To determine the physiological roles of SHPTP2 in vivo, we made dominant negative transgenic (Tg) mice that express only two SH2domains of SHPTP2. The 16 Tg mice out of 230 FO offspring were identified by Southern blot analysis. The transgene product (MW 28 kDa) was expressed in all tissues including 3 insulin-sensitive tissues (skeletal muscle, liver and adipose tissue) to regulate in vivo glucose homeostasis. When we examined 2 lines of Tg mice (S6 and S161), there was no difference in the phenotype or growth rate between Tg and non-Tg mice. However, plasma insulin levels after 4-hr fasting in the morning were higher in Tg mice (S6: Tg 142±14μU/ml vs non-Tg 42±6μU/ml, S161: Tg 106±15μU/ml vs non-Tg 45±8μU/ml (mean±SE), p<0.01), although blood glucoselevels were not different. These data suggest that our Tg mice are a possible new animal model for elucidating the mechanism of insulin resistance.