The present study was undertaken to investigate the nature of the whole body insulin resistance that characterizes patients with complete cervical spinal cord lesion. Nine patients with C-5-C-7 lesions and ten age-matched healthy individuals were studied. Whole body insulin-mediated glucose utilization was reduced by 43% in the quadriplegic patients compared with the controls (P < 0.001). In the quadriplegic patients, lean body mass corresponded to 66 +/- 3% of total body mass. Despite whole body insulin resistance, in isolated vastus lateralis muscle, basal and insulin-stimulated 3-O-methylglucose transport, as well as protein expression of the insulin or exercise-regulatable glucose transporter, GLUT-4, and glycogen content were comparable between the patients and controls. Strikingly, muscle fiber area was reduced by 44% (P < 0.05), percentage of type IIb fibers was increased (P < 0.01), and there was a complete loss of type I fibers in the patients. In conclusion, the dissociation between whole body insulin-mediated glucose uptake and skeletal muscle glucose transport in quadriplegic patients primarily reflects the decreased muscle mass. Furthermore, these findings demonstrate a remarkable capacity of skeletal muscle to maintain an intact glucose transport system despite severe morphological alterations.