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PMID: 10642598 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

The Journal of clinical investigation ·Vol. 105 ·No. 2 ·2000-01-00 ·Pages 199-205

Kido Y, Burks DJ, Withers D, Bruning JC, Kahn CR, White MF, Accili D

Abstract

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.

MeSH Terms
Adipose Tissue/enzymology Animals Blood Glucose/metabolism Cell Size/genetics Diabetes Mellitus, Type 2/blood,genetics Disease Models, Animal Heterozygote Homozygote Hyperglycemia/diagnosis,genetics Insulin/blood Insulin Receptor Substrate Proteins Insulin Resistance/genetics Intracellular Signaling Peptides and Proteins Islets of Langerhans/cytology,metabolism Liver/enzymology Male Mice Mice, Knockout Muscle, Skeletal/enzymology Mutation Organ Specificity/genetics Phosphatidylinositol 3-Kinases/metabolism Phosphoproteins/genetics Receptor, Insulin/genetics
Chemicals
Blood Glucose Insulin Insulin Receptor Substrate Proteins Intracellular Signaling Peptides and Proteins Irs1 protein, mouse Irs2 protein, mouse Phosphoproteins Phosphatidylinositol 3-Kinases Receptor, Insulin
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Kido Y
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20842, USA.
Burks D J
Withers D
Bruning J C
Kahn C R
White M F
Accili D
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI7917
Published
2000-01-00
Pages
199-205
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC377430
Subset
IM
External Links
PubMed source DOI: 10.1172/JCI7917 PMC Full Text View journal details
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