Insulin receptor substrate-1 (IRS-1) is the major substrate of both the insulin receptor and the IGF-1 receptor. In this study, we created IRS-1 transgenic (IRS-1-Tg) mice which express human IRS-1 cDNA under control of the mouse IRS-1 gene promoter. In the IRS-1-Tg mice, IRS-1 mRNA expression was significantly increased in almost all tissues, but its protein expression was increased in very limited tissues (epididymal fat and skeletal muscle). IRS-1-Tg mice showed glucose intolerance and significantly enlarged epididymal fat mass, as well as elevated serum TNF-alpha concentrations. Importantly insulin signaling was significantly attenuated in the liver of IRS- 1-Tg mice, which may contribute to the glucose intolerance. Our results suggest that excess IRS- I expression may not provide a beneficial impact on glucose homeostasis in vivo. (C) 2007 Elsevier Inc. All rights reserved.