The genetics of diabetes susceptibility in mice

Abstract

The factors associated with a diabetes-susceptible genotype in mice exhibiting various forms of heritable glucose intolerance syndromes are discussed. Genetic models of insulin-dependent and non-insulin-dependent diabetes in mice are described. Although single gene mutations can be defined for each model that are major contributors to diabetogenic stress, polygenic interactions are required for the expression of a diabetic phenotype, and environmental factors are also contributory. Several strongly penetrant single gene mutations are capable of affecting obesity and insulin-resistant states. Analysis of inbred strain genomic interactions with one of these recessive obesity-producing genes, diabetes (db), suggests that development of a diabetic phenotype is dependent on the strength of an interaction between the db gene and sulfotransferase enzymes. Specifically, diabetes-susceptible vs. resistant inbred strain backgrounds can be distinguished by the extent to which the db mutation elicits an accelerated sequestration by sulfoconjugation of tissue estrogens while androgens remain free. In a male gender- (and Y chromosome-)associated model of transient glucose intolerance, stress as well as a requirement for both adrenal and testicular secretions are each components of the susceptibility background. In the obesity-associated diabetes models, autoimmunity, when it occurs, is a secondary reflection of pancreatic beta cell destruction. The nonobese diabetic (NOD) mouse, in contrast, represents a model in which autoimmunity against beta cells is a primary event in the development of insulin-dependent diabetes. In NOD mice, a gene that is either the unique class II gene in the major histocompatibility complex or is in linkage disequilibrium with this complex makes a major (recessivelike) contribution to diabetes susceptibility. However, diabetogenesis can be mediated only through a multifactorial interaction among this susceptibility locus and multiple unlinked genetic loci regulating immune responsiveness. In addition, the NOD mouse represents one of the best models of diabetes available for demonstrating a critical interaction between heredity and environmental factors. The polygenic nature of the various heritable forms of glucose intolerance syndromes in mice points to a comparable or even greater genetic heterogeneity underlying the major types of diabetes in humans.