The dam breaks: disruption of the blood-brain barrier in diabetes mellitus
2006; American Physical Society; Volume: 291; Issue: 6 Linguagem: Inglês
10.1152/ajpheart.00751.2006
ISSN1522-1539
Autores Tópico(s)Connexins and lens biology
ResumoEDITORIAL FOCUSThe dam breaks: disruption of the blood-brain barrier in diabetes mellitusWilliam A. BanksWilliam A. BanksPublished Online:01 Dec 2006https://doi.org/10.1152/ajpheart.00751.2006This is the final version - click for previous versionMoreFiguresReferencesRelatedInformationPDF (39 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat at the end of the century before the last, a young graduate student performed an experiment that would forever change the way we look at the microvasculature of the brain. He injected basic dyes into the blood and noted that nearly every tissue of the body was colored by the dye except for the central nervous system (CNS). This experiment and the observation that bile salts could cause seizures when injected into the brain but not intravenously were the seminal 19th century observations giving rise to the concept of a blood-brain barrier (BBB).The young graduate student, Paul Ehrlich, would get many things right in his career, winning a Nobel prize in 1908 for his work on antibiotics. But the BBB he got wrong. Ehrlich thought the brain did not stain because the dye was not taken up by brain tissue, not because a barrier prevented the dye from reaching the brain. Indeed, that a BBB really existed and that it resided at the level of the capillary bed and the choroid plexus were not finally established until the late 1960s. Elegant physiological experiments by Davson and Segal (10) and electron microscopy studies by Reese and Karnovsky (24) demonstrated the basis of the BBB: the capillary bed of adult mammals is modified to exclude the production of a plasma ultrafiltrate. The major modifications include a greatly decreased rate of pinocytosis, a lack of intracellular pores and fenestrae, and obliteration of the intercellular space between brain endothelial cells by tight junctions that essentially “cement” apposing endothelial cells together.The lack of production of an ultrafiltrate means that circulating proteins such as albumin do not exude from blood into brain. This is the basis for Ehrlich's 120-year-old observation: basic dyes bind to albumin so tightly that they are a visible proxy for plasma protein passage across the BBB. On the one hand, this is good news for the brain: circulating riffraff is kept out of a pristine CNS by the BBB; on the other hand, how is the brain to be nourished without the production of a plasma ultrafiltrate? The realization that the BBB also addresses this latter need of the CNS is the basis for the modern view of the role of the BBB in CNS function and disease. In addition to the role of barrier, the BBB also decides what shall be imported into and what shall be exported from the CNS. Hence, in addition to being a barrier, the BBB has nutritional, communication, and homeostatic roles (1, 4, 5, 9, 11, 18, 25, 26).Old concept meets ancient disease in the article of Huber et al. (13) in this issue of American Journal of Physiology-Heart and Circulatory Physiology. Diabetes mellitus was known to the ancients, but modern medicine still struggles with effectively treating it. Microvascular and macrovascular disease affecting peripheral tissues, including the peripheral nervous system, macrovascular disease affecting the CNS, and microvascular disease at the retinal-blood barrier are well-known hallmarks of advanced diabetes, regardless of whether the diabetes is caused by insulinopenia or insulin resistance. Given all this, it could be erroneously assumed that study of the brain microvasculature (also known as the BBB) in diabetes is a huge field. In fact, only a handful of studies have been done. A search engine pairing of “blood-brain barrier” and “diabetes mellitus” finds 34 articles; pairing “blood-brain barrier” with “multiple sclerosis” or “HIV-1” finds 394 and 100 articles, respectively. This lack of work, in part, has been because it was thought that brain microvasculature and brain function were both preserved in diabetes. Slowly, both of these perceptions have changed.It is now clear that diabetics have alterations in cognitive function (16). There have also been hints that BBB function is changed, at least in insulinopenic animal models of diabetes. Morphological alterations of the capillary bed and alterations of transporter function have been noted (12, 19). The latter includes an alteration in how insulin itself is transported across the BBB as well as the ability of insulin to control leptin transport (3, 17). However, the work to date simply illustrates that the area of BBB function in diabetes is ripe for study and that even fundamental questions are unanswered.Huber et al.'s (13) paper begins to fill this void. It has an elegant, simple approach to studying one of the most fundamental aspects of the BBB: its barrier function. The work clearly shows that barrier function fails with increasing duration of diabetes. Huber et al. (13) take advantage of a classic but seldom-used approach to the study of barrier function, that of using various sized molecular weight markers to measure leakiness (20, 28). As the ultrastructural work of Reese and Karnovsky (24) showed, BBB impermeability is imposed by tight junctions that block leakage between endothelial cells (the paracellular pathway) and by other modifications (a decreased number of intracellular pores and fenestrae and decreased rate of pinocytosis) that limit leakage across a cell (the transcytotic pathway). Traditionally, the transcellular pathway is considered to be molecular weight independent (because the 50- to 100-nm-diameter vesicles are so much larger than even the largest marker, albumin, with a 7-nm diameter), whereas the paracellular pathway can display molecular weight dependence as disrupted tight junctions begin to close. Traditional studies show that most BBB disruption is predominantly transcytotic, not paracellular (20). However, recent work has suggested that tight junctions are physiologically regulated, so that the paracellular pathway may have some flux, partially opening under unknown, physiological influences.Huber et al.'s (13) work clearly shows a time-dependent, molecular weight-dependent failure of barrier function. At first, it may seem that the molecular weights of sucrose, inulin, and albumin at 342, 5,000, and 65,000 Da are biased toward the low end. But leakiness relates to volume of the molecules, and this is better approximated by the square root of the molecular weight than by the molecular weight itself. The square root values of 18.4, 70, and 255 approximate a geometric progression based on 4 and so are ideally suited to assessment of molecular dependent leakage. The molecular weight dependent-pattern suggests that paracellular pathways predominate in failure of the diabetic BBB. This is consistent with work showing altered tight junction proteins in diabetic animals (8). This, in turn, raises a fundamental question: is such failure a nonspecific response in a very sick animal or does it give a clue to tight junction regulation? Insulin, glucose, and triglycerides each have direct effects on brain endothelial cell function (2, 6, 7, 21); could one of them be important in tight junction regulation also?One of the most important observations of the paper by Huber et al. (13) is that not all regions of the BBB are equally susceptible to disruption. Midbrain was the first to show an enhanced leakage to sucrose after 28 days of diabetes, followed by hippocampus, cortex, and basal ganglia. Other regions showed no disruption even after 90 days of diabetes. Such regional variation is consistent with work showing complex temporal and regional alterations in BBB transporters after insults to the CNS (23, 27). Such variation illustrates that the BBB is not a simple monolithic barrier but a complex regulatory interface that is itself regulated by global and regional factors. Future work will need to relate regional BBB changes to altered functions of the CNS.The work by Huber et al. (13) gives us a firm basis for future work on the diabetic BBB. As such, the work opens up the field to a series of tantalizing questions. For example, healthy aging does not lead to BBB disruption, but the aged BBB is more susceptible to disruption (22). Does diabetes mellitus also increase susceptibility of the brain microvasculature to injury from hypertension and stroke? If so, how much does BBB susceptibility contribute to the worse outcomes diabetics have with hypertension or after stroke? Is the BBB altered in insulin-resistant diabetes? Well over 90% of humans with diabetes are insulin resistant, not insulin deficient, but almost all basic research is done in insulinopenic models. The explosion of work in feeding has produced many rodent models of obesity, most of which have insulin resistance. It is already established that insulin transport itself is impaired in these models (14, 15). Finally, given that the BBB is more than just a barrier, are its other functions altered as well? What effect does diabetes have on the nutritional, homeostatic, communication, secretory, and enzymatic functions of the BBB? Is immune cell trafficking into the CNS, an event that is highly regulated by an interplay between the immune and brain endothelial cells, altered? Some of the early work cited above would suggest that these “higher” functions of the BBB are indeed altered. The third century of BBB research will have to address new questions on how one of the most ancient of diseases alters the regulatory functions of this monolayer of cells interfacing between the peripheral tissues and the CNS.AUTHOR NOTESAddress for reprint requests and other correspondence: W. A. Banks, 915 N. Grand Blvd., St. Louis, MO 63106 (e-mail: bankswa@slu.edu) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationREFERENCES1 Abbott NJ, Ronnback L, and Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 7: 41–53, 2006.Crossref | PubMed | ISI | Google Scholar2 Banks WA, Coon AB, Robinson SM, Moinuddin A, Shultz JM, Nakaoke R, and Morley JE. Triglycerides induce leptin resistance at the blood-brain barrier. Diabetes 53: 1253–1260, 2004.Crossref | PubMed | ISI | Google Scholar3 Banks WA, Jaspan JB, and Kastin AJ. Effect of diabetes mellitus on the permeability of the blood-brain barrier to insulin. Peptides 18: 1577–1584, 1997.Crossref | PubMed | ISI | Google Scholar4 Banks WA and Kastin AJ. Editorial review: peptide transport systems for opiates across the blood-brain barrier. Am J Physiol Endocrinol Metab 259: E1–E10, 1990.Link | ISI | Google Scholar5 Begley DJ. Peptides and the blood-brain barrier. In: Handbook of Experimental Pharmacology. Physiology and Pharmacology of the Blood-Brain Barrier, edited by Bradbury MWB. Berlin: Springer-Verlag, 1992, vol. 103, p. 151–203.Crossref | Google Scholar6 Cangiano C, Cardelli-Cangiano P, Cascino A, Patrizi MA, Barberini F, Rossi F, Capocaccia L, and Strom R. On the stimulation by insulin of tryptophan transport across the blood-brain barrier. Biochem Int 7: 617–627, 1983.PubMed | Google Scholar7 Catalan RE, Martinez AM, Aragones MD, Miguel BG, and Robles A. Insulin action on brain microvessels: effect on alkaline phosphatase. Biochem Biophys Res Commun 150: 583–590, 1988.Crossref | PubMed | ISI | Google Scholar8 Chehade JM, Hass MJ, and Mooradian AD. Diabetes-related changes in rat cerebral occlusion and zonula occludens-1 (ZO-1) expression. Neurochem Res 27: 249–252, 2002.Crossref | PubMed | ISI | Google Scholar9 Davson H and Segal MB. Special aspects of the blood-brain barrier. In: Physiology of the CSF and Blood-Brain Barriers. Boca Raton, FL: CRC Press, 1996, p. 303–485.Google Scholar10 Davson H and Segal MB. The return of the cerebrospinal fluid to the blood: the drainage mechanism. In: Physiology of the CSF and Blood-Brain Barriers. Boca Raton, FL: CRC Press, 1996, p. 489–523.Google Scholar11 Engelhardt B and Wolburg H. Minireview: transendothelial migration of leukocytes: through the front door or around the side of the house? Eur J Pharmacol 34: 2955–2963, 2004.Google Scholar12 Horani MH and Mooradian AD. The effect of diabetes on the blood brain barrier. Curr Pharm Des 9: 833–840, 2003.Crossref | PubMed | ISI | Google Scholar13 Huber JD, VanGilder RL, and Houser KA. Streptozotocin-induced diabetes progressively increases blood-brain barrier permeability in specific brain regions in rats. Am J Physiol Heart Circ Physiol 291: H2660–H2668, 2006.Link | ISI | Google Scholar14 Israel PA, Park CR, Schwartz MW, Green PK, Sipols AJ, Woods SC, Porte D Jr, and Figlewicz DP. Effect of diet-induced obesity and experimental hyperinsulinemia on insulin uptake into CSF of the rat. Brain Res Bull 30: 571–575, 1993.Crossref | PubMed | ISI | Google Scholar15 Kaiyala KJ, Prigeon RL, Kahn SE, Woods SC, and Schwartz MW. Obesity induced by a high-fat diet is associated with reduced brain insulin transport in dogs. Diabetes 49: 1525–1533, 2000.Crossref | PubMed | ISI | Google Scholar16 Kalmijn S, Feskens EJ, Launer LJ, Stijnen T, and Krobhout D. Glucose intolerance, hyperinsulinemia and cognitive function in a general population of elderly men. Diabetologia 38: 1096–1102, 1995.Crossref | PubMed | ISI | Google Scholar17 Kastin AJ and Akerstrom V. Glucose and insulin increase the transport of leptin through the blood-brain barrier in normal mice but not in streptozotocin-diabetic mice. Neuroendocrinology 73: 237–242, 2001.Crossref | PubMed | ISI | Google Scholar18 Kastin AJ, Pan W, Zadina JE, and Banks WA. The endocrine brain. In: Principles and Practice of Endocrinology and Metabolism, edited by Becker, KL. Philadelphia, PA: Lippincott Williams and Wilkins, 2001, p. 1611–1615.Google Scholar19 Lorenzi M. The blood-brain barrier in diabetes mellitus. In: Circulating Regulatory Factors and Neuroendocrine Function, edited by Porter JC and Jezova D. New York: Plenum, 1990, p. 381–390.Google Scholar20 Mayhan WG and Heistad DD. Permeability of blood-brain barrier to various sized molecules. Am J Physiol Heart Circ Physiol 248: H712–H718, 1985.Link | ISI | Google Scholar21 Mayhan WG and Patel KP. Acute effects of glucose on reactivity of cerebral microcirculation: role of activation of protein kinase C. Am J Physiol Heart Circ Physiol 269: H1297–H1302, 1995.Link | ISI | Google Scholar22 Oztas B, Kaya M, and Camurcu S. Age related changes in the effect of electroconvulsive shock on the blood brain barrier permeability in rats. Mech Ageing Dev 51: 149–155, 1990.Crossref | PubMed | ISI | Google Scholar23 Pan W and Kastin AJ. Transport of cytokines and neurotrophins across the blood-brain barrier and their regulation after spinal cord injury. In: Blood-Spinal Cord and Brain Barriers in Health and Disease, edited by Sharma HS and Westman J. Amsterdam: Elsevier, 2004, p. 395–407.Google Scholar24 Reese TS and Karnovsky MJ. Fine structural localization of a blood-brain barrier to exogenous peroxidase. J Cell Biol 34: 207–217, 1967.Crossref | PubMed | ISI | Google Scholar25 Spector R. Micronutrient homeostasis in mammalian brain and cerebrospinal fluid. J Neurochem 53: 1667–1674, 1989.Crossref | PubMed | ISI | Google Scholar26 Taylor EM. The impact of efflux transporters in the brain on the development of drugs for CNS disorders. Clin Pharmacokinet 41: 81–92, 2002.Crossref | PubMed | ISI | Google Scholar27 Xiang S, Pan W, and Kastin AJ. Strategies to create a regenerating environment for the injured spinal cord. Curr Pharm Des 11: 1267–1277, 2005.Crossref | PubMed | ISI | Google Scholar28 Ziylan YZ, Robinson PJ, and Rapoport SI. Blood-brain barrier permeability to sucrose and dextran after osmotic opening. Am J Physiol Regul Integr Comp Physiol 247: R634–R638, 1984.Link | ISI | Google Scholar Cited ByA New Hypothesis for Alzheimer’s Disease: The Lipid Invasion Model25 March 2022 | Journal of Alzheimer's Disease Reports, Vol. 6, No. 1Occipital blood-brain barrier permeability is an independent predictor of visual outcome in type 2 diabetes, irrespective of the retinal barrier: A longitudinal study23 January 2018 | Journal of Neuroendocrinology, Vol. 30, No. 1Physiology and Pathophysiology of the Blood-Brain Barrier: P-Glycoprotein and Occludin Trafficking as Therapeutic Targets to Optimize Central Nervous System Drug Delivery5 January 2023 | Journal of Investigative Medicine, Vol. 60, No. 8Acute Functional Neurotoxicity of Lanthanum(III) in Primary Cortical Networks22 December 2010 | Toxicological Sciences, Vol. 120, No. 1Maternal Diabetes Induced Hydrocephaly in Newborn RatsJournal of Biological Sciences, Vol. 9, No. 6Brain Ventricular Enlargement in Embryonic, Neonatal and Adulthood Stages of Rats Born from Diabetic MothersJournal of Biological Sciences, Vol. 8, No. 5Tight junctions contain oligomeric protein assembly critical for maintaining blood–brain barrier integrity in vivo11 October 2007 | Journal of Neurochemistry, Vol. 0, No. 0Blood–Brain Barrier Pathology in Alzheimer's and Parkinson's Disease: Implications for Drug Therapy22 June 2017 | Cell Transplantation, Vol. 16, No. 3 More from this issue > Volume 291Issue 6December 2006Pages H2595-H2596 Copyright & PermissionsCopyright © 2006 by the American Physiological Societyhttps://doi.org/10.1152/ajpheart.00751.2006PubMed16877556History Published online 1 December 2006 Published in print 1 December 2006 Metrics Downloaded 271 times See more details Referenced in 1 Wikipedia pages 23 readers on Mendeley 10 CITATIONS 10 Total citations 1 Recent citation 1.66 Field Citation Ratio 0.15 Relative Citation Ratio publications10supporting0mentioning7contrasting0Smart Citations10070Citing PublicationsSupportingMentioningContrastingView CitationsSee how this article has been cited at scite.aiscite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made. 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