Influence of the Major Histocompatibility Complex

Inbred strains of genetically diabetic (db/db) male mice with H-2^b haplotype were heretofore found resistant to the diabetogenic action of the db mutation, whereas C3HeB/FeJ-db/db males with H-2^k haplotype were susceptible. To determine whether the major histocompatibility complex was linked to diabetes predisposition, we mated C3H.SW/SnJ females (H-2^b haplotype) with C3HeB/FeJ-+/db males, identified the +/db heterozygotes in the F₁ generation (all H-2^b/H-2^k), and intercrossed these to produce F₂ db/db male offspring that were classed and studied according to the three segregating H-2 genotypes. We found an accelerated diabetes pathogenesis in terms of early onset of severe hyperglycemia, destruction of pancreatic beta cells, and mortality that was not linked to H-2. Of 9 F₂ male diabetics with H-2^b/H-2^b genotype, 14 with H-2^b/ H-2^k genotype, and 5 with H-2^k/H-2^k genotype, all showed a more severe syndrome than did the grandparental-type C3HeB/FeJ-db/db males. We conclude that on the C3H inbred background, the major histocompatibility complex is not a major background modifier of the diabetes syndrome. The complexity of the results suggests residual non-H-2-related genetic variance between the two grandparental C3H stocks, with C3H.SW/SnJ females possessing diabetes susceptibility factors apparently lacking in C3HeB/FeJ (a stock bred to be free of the milk-borne mouse mammary tumor virus). Since C3H.SW/SnJ females transmitted to F₂ males unknown diabetogenic factor(s) that did not appear to segregate, inheritance of a virus was suggested. The lack of association between H-2 and severity of the diabetes syndrome in these obese and insulin-resistant db/db mice makes the mouse model comparable to the human type II (non-insulin-dependent) diabetes syndrome that also appears not to be associated with HLA haplotype.