DEVELOPMENT OF A NOVEL POLYGENIC MODEL OF NIDDM IN MICE HETEROZYGOUS FOR IR AND IRS-1 NULL ALLELES

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.