title: Inhibition of MEK1 Signaling Pathway in the Liver Ameliorates Insulin Resistance.
abstract: 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.
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan; Department of Endocrinology, Diabetes and Geriatric Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita, Akita 010-8543, Japan.
authors.forename: Atsunori
authors.initials: A
authors.lastname: Ueyama
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Ban
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Fukazawa
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Hirayama
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Minako
authors.initials: M
authors.lastname: Takeda
authors.affiliation: Chugai Research Institute for Medical Science, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Yata
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Muramatsu
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Hoshino
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Marii
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Matsuo
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kawashima
authors.affiliation: Project Planning & Coordination Department, Chugai Pharmaceutical Co., Ltd., 2-1-1 Nihonbashi, Muromachi, Chuo-ku, Tokyo 103-8324, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Iwase
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Takehisa
authors.initials: T
authors.lastname: Kitazawa
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Youichi
authors.initials: Y
authors.lastname: Kushima
authors.affiliation: Department of Endocrinology, Diabetes and Geriatric Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita, Akita 010-8543, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kawabe
mesh_terms: D000256:Adenoviridae; D000818:Animals; D001549:Benzamides / Q000627:therapeutic use; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D003374:Coumarins / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004032:Diet; D004195:Disease Models, Animal; D005947:Glucose / Q000627:therapeutic use; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008297:Male; D051379:Mice; D010078:Oxazines / Q000627:therapeutic use; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D001549:Benzamides; D001786:Blood Glucose; C559138:CH 4987655; D003374:Coumarins; D007004:Hypoglycemic Agents; D007328:Insulin; D010078:Oxazines; D034741:RNA, Small Interfering; C577924:RO5126766; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D005947:Glucose
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