Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles

Cell. 1997 Feb 21;88(4):561-72. doi: 10.1016/s0092-8674(00)81896-6.


NIDDM is a polygenic disease characterized by insulin resistance in muscle, fat, and liver, followed by a failure of pancreatic beta cells to adequately compensate for this resistance despite increased insulin secretion. Mice double heterozygous for null alleles in the insulin receptor and insulin receptor substrate-1 genes exhibit the expected approximately 50% reduction in expression of these two proteins, but a synergism at a level of insulin resistance with 5- to 50-fold elevated plasma insulin levels and comparable levels of beta cell hyperplasia. At 4-6 months of age, 40% of these double heterozygotes become overtly diabetic. This NIDDM mouse model in which diabetes arises in an age-dependent manner from the interaction between two genetically determined, subclinical defects in the insulin signaling cascade demonstrates the role of epistatic interactions in the pathogenesis of common diseases with non-Mendelian genetics.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles
  • Animals
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / mortality
  • Diabetic Ketoacidosis / genetics
  • Diabetic Ketoacidosis / mortality
  • Disease Models, Animal
  • Genotype
  • Heterozygote
  • Hyperinsulinism / physiopathology
  • Hyperplasia
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance / genetics
  • Islets of Langerhans / pathology
  • Liver / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout*
  • Muscles / physiology
  • Phosphoproteins / genetics*
  • Receptor, Insulin / genetics*
  • Signal Transduction / physiology


  • Blood Glucose
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • Phosphoproteins
  • Receptor, Insulin