Nature Genetics
20, 294 - 298 (1998)
doi:10.1038/3112
Impaired glucose tolerance in mice with a targeted impairment of insulin
action in muscle and adipose tissueDavide Lauro1, Yoshiaki Kido1, Arthur L. Castle2, Mary-Jane Zarnowski2, Hideki Hayashi3, Yousuke Ebina3
& Domenico Accili11
Developmental Endocrinology Branch, National Institute
of Child Health and Human Development,National Institutes of Health,
Bethesda, Maryland 20892, USA. 2
Diabetes Branch, National Institute of Diabetes and
Digestive and Kidney Diseases, National Institutes of Health,
Bethesda, Maryland 20892, USA. 3
Institute for Enzyme Research, University of Tokushima, Tokushima 770, Japan.
Correspondence should be addressed to Domenico Accili accilid@mail.nih.govType 2 diabetes is a complex metabolic disorder characterized by peripheral
insulin resistance and impaired  cell function1,2. Insulin
resistance is inherited as a non-mendelian trait3. In genetically
predisposed individuals, resistance of skeletal muscle and adipose tissue
to insulin action precedes the onset of clinical diabetes, and is thought
to contribute to hyperglycaemia by leading to impaired cell function
and increased hepatic glucose production4,5. It is not clear
whether cell and liver defects are also genetically determined2. To test the hypothesis that insulin resistance in muscle and fat
is sufficient to cause type 2 diabetes in the absence of intrinsic cell
and liver abnormality, we generated transgenic mice that were insulin-resistant
in skeletal muscle and adipose tissue. These mice developed all the prodromal
features of type 2 diabetes but, despite the compounded effect of peripheral
insulin resistance and a mild impairment of cell function, failed to
become diabetic. These findings indicate the need for a critical re-examination
of the primary site(s) of insulin resistance in diabetes.
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