Regulation of insulin transport across the blood‐brain barrier by CNS insulin receptor signaling

Abstract

AbstractBackgroundImpairments in the regulation of central nervous system (CNS) insulin are clearly associated not only with metabolic syndrome and diabetes mellitus but also with Alzheimer’s disease (AD), age‐related cognitive decline, and mild cognitive impairment (MCI). Evidence exists for both decreased brain insulin levels and impaired brain insulin signaling (i.e., insulin resistance) as causes for this decreased insulin action. Insulin therapy can improve cognition in both healthy subjects as well as those suffering from cognitive impairments. While much of the focus in this area has been placed on overcoming CNS insulin resistance at the molecular level, we believe the impairment could lie at the blood‐brain barrier (BBB). CNS insulin is derived from the blood and crosses the BBB by a saturable transport system. Therefore, the insulin resistance observed in the CNS and at the neurovascular unit in these diseases could be a consequence of insulin deficiency and inadequate insulin BBB transport. Much focus has been placed on the peripheral mediators of insulin transport, with the direct role of the CNS often ignored. Therefore, the goal of this study was to investigate the communication of the neurovascular unit (NVU) in mediating CNS insulin levels in AD.MethodWe utilized the multiple‐time regression analysis technique to measure 125I‐insulin pharmacokinetics at the BBB. We were able to define the transport rate for 125I‐insulin and amount of vascular binding due to changes in CNS insulin receptor signaling. First, we inhibited CNS insulin receptor signaling by administering 1 μg S961 by intracerebroventricular (icv) injection. Second, we evaluated 125I‐insulin transport in mice lacking the insulin receptor in astrocytes.ResultAcute, broad inhibition of the CNS insulin receptor following icv delivery of S961, a selective antagonist, led to decreased 125I‐insulin transport across the BBB that was sex specific in CD‐1 mice. Follow‐up studies revealed the astrocytic insulin receptor may be responsible for this decreased transport as mice lacking the insulin receptor in astrocytes, GFAP insulin receptor knock‐out (GIRKO) mice, also have decreased 125I‐insulin BBB transport.ConclusionThese studies suggest the insulin receptor present on specific cell types within the CNS have a regulatory role in mediating insulin uptake by the brain.