Inhibition of MEK1 signaling pathway in the liver ameliorates insulin resistance
Open accessAbstract
Although mitogen-activated protein kinase kinase (MEK) is a key signaling molecule and a negative regulator of insulin action, it is still uncertain whether MEK can be a therapeutic target for amelioration of insulin resistance (IR) in type 2 diabetes (T2D) in vivo. To clarify whether MEK inhibition improves T2D, we examined the effect of continuous MEK inhibition with two structurally different MEK inhibitors, RO5126766 and RO4987655, in mouse models of T2D. RO5126766 and RO4987655 were administered via dietary admixture. Both compounds decreased blood glucose and improved glucose tolerance in doses sufficient to sustain inhibition of extracellular signal-regulated kinase (ERK)1/2 phosphorylation downstream of MEK in insulin-responsive tissues in db/db mice. A hyperinsulinemic-euglycemic clamp test showed increased glucose infusion rate (GIR) in db/db mice treated with these compounds, and about 60% of the increase was attributed to the inhibition of endogenous glucose production, suggesting that the liver is responsible for the improvement of IR. By means of adenovirus-mediated Mek1 shRNA expression, we confirmed that blood glucose levels are reduced by suppression of MEK1 expression in the liver of db/db mice. Taken together, these results suggested that the MEK signaling pathway could be a novel therapeutic target for novel antidiabetic agents.
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Phospho-ERK was inhibited in liver tissue of oleacein-treated mice.
“Also, phospho-ERK, a serine/threonine kinase downstream effector of the mitogen-activated protein kinase (MAPK) cascade, was inhibited in liver tissue of treated mice, thereby suggesting greater responsiveness to insulin and less severity of IR, in situations of chronic high-fat hypernutrition [88].”
From Mediterranean diet nutrients to turn the tide against insulin resistance and related diseases (2020) · cites this paper as [88]
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Mediterranean diet nutrients to turn the tide against insulin resistance and related diseases
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“Also, phospho-ERK, a serine/threonine kinase downstream effector of the mitogen-activated protein kinase (MAPK) cascade, was inhibited in liver tissue of treated mice, thereby suggesting greater responsiveness to insulin and less severity of IR, in situations of chronic high-fat hypernutrition [88].”
BackgroundLombardo, G. E., Lepore, S. M., Morittu, V. M., Arcidiacono, B., Colica, C., Procopio, A., Maggisano, V., Bulotta, S., Costa, N., Mignogna, C., et al. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00116 · Cited by 55 · see citing works
- Authors
- Ueyama, A., Ban, N., Fukazawa, M., Hirayama, T., Takeda, M., Yata, T., Muramatsu, H., Hoshino, M., Yamamoto, M., Matsuo, M., Kawashima, Y., Iwase, T., Kitazawa, T., Kushima, Y., Yamada, Y., & Kawabe, Y.
- Affiliations
- Akita University (JP)
- Chugai Pharmaceutical Co., Ltd. (Japan) (JP)
- Chugai Research Institute For Medical Science, Inc. (Japan) (JP)
- Corresponding author
- Ueyama, Atsunori
- Venue
- Journal of Diabetes Research
- Publisher
- Hindawi Limited
- Published
- 2016
- Volume
- 2016
- Pages
- 1-13
- ISSN
- 2314-6745 (ISSN-L)
- 2314-6753
- PMC
- PMC4709921
- OpenAlex
- W2266857411
- Cited by
- 7
- References
- 40
- Citations by year
- 2025: 2 · 2021: 1 · 2020: 2 · 2019: 1 · 2018: 1
- FWCI
- 0.14
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Diabetes Research (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Chugai Pharmaceutical
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
- Keywords
- MEK1 inhibition, insulin resistance, type 2 diabetes, liver, ERK1/2 phosphorylation, MEK inhibitors, db/db mice, glucose production, glucose tolerance
- MeSH terms
- Adenoviridae, Animals, Benzamides, Blood Glucose, Body Weight, Coumarins, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Diet, Disease Models, Animal, Glucose, Glucose Tolerance Test, Hypoglycemic Agents, Insulin, Insulin Resistance, Liver, Male, Oxazines, Phosphorylation, Glucose Clamp Technique, Signal Transduction, RNA, Small Interfering, MAP Kinase Kinase 1, Mice
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