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      Regulation of Tight-Junction Integrity by Insulin in an In Vitro Model of Human Blood-Brain Barrier.

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          Abstract

          Although insulin receptor is expressed at the human blood-brain barrier (BBB), the physiological and pathologic roles of insulin signaling in biologic responses at the BBB remain unclear. Here, we investigate insulin signaling at the human BBB using human cerebral microvascular endothelial cell line (hCMEC/D3) as a well-established in vitro model. Western blot analysis showed that insulin induced phosphorylation of extracellular signal-regulated kinase and insulin receptor substrate-1 in hCMEC/D3 cells. Short-term insulin stimulation increased cell proliferation via the canonical phosphoinositide-3 kinase/protein kinase B and mitogen-activated protein kinase signaling pathways, suggesting that insulin signaling is involved in the regulation of biologic responses in the human BBB. We also found that insulin rapidly increased tight-junction integrity of hCMEC/D3 cells via the phosphoinositide-3 kinase/protein kinase B/glycogen synthase kinase-3 β signaling pathway. Inhibition of insulin/insulin-like growth factor-1 receptor kinase by AG1024 blocked the increase of tight-junction integrity. In addition, high-insulin/high-glucose treatment (as a model of hyperglycemia and hyperinsulinemia) synergistically reduced the tight-junction integrity in hCMEC/D3 cells, although either condition alone had little or no effect. Our findings suggest that, in addition to the established role of interactions of astrocytes and pericytes with brain capillary endothelial cells, insulin signaling from the blood side of the BBB contributes to maintenance of homeostasis by regulating cell proliferation and tight-junction integrity.

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          Author and article information

          Journal
          J Pharm Sci
          Journal of pharmaceutical sciences
          Elsevier BV
          1520-6017
          0022-3549
          Sep 2017
          : 106
          : 9
          Affiliations
          [1 ] Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; Department of Pharmaceutical Microbiology, School of Pharmacy, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; Department of Pharmaceutical Microbiology, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; AMED-CREST, Japan Agency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda, Tokyo 100-0004, Japan.
          [2 ] Department of Pharmaceutical Microbiology, School of Pharmacy, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
          [3 ] Department of Pharmaceutical Microbiology, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
          [4 ] Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
          [5 ] Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; Department of Pharmaceutical Microbiology, School of Pharmacy, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; Department of Pharmaceutical Microbiology, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; AMED-CREST, Japan Agency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda, Tokyo 100-0004, Japan. Electronic address: sohtsuki@kumamoto-u.ac.jp.
          Article
          S0022-3549(17)30272-1
          10.1016/j.xphs.2017.04.036
          28456720

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