Inhibition of MEK1 Signaling Pathway in the Liver Ameliorates Insulin Resistance
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...
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| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2016-01-01
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| Series: | Journal of Diabetes Research |
| Online Access: | http://dx.doi.org/10.1155/2016/8264830 |
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| author | Atsunori Ueyama Nobuhiro Ban Masanori Fukazawa Tohru Hirayama Minako Takeda Tatsuo Yata Hiroyasu Muramatsu Masaki Hoshino Marii Yamamoto Masao Matsuo Yuka Kawashima Tatsuhiko Iwase Takehisa Kitazawa Youichi Kushima Yuichiro Yamada Yoshiki Kawabe |
| author_facet | Atsunori Ueyama Nobuhiro Ban Masanori Fukazawa Tohru Hirayama Minako Takeda Tatsuo Yata Hiroyasu Muramatsu Masaki Hoshino Marii Yamamoto Masao Matsuo Yuka Kawashima Tatsuhiko Iwase Takehisa Kitazawa Youichi Kushima Yuichiro Yamada Yoshiki Kawabe |
| author_sort | Atsunori Ueyama |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d980abab82b34983b7c7c2bfc19dda0e |
| institution | Kabale University |
| issn | 2314-6745 2314-6753 |
| language | English |
| publishDate | 2016-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Diabetes Research |
| spelling | doaj-art-d980abab82b34983b7c7c2bfc19dda0e2025-02-03T01:27:49ZengWileyJournal of Diabetes Research2314-67452314-67532016-01-01201610.1155/2016/82648308264830Inhibition of MEK1 Signaling Pathway in the Liver Ameliorates Insulin ResistanceAtsunori Ueyama0Nobuhiro Ban1Masanori Fukazawa2Tohru Hirayama3Minako Takeda4Tatsuo Yata5Hiroyasu Muramatsu6Masaki Hoshino7Marii Yamamoto8Masao Matsuo9Yuka Kawashima10Tatsuhiko Iwase11Takehisa Kitazawa12Youichi Kushima13Yuichiro Yamada14Yoshiki Kawabe15Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, JapanResearch Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, JapanResearch Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, JapanResearch Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, JapanResearch Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, JapanChugai Research Institute for Medical Science, 1-135 Komakado, Gotemba, Shizuoka 412-8513, JapanResearch Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, JapanResearch Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, JapanResearch Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, JapanResearch Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, JapanResearch Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, JapanProject Planning & Coordination Department, Chugai Pharmaceutical Co., Ltd., 2-1-1 Nihonbashi, Muromachi, Chuo-ku, Tokyo 103-8324, JapanResearch Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, JapanResearch Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, JapanDepartment of Endocrinology, Diabetes and Geriatric Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita, Akita 010-8543, JapanResearch Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, JapanAlthough 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.http://dx.doi.org/10.1155/2016/8264830 |
| spellingShingle | Atsunori Ueyama Nobuhiro Ban Masanori Fukazawa Tohru Hirayama Minako Takeda Tatsuo Yata Hiroyasu Muramatsu Masaki Hoshino Marii Yamamoto Masao Matsuo Yuka Kawashima Tatsuhiko Iwase Takehisa Kitazawa Youichi Kushima Yuichiro Yamada Yoshiki Kawabe Inhibition of MEK1 Signaling Pathway in the Liver Ameliorates Insulin Resistance Journal of Diabetes Research |
| title | Inhibition of MEK1 Signaling Pathway in the Liver Ameliorates Insulin Resistance |
| title_full | Inhibition of MEK1 Signaling Pathway in the Liver Ameliorates Insulin Resistance |
| title_fullStr | Inhibition of MEK1 Signaling Pathway in the Liver Ameliorates Insulin Resistance |
| title_full_unstemmed | Inhibition of MEK1 Signaling Pathway in the Liver Ameliorates Insulin Resistance |
| title_short | Inhibition of MEK1 Signaling Pathway in the Liver Ameliorates Insulin Resistance |
| title_sort | inhibition of mek1 signaling pathway in the liver ameliorates insulin resistance |
| url | http://dx.doi.org/10.1155/2016/8264830 |
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