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We have previously characterized an allosteric monoclonal antibody to the human insulin receptor (IR), XMetA, that activated metabolic signaling leading to enhanced glucose transport in cultured cells, and chronically reduced fasting blood glucose levels in mouse models of diabetes mellitus. Under acute dosing conditions, the large size of an IR\u2010binding antibody like XMetA (\u223c150\u2009kDa) could lead to a more rapid access into liver, an insulin sensitive tissue with well\u2010fenestrated capillaries, when compared to other insulin sensitive tissues with non\u2010fenestrated capillaries, such as muscle and adipose. Thus, in the present study we administered XMetA (10\u2009mg\/kg) and insulin (0.5\u2009U\/kg) via IV injection, and for 90\u2009min compared their effects on blood glucose lowering and IR activation in three of the major insulin\u2010sensitive tissues of the normal fasted mouse: liver, adipose, and muscle. Like insulin, XMetA lowered blood glucose levels, although the effect was less rapid. Insulin activated IR autophosphorylation and Akt phosphorylation in liver, fat, and muscle. In contrast, IR activation by XMetA was primarily observed in the liver. Both insulin and XMetA lowered \u03b2\u2010hydroxybutyrate levels in plasma; however, only insulin reduced both non\u2010esterified fatty acids (NEFA) and glycerol concentrations. These data indicate that, in normal mice, acute glucose regulation by XMetA is largely mediated by its action on the liver. J. Cell. 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