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

Type 2 diabetes is characterized by abnormalities of insulin action in musc le, adipose tissue, and Liver and by altered beta-cell function. To analyze the role of the insulin signaling pathway in these processes, we have gene rated mice with combined heterozygous null mutations in insulin receptor (i r), 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(+/-), an d 5% of ir(+/-) mice. Although combined heterozygosity for ir/irs-1(+/-) an d ir/irs-2(+/-) results in a similar number of diabetic mice, there are sig nificant differences in the underlying metabolic abnormalities. ir/irs-1(+/ -) mice develop severe insulin resistance in skeletal muscle and liver, wit h compensatory beta-cell hyperplasia, In contrast, ir/irs-2(+/-) mice devel op severe insulin resistance in liver, mild insulin resistance in skeletal muscle, and modest beta-cell hyperplasia. Triple heterozygotes develop seve re insulin resistance in skeletal muscle and liver and marked beta-cell hyp erplasia. These data indicate tissue-specific differences in the roles of I RSs to mediate insulin action, with irs-1 playing a prominent role in skele tal 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.