Insulin Binding to the Blood‐Brain Barrier in the Streptozotocin Diabetic Rat

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Abstract
125I-Insulin binding to isolated brain microvessels from control, streptozotocin diabetic, and insulin-treated diabetic rats was measured. The binding was highest in the control (21.1 ± 1.8%/mg capillary protein) and lowest in the diabetic (14.8 ± 1.9%, p < 0.01) animals. Administration of 2 U of protamine zinc insulin per day increased the maximum binding in the diabetic rats to 17.2 ± 2.1%. Scatchard analyses of the binding showed that the major difference between the diabetic and the control animals was a decrease in the number of both high- and low-affinity sites in the diabetic animals. To test whether the failure of up-regulation in the hypoinsulinemic diabetic animal was related to an inherent defect in the endothelial cell or resulted from the diabetic milieu, cultured brain endothelial cells were tested for their capacity to up- and down-regulate their insulin receptors in vitro. In response to 100 ng/ml insulin for 12 h, these cells down-regulated their insulin receptors. When the insulin was removed, the insulin receptors returned to control levels. These studies showed that in vitro brain capillary endothelial cells have the capacity to increase their insulin receptors in response to a low-insulin environment, whereas in vivo the microvessels decrease their insulin receptors in response to diabetes. Furthermore, insulin levels in both plasma (33.4 ± 3.5 μU/ml in controls versus 21.9 ± 2.1 in diabetic, p < 0.02) and brain 2.6 ± 0.4 μU/g wet weight in control versus 0.32 ± 0.30 in diabetic, p < 0.02) were lower in the diabetic animals. However, the ratio of brain to plasma insulin levels was lower in the diabetic (0.029 ± 0.011) than in the control animals (0.092 ± 0.024, p < 0.02), implying that there is a selective decrease in the brain insulin relative to the plasma insulin in diabetes. These findings suggest that the brain capillaries may be involved in transport of insulin from the blood to the underlying brain cells and that a specific defect occurs in the diabetic brain capillary that can cause a further deficiency in brain insulin in poorly controlled diabetes.