Expression of a dominant negative SHP-2 in transgenic mice induces insulinresistance

To elucidate the roles of SHP-2 genic (Tg) mice expressing a dominant negat ive mutant lacking protein tyrosine phosphatase domain (Delta PTP). On exam ining two lines of Tg mice identified by Southern blot, the transgene produ ct Tvas expressed in skeletal muscle, liver, and adipose tissues, and insul in-induced association of insulin receptor substrate 1 with endogenous SHP- 2 was inhibited, confirming that Delta PTP has a dominant negative property . The intraperitoneal glucose loading test demonstrated an increase in bloo d glucose levels in Tg mice. Plasma insulin levels in Tg mice after 4 h fas ting were 3 times greater with comparable blood glucose levels. To estimate insulin sensitivity by a constant glucose, insulin, and somatostatin infus ion, steady state blood glucose levels were higher, suggesting the presence of insulin resistance. Furthermore, we observed the impairment of insulin- stimulated glucose uptake in muscle and adipocytes in the presence of physi ological concentrations of insulin. Moreover, tyrosine phosphorylation of i nsulin receptor substrate-1 and stimulation of phosphatidylinositol 3-kinas e and Akt kinase activities by insulin were attenuated in muscle and liver. These results indicate that the inhibition of endogenous SHP-2 function by the overexpression of a dominant negative mutant may lead to impaired insu lin sensitivity of glucose metabolism, and thus SHP-2 may function to modul ate insulin signaling in target tissues.