The source of cerebral insulin

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Abstract

Insulin and its receptor are found throughout the central nervous system (CNS). Insulin administered into the CNS can exert powerful effects, yet the consensus is that little or no insulin is produced in the CNS. Therefore, CNS insulin is essentially dependent on the ability of peripheral insulin to cross the blood–brain barrier (BBB). Insulin is known to cross the BBB by a saturable transport mechanism. This transporter shows some thematic similarities to other transporters for peptides or regulatory proteins. It is unevenly distributed throughout the CNS with the olfactory bulbs having the fastest transport rate of any brain region. It is partially saturated at euglycemic levels, suggesting that its main signaling function occurs at physiological blood levels, rather than as a brake to hypoglycemic events. One probable function of the BBB transporter is to allow CNS insulin to act as a counter-regulatory hormone to peripheral insulin. The transporter is regulated, with the transport rate of insulin being altered during development and by fasting, obesity, hibernation, diabetes mellitus and Alzheimer's disease. Enhancement of insulin transport by lipopolysaccharide could be the basis for the insulin resistance seen with bacterial infections. Inhibition of insulin transport across the BBB by dexamethasone could be the basis for the enhanced appetite seen with glucocorticoid treatments. Insulin itself also has effects on the BBB, altering enzymatic and transporter functions. Overall, BBB transport of insulin provides a mechanism for peripheral insulin to act within the CNS as a regulatory peptide.

Introduction

A pancreatic extract capable of lowering blood glucose was isolated by Banting and Best (1922). This substance, insulin, is important not only because it is central to understanding and treating diabetes mellitus, one of the most dreaded diseases of mankind, but also because it has been the targeted molecule used in the development of many other fields Kahn (1995). It was an early and dramatic example of the power hormones play and so helped to foster the growth of the field of endocrinology. It was one of the first proteins to be extracted on mass scale for use in the treatment of human diseases and so not only fostered the field of protein chemistry but the emergence of a major pharmaceutical company. Despite some 8 decades of intense scientific interest and over 170,000 publications in medline, there is still much about insulin which is not understood.

Insulin has once again been central to pioneering work in another important area: an understanding of how the central nervous system (CNS) communicates with the peripheral tissues. An interest in insulin and the CNS can be traced back 50 years, but the first seminal observation in this regard is probably the study of Margolis and Altszuler (1967). That insulin directly affects the CNS is clear: insulin receptors are found throughout the CNS and insulin injected into the brain affects CNS functioning. Little or no insulin is produced in the CNS, which means that the insulin acting there is of pancreatic origin. This raises the question of how insulin produced by the pancreas and circulating in the blood could enter the CNS. This is a major question because lipid insoluble substances the size of insulin are largely excluded from the CNS by the blood–brain barrier (BBB).

Thus, an understanding of the source of CNS insulin is largely synonymous with an understanding of the ways the BBB and insulin interact. Because the BBB is not an inert structure, but a dynamic interface separating the blood from the fluids of the CNS, one must consider certain of its characteristics relevant to how it works with regards to insulin. This is particularly true because our knowledge of how the BBB interacts with protein hormones like insulin is far from complete. Therefore, an understanding of how the BBB interacts with peptides and other regulatory proteins is crucial if one is to anticipate future discoveries of how the BBB regulates levels of insulin in the CNS.

Section snippets

A general overview of BBB function

The term blood–brain barrier in its most restrictive sense refers to the vascular bed of the CNS, which is specially modified to prevent the unrestricted transfer of molecules between the blood and the extracellular fluid of the CNS. In this sense, the term BBB is distinguished from other barriers, which also regulate transfer, such as the choroid plexus and the barriers at the circumventricular organs Johanson, 1988, Gross and Weindl, 1987. In a broader sense, the term BBB can include these

Early studies and controversies

The idea that insulin could cross the BBB was first suggested by Margolis and Altszuler (1967). They used the newly available technique of radioimmunoassay to show that levels of insulin in the CSF increased with peripheral infusions of insulin. These findings contradicted previous studies, some dating back to as early as 1954, which used radioactively labeled insulin or bioassays for insulin. The authors concluded that insulin crossed the BBB, possibly by way of a saturable transport system.

Physiological roles of transport

The insulin transporter is largely saturated by serum levels of insulin which do not induce hypoglycemia Banks et al., 1997a, Banks et al., 1997c. This suggests that the signal which blood-borne insulin conveys to the brain by crossing the BBB is not related to reversal of hypoglycemia but is more likely to be conveying information about physiological parameters.

Insulin given directly into the CNS has effects which are often opposite to those when given peripherally. For example, CNS insulin

Pathophysiology of the insulin transporter

As expected of a transporter which can be regulated by physiological events, the insulin transporter is also altered in disease states. In some cases, these alterations may be adaptive to the disease state, whereas in others the changes may be causal of the disease.

Transport across the BBB of insulin Stein et al., 1987, Kaiyala et al., 2000, like that of leptin (Banks et al., 1999a), is reduced with obesity. Consistent with such a decreased transport, the obese Zucker rat has lower levels of

Effects of insulin on BBB function

Insulin has effects on BBB function, including an ability to affect the transport of other substances. Binding sites for insulin have been described at both the choroid plexus and on brain endothelial cells Baskin et al., 1986, Miller and Borchardt, 1991. Whereas some of these binding sites may represent transporters, others may represent transmembrane-signaling receptors. This would provide a mechanism for insulin's actions on BBB function.

An example of insulin's effects on the BBB is the

Conclusions

Insulin is transported across the BBB by a saturable transporter. Little or no insulin is produced in the CNS, so that CNS insulin is largely derivative from peripheral insulin. As such, CNS insulin is dependent on the BBB transport of peripheral insulin. This transporter is not static but has been shown to alter the transport rate of insulin into the CNS under a variety of circumstances. For example, insulin transport is likely faster in neonates than in adults and slower in Alzheimer's

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