Previous studies in the homozygous athymic nude mouse (USC colony) have indicated a diabetic state characterized by spontaneous hyperglycemia, abnormal glucose tolerance, and normal or relatively decreased plasma insulin levels. Pancreatic islet cell population assessed by morphometric and immunohistochemical studies demonstrated normal insulin-secreting cells in the hyperglycemic nude mouse. To further elucidate the pathogenesis of the hyperglycemic state in the athymic nude mouse, we have studied the effects of insulin on the transport of glucose in skeletal muscle by measuring basal and insulin-stimulated uptake of a nonmetabolizable glucose analogue, 2-deoxy-D-glucose by using the perfused hindquarter preparation. Although basal 2-deoxy-D-glucose uptake by peripheral skeletal muscle was similar in the hyperglycemic and control mice, the insulin-stimulated uptake of 2-deoxy-D-glucose was significantly decreased in the athymic nude mouse at both 0.1 milliunits/ml and supraphysiologic concentrations of insulin (1 milliunit/ml) when compared with control mice (P less than 0.05 and P less than 0.001, respectively). This form of peripheral insulin insensitivity with normal pancreatic beta cell reserve, in addition to the lean body mass of the diabetic animal, mimics in part the peripheral insulin insensitivity seen in non-insulin-dependent diabetes mellitus.