Spontaneous diabetes mellitus syndrome in the rat. I. Association with the major histocompatibility complex.

Abstract

A syndrome of spontaneous diabetes mellitus was previously described in a partially inbred rat strain called BB Wistar. These studies determined whether there is major histocompatibility complex (MHC) linkage or association with other predisposing haplotype-associated factors of development. BB rats are RT1 (MHC) genotype u/u. Using BB .times. Lewis F1 hybrid matings, an F2 study analyzed 128 rats from 8 primary and 3 additional litters from a breeding pair producing a diabetic offspring. Four of 128 F2 rats, all from the 48 progeny of same breeding pair, became clinically diabetic. The 4 diabetics were all genotype u/u (P = 0.03). In the primary F2 litters, haplotype distribution was not different from the 1:2:1 expected ratio. In the 4 litters from the F1 breeding pair producing diabetics, there was an increased number of u/u animals. Two-way analysis of variance revealed significant differences in pancreatic insulin content between litters (diabetics excluded), P < 0.001, and between haplotypes P < 0.007 with heterozygous u/l < u/u < l/l progeny. The glucagon content showed no significant differences. These data demonstrate MHC linkage with spontaneous diabetes in this rat model, penetrance similar to the human disease and a possible association of MHC haplotype with pancreatic inflammation and insulin content in nondiabetic F2 siblings.