Evidence of a defect in insulin-receptor recycling in adipocytes from older rats.

Although insulin-stimulated glucose uptake is known to be decreased in adipocytes isolated from old obese rats, the cause of this defect is not totally understood. In the present study, we examined the possibility that insulin resistance is associated with defects in the intracellular processing of the insulin-receptor complex. Adipocytes were isolated from control (2-mo-old rats) and obese, insulin-resistant rats (12-mo-old rats), and the following measurements were made: 1) insulin-stimulated glucose uptake; 2) insulin binding; 3) insulin-receptor internalization and recycling; 4) accumulation of insulin within the cell; and 5) rate of loss of insulin from the cell. The results indicated that maximal insulin-stimulated glucose uptake was significantly reduced in adipocytes from obese, insulin-resistant rats (increase over basal value was 500 +/- 53% in obese rats and 1,200 +/- 96 in control rats, P less than 0.01). 125I-insulin (A14) binding (cell-associated radioactivity) and the internalization of the hormone-receptor complex were not different in the two groups of animals studied. In contrast, insulin-receptor recycling was significantly decreased in adipocytes from obese rats (72.0 +/- 6.1 vs. 93.6 +/- 2.6%, P less than 0.01). In addition, loss of intracellular radioactivity was significantly prolonged in insulin-resistant rats (t1/2 = 12.05 +/- 0.9 vs. 9.4 +/- 0.3 min, P less than 0.05). Thus adipocytes isolated from the older rats were resistant to the insulin effect on glucose uptake, and this defect was not associated with a reduction in insulin binding. However, there was a decrease in insulin receptor recycling, and this phenomenon may be related to the insulin resistance present in these cells.