Effect of diabetes mellitus on the permeability of the blood-brain barrier to insulin.

Insulin derived from the peripheral circulation has been shown to exert various effects on the brain due to its ability to cross the blood-brain barrier (BBB). The relation between diabetes mellitus and insulin has been extensively studied for peripheral tissues but not for central nervous system tissues. We examined the effects that streptozotocin- or alloxan-induced diabetes have on the transport of insulin across the murine BBB. We used multiple-time regression analysis to measure the unidirectional influx rate constant (Ki) and vascular association (Vi) of intravenously injected, radioactively labeled human insulin (I-Ins). Treatment with streptozotocin induced an enhancement of both the Ki and Vi of I-Ins that correlated with the onset of diabetes. Brain perfusion showed that the enhanced uptake was not due to altered vascular space or levels of insulin in the serum. Alloxan enhanced Ki and Vi after 5 days but the early phase of diabetes was associated with a decreased Ki. Hyperglycemia induced by the intraperitoneal injection of glucose elevated the Vi but abolished the Ki. Furthermore, altered I-Ins uptake by brain was not associated with changes in brain or body weight. These results show that there is an increased uptake of I-Ins by the brain in the diabetic state that is not due to acute changes in the serum levels of glucose or insulin, altered vascular space, or catabolic events. Chronic changes in levels of glucose, insulin or other hormone or neuroendocrine agents are likely to underlie the altered rate of transport of insulin across the BBB of diabetic mice.