ArticlesUptake and degradation of blood-borne insulin by the olfactory bulb
Introduction
Insulin released from the pancreas into the blood facilitates the uptake of serum glucose into fat, muscle, and other tissues. Insulin also enters the central nervous system (CNS) by being transported across the blood-brain barrier (BBB) by a unidirectional, saturable system [3], [12], [16], [43]. Although the CNS consumes glucose at a very high rate, insulin is not involved in the transport of glucose across the BBB. Instead, insulin within the CNS appears to affect regulation of appetite and related functions [11], [16], [27], [40], [44], [45]. Some of the effects of CNS insulin are opposite to those of blood-borne insulin, suggesting that by crossing the BBB, insulin can act as its own counter-regulatory hormone [2], [6], [19], [20], [39]. The functional appearance of insulin within the brain illustrates the role played by the BBB in the regulation of communication between the CNS and peripheral tissues.
Insulin receptors are found throughout the brain, suggesting that insulin could have widespread effects within the CNS. The receptors in brain differ from peripheral receptors in molecular weight, antigenicity, and carbohydrate composition [26]. One of the highest concentrations of insulin [10], insulin receptors, and mRNA for insulin receptors [1], [23], [24], [28], [29], [35], [36], [48] is found in the olfactory bulb. The action of insulin at the olfactory bulb has been studied with regard to odor perception, glucose tolerance, dopamine metabolism [31], [38], norepinephrine metabolism [31], and insulin sensitivity [15], [42]. The insulin receptors of the olfactory bulb, in comparison with other brain regions, are particularly sensitive to changes during starvation, [33] with aging, [46] and are resistant to change during postnatal development [34].
Insulin is not produced by the brain so that its higher concentration within the olfactory bulb reflects either a lower rate of degradation or a higher rate of transport across the BBB. The transporter for insulin is adaptive, showing differences in activity between neonatal and adult animals, with hibernation, in various other regions of the brain, and with the occurrence of diabetes [4], [7], [17], [18], [19], [21]. Therefore, an altered transport rate at the BBB of the olfactory bulb is a reasonable hypothesis. To determine why the level of insulin is higher in the olfactory bulb, we compared the rate of degradation and the rate of transport across the BBB for the olfactory bulb, whole brain, and spinal cord.
Section snippets
Radioactive labeling of insulin
Human insulin was obtained from Sigma Chemical Co (St. Louis, MO, USA; 28 U/mg). The insulin was radioactively labeled with 125I by the chloramine T method and purified on high-performance liquid chromatography (HPLC). The 125I-insulin (I-Ins) had a specific activity of about 55 Ci/g.
Measurement of uptake rates
The rate of uptake of I-Ins from blood by whole brain, olfactory bulb, and spinal cord was measured as the unidirectional influx constant (Ki) in mice as previously described [5] by the method of multiple-time
Uptake rates
The values for Ki in units of μl/g-min were 0.658 ± 0.147 for brain, 4.97 ± 0.86 for olfactory bulb, and 3.73 ± 0.55 for spinal cord (Fig. 1 ). In all cases, the relation between tissue/serum ratios and Expt was statistically significant [brain: n = 8, r = 0.878, P < 0.005; olfactory bulb: n = 8, r = 0.921, P < 0.005; spinal cord: n = 8, r = 0.940, P < 0.001], that indicates a reliable measure for blood to tissue influx. The Prism program showed that a significant difference existed among
Discussion
These results show that regional differences exist for both BBB transport and enzymatic degradation rates among the tissues of the olfactory bulb, spinal cord, and whole brain. The highest rates of transport and of degradation were found for the olfactory bulb. This shows that the mechanism for the higher concentrations of insulin within the olfactory bulb is explained by faster transport, not slower degradation.
Transport of blood-borne insulin into all three regions was shown to be saturable.
Acknowledgements
We wish to thank Weitao Huang for technical assistance. Supported by the VA and RO1MH54979.
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