Metformin induces up-regulation of blood–brain barrier functions by activating AMP-activated protein kinase in rat brain microvascular endothelial cells

Takata, Fuyuko; Dohgu, Shinya; Matsumoto, Junichi; Machida, Takashi; Kaneshima, Shuji; Matsuo, Mai; Sakaguchi, Shoji; Takeshige, Yuki; Yamauchi, Atsushi; Kataoka, Yasufumi

doi:10.1016/j.bbrc.2013.03.036

Cited by 71 publications

(56 citation statements)

References 15 publications

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“…In doing so, this work has revealed an elusive link between the stress-sensing components and the cell polarity pathways (see legend, Figure 10), and improved our understanding of molecular mechanisms of how epithelial monolayers are protected despite being constantly bombarded by energetic stressors by fortifying cell-cell junctions against stress-induced collapse. Because GIV serves as a junctional scaffold in both epithelial (Sasaki et al, 2015) and endothelial cells (Ichimiya et al, 2015), it is possible that the stress-triggered mechanisms outlined here also account for the protective role of AMPK on cell junctions observed consistently in a variety of tissue and cell types, in both epithelial (Garnett et al, 2013; Patkee et al, 2016; Seo-Mayer et al, 2011; Spruss et al, 2012) and endothelial (Castanares-Zapatero et al, 2013; Liu et al, 2014; Takata et al, 2013) cells, in the face of diverse chemical, bacterial and metabolic stressors. Given the overlapping substrate specificity of AMPK and its related kinases [reviewed in (Shackelford and Shaw, 2009)], it seems likely that AMPK-related family members such as the MARKs, may phosphorylate S245 on GIV under other conditions or in specific tissues.…”

Section: Resultsmentioning

confidence: 97%

“…Together, these discoveries established the first links between energetic stress, cell polarity and oncogenesis. Since then, multiple studies have reported the protective role of AMPK in maintaining cell-cell junctions across a variety of cell types in diverse tissue types [lung (Garnett et al, 2013), heart (Castanares-Zapatero et al, 2013), the blood-brain barrier (Liu et al, 2014; Takata et al, 2013), kidney (Seo-Mayer et al, 2011), intestine (Spruss et al, 2012)] while mounting a pathologic response to a variety of stressors, from bacterial invasion (Patkee et al, 2016) to ischemia (Seo-Mayer et al, 2011). …”

Section: Introductionmentioning

confidence: 99%

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AMP-activated protein kinase fortifies epithelial tight junctions during energetic stress via its effector GIV/Girdin

Aznar

Patel

Rohena

et al. 2016

eLife

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Loss of epithelial polarity impacts organ development and function; it is also oncogenic. AMPK, a key sensor of metabolic stress stabilizes cell-cell junctions and maintains epithelial polarity; its activation by Metformin protects the epithelial barrier against stress and suppresses tumorigenesis. How AMPK protects the epithelium remains unknown. Here, we identify GIV/Girdin as a novel effector of AMPK, whose phosphorylation at a single site is both necessary and sufficient for strengthening mammalian epithelial tight junctions and preserving cell polarity and barrier function in the face of energetic stress. Expression of an oncogenic mutant of GIV (cataloged in TCGA) that cannot be phosphorylated by AMPK increased anchorage-independent growth of tumor cells and helped these cells to evade the tumor-suppressive action of Metformin. This work defines a fundamental homeostatic mechanism by which the AMPK-GIV axis reinforces cell junctions against stress-induced collapse and also provides mechanistic insight into the tumor-suppressive action of Metformin.DOI: http://dx.doi.org/10.7554/eLife.20795.001

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Section: Resultsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

AMP-activated protein kinase fortifies epithelial tight junctions during energetic stress via its effector GIV/Girdin

Aznar

Patel

Rohena

et al. 2016

eLife

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“…It has been observed that metformin can cross blood brain barrier and provokes effect in the central nervous system (CNS) and in the metabolism. 20,21 Changes in CNS during early phases is one the keys to change CNS structure and function, which induces a permanent changes in organism The data represent the mean § SEM obtained from each experimental group. * V P < 0.05, compared to control, by Student's t-test.…”

Section: Discussionmentioning

confidence: 99%

Early treatment with metformin induces resistance against tumor growth in adult rats

Trombini

Franco

Miranda

et al. 2015

Cancer Biology & Therapy

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These authors contributed equally to this work.Keywords: adolescence, antidiabetic, early treatment, metformin, prevention, tumor growth inhibition, Walker 256 tumor Abbreviations: AUC, area under the curve; HOMA-IR, homeostasis model assessment of insulin resistance; HOMA-b, homeostasis model assessment of b-cell function; LBW, body weight loss; MHC-I, major histocompatibility complex class I; NAL, nasal anal length; VEGF, vascular endothelial growth factor.It is known that antidiabetic drug metformin, which is used worldwide, has anti-cancer effects and can be used to prevent cancer growth. We tested the hypothesis that tumor cell growth can be inhibited by early treatment with metformin. For this purpose, adult rats chronically treated with metformin in adolescence or in adulthood were inoculated with Walker 256 carcinoma cells. Adult rats that were treated with metformin during adolescence presented inhibition of tumor growth, and animals that were treated during adult life did not demonstrate any changes in tumor growth. Although we do not have data to disclose a molecular mechanism to the preventive metformin effect, we present, for the first time, results showing that cancer growth in adult life is dependent on early life intervention, thus supporting a new therapeutic prevention for cancer.

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“…Its concentration in the hypothalamus matched the level in plasma. Another study found that metformin induced upregulation of BBB actions via AMPK activation (Takata et al 2013). However, the BBB is well known for its highly selective permeability, which allows the passage of water, some gases and lipid-soluble molecules by passive diffusion, as well as the selective transport of molecules such as glucose and amino acids that are crucial to neural function.…”

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confidence: 99%

Metformin and thyroid disease

Meng

Chen

et al. 2017

Journal of Endocrinology

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An intriguing area of research in thyroidology is the recently discovered association of insulin resistance with thyroid functional and morphological abnormalities. Individuals with hyperinsulinemia have larger thyroid gland and a higher prevalence of thyroid nodules and cancer. Accordingly, patients treated with metformin have a smaller thyroid volume and a lower risk of incident goiter, thyroid nodule and cancer. Multiple studies in vitro and in vivo have demonstrated that metformin can inhibit the growth of thyroid cells and different types of thyroid cancer cells by affecting the insulin/IGF1 and mTOR pathways. Besides, metformin treatment was associated with a decrease in the levels of serum thyroid-stimulating hormone (TSH) in diabetic patients possibly by enhancing the effects of thyroid hormones in the pituitary and activating the adenosine monophosphate-activated protein kinase (AMPK). Based on this evidence, metformin appears to be a promising therapeutic tool in patients with thyroid disease. More clinical studies are necessary to evaluate the clinical significance of metformin for the treatment of thyroid diseases.

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Metformin induces up-regulation of blood–brain barrier functions by activating AMP-activated protein kinase in rat brain microvascular endothelial cells

Cited by 71 publications

References 15 publications

AMP-activated protein kinase fortifies epithelial tight junctions during energetic stress via its effector GIV/Girdin

AMP-activated protein kinase fortifies epithelial tight junctions during energetic stress via its effector GIV/Girdin

Early treatment with metformin induces resistance against tumor growth in adult rats

Metformin and thyroid disease

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