Insulin binding and action in isolated rat hepatocytes: effect of obesity and fasting

Insulin binding and action on [14C]glucose incorporation into glycogen were studied in freshly isolated hepatocytes from control, obese, and 48-h fasted-obese rats. Tracer 125I-insulin binding was reduced in the obese animals from 20.8 +/- 1.3% in the controls of 15.9 +/- 0.8% (mean +/- SE). The change in binding was due to a decrease in receptor number with no change in affinity. Fasting the obese animal for 48 h restored the tracer 125I-insulin binding and the receptor number to control levels. Physiologic concentrations of insulin caused an 86% stimulation of net [14C]glucose incorporation into glycogen above the basal level of 9.0 +/- 1.0 nmol incorporated . 10(6) cells-1 . h-1 with an ED50 of 4.0 ng/ml. In obese (greater than 500 g) animals the maximum insulin response measured by percent increase above basal (49%) was reduced, and the ED50 (5.8 ng/ml) was increased. When the obese animals were fasted, the basal and maximum insulin responses were further depressed, but the ED50 was restored to control levels. In conclusion, hepatocytes from obese animals show both a receptor and postreceptor defect. Fasting the animals restores the receptor status to normal, but the postreceptor metabolic defect remains.