Research reportEffect of LPS on the permeability of the blood–brain barrier to insulin
Introduction
Insulin is secreted by the β cells in the pancreatic islets of Langerhans. Insulin consists of two peptide chains linked by two sulfhydryl bonds with a structure that is highly conserved across species. As a result, insulin from one species is often active in another. Human insulin has a molecular weight of 5786 and the human pancreas releases about 1 mg/24 h. Release of insulin is primarily regulated by levels of glucose and glucagon in the serum and is under cholinergic control, although α- and β-adrenergic tone can also affect secretion. About 50% of insulin is cleared by the liver where it inhibits glucose release. Insulin entering the circulation greatly facilitates the uptake of serum glucose by fat and muscle, but has little effect on the uptake of glucose by the brain. An absence of, or resistance to, insulin results in diabetes mellitus. Resistance to the peripheral effects of insulin occurs with inflammation and infection.
Insulin receptors are found throughout the brain, suggesting that insulin could have widespread effects within the central nervous system (CNS). The central action of insulin appears to counterbalance its activities in the periphery. Rather than promoting feeding and inducing hypoglycemia as it does in the periphery, insulin in the CNS encourages weight loss, probably through actions on neuropeptide Y [17], [18] and can induce hyperglycemia [17]. Centrally administered insulin also has been shown to affect sympathetic nerve activity [36], ischemic events [50], brain metabolism [23], and the production [48] as well as action [15] of other satiety hormones.
Unlike many regulatory proteins or small peptides produced by peripheral tissues, little or no insulin is synthesized by the brain. Therefore, to act at its central receptors, blood-born insulin must cross the blood–brain barrier (BBB). Insulin is transported across the BBB by a saturable transport system in the blood to brain [1], [6], but not the brain to blood [9], direction. Binding sites for insulin, which may represent the transporters, have been found on both the vascular endothelial and the choroid plexus epithelial cells which constitute the BBB [5], [20], [34]. The permeability of the BBB to insulin appears to be regulated by physiological events, such as fasting, starvation, or refeeding [16], [17], hibernation in marmots [17], [18], and brain development [12], [19]. Some pathophysiological states may also exert effects on the permeability of the BBB to insulin. For example, there is an increased uptake of insulin by the brain in diabetic mice [2].
Other work has suggested that substances such as tumor necrosis factor-α (TNF-α) [12], nitric oxide (NO) [7], and prostaglandins [35] may change the permeability of the BBB. These substances may also cross the BBB [22], exert effects on the CNS [21], and induce peripheral insulin resistance [28], [44]. Lipopolysaccharide (LPS), a bacterial wall endotoxin, is a powerful releaser of cytokines, prostaglandine E2, and NO [8] and can affect the permeability of the BBB [7], [30]. Here, we look at the effects of LPS on the permeability of the BBB to human insulin in mice.
Section snippets
Radioactive labeling of insulin and albumin
Human insulin was obtained from Sigma Chemical Co. The insulin (5 μg) and bovine serum albumin (5 μg) were radioactively labeled with 131I and 125I, respectively, by the chloramine T method and purified by filtration on a column of Sephadex G-10. Incorporations of 131I to insulin and 125I by albumin, as determined by trichloroacetic acid (TCA) precipitation, were each greater than 90%. The 131I–insulin had a specific activity of about 55 Ci/g.
Measurement of BBB permeability
Male CD-1 mice (Charles River, Wilmington, MA; 25∼35
Results
The initial pilot study suggested that the peak uptake of 131I–insulin by the brain was at the time between 16 and 24 h after a single i.p. injection of LPS (data not shown). Based upon this, 131I–insulin uptake by the brain was determined 24 h after injections of LPS in subsequent studies. Statistically significant increases in 131I–insulin uptake by the brain were found [F(3,27)=4.840] 24 h after one (P=0.0019, n=10/group), three (P<0.0001, n=10/group), and five (P<0.0001, n=10/group)
Discussion
In this study, we showed that intraperitoneal LPS enhanced the permeability of the BBB to insulin through two distinct mechanisms: enhanced saturable transport (Fig. 3) and disruption of the BBB (Fig. 2). The ability of bacterial LPS or cytokines released by LPS to enhance the permeability of the BBB to insulin suggests that systemic bacterial infections or other inflammation states could facilitate the transport of insulin into the CNS, which in turn, could alter insulin’s central effects.
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