NIDDM is a polygenic disease characterized by insulin resistance in mu
scle, fat, and liver, followed by a failure of pancreatic beta cells t
o adequately compensate for this resistance despite increased insulin
secretion. Mice double heterozygous for null alleles in the insulin re
ceptor and insulin receptor substrate-1 genes exhibit the expected sim
ilar to 50% reduction in expression of these two proteins, but a syner
gism at a level of insulin resistance with 5- to 50-fold elevated plas
ma insulin levels and comparable levels of beta cell hyperplasia. At 4
-6 months of age, 40% of these double heterozygotes become overtly dia
betic. This NIDDM mouse model in which diabetes arises in an age-depen
dent manner from the interaction between two genetically determined, s
ubclinical defects in the insulin signaling cascade demonstrates the r
ole of epistatic interactions in the pathogenesis of common diseases w
ith non-Mendelian genetics.