Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2

J Clin Invest. 2000 Jan;105(2):199-205. doi: 10.1172/JCI7917.


Type 2 diabetes is characterized by abnormalities of insulin action in muscle, adipose tissue, and liver and by altered beta-cell function. To analyze the role of the insulin signaling pathway in these processes, we have generated mice with combined heterozygous null mutations in insulin receptor (ir), insulin receptor substrate (irs-1), and/or irs-2. Diabetes developed in 40% of ir/irs-1/irs-2(+/-), 20% of ir/irs-1(+/-), 17% of ir/irs-2(+/-), and 5% of ir(+/-) mice. Although combined heterozygosity for ir/irs-1(+/-) and ir/irs-2(+/-) results in a similar number of diabetic mice, there are significant differences in the underlying metabolic abnormalities. ir/irs-1(+/-) mice develop severe insulin resistance in skeletal muscle and liver, with compensatory beta-cell hyperplasia. In contrast, ir/irs-2(+/-) mice develop severe insulin resistance in liver, mild insulin resistance in skeletal muscle, and modest beta-cell hyperplasia. Triple heterozygotes develop severe insulin resistance in skeletal muscle and liver and marked beta-cell hyperplasia. These data indicate tissue-specific differences in the roles of IRSs to mediate insulin action, with irs-1 playing a prominent role in skeletal muscle and irs-2 in liver. They also provide a practical demonstration of the polygenic and genetically heterogeneous interactions underlying the inheritance of type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / enzymology
  • Animals
  • Blood Glucose / metabolism
  • Cell Size / genetics
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / genetics*
  • Disease Models, Animal
  • Heterozygote
  • Homozygote
  • Hyperglycemia / diagnosis
  • Hyperglycemia / genetics
  • Insulin / blood
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance / genetics*
  • Intracellular Signaling Peptides and Proteins
  • Islets of Langerhans / cytology
  • Islets of Langerhans / metabolism
  • Liver / enzymology
  • Male
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / enzymology
  • Mutation
  • Organ Specificity / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoproteins / genetics*
  • Receptor, Insulin / genetics*


  • Blood Glucose
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Irs1 protein, mouse
  • Irs2 protein, mouse
  • Phosphoproteins
  • Phosphatidylinositol 3-Kinases
  • Receptor, Insulin