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Journal of Diabetes Research
Volume 2016, Article ID 8264830, 13 pages
http://dx.doi.org/10.1155/2016/8264830
Research Article

Inhibition of MEK1 Signaling Pathway in the Liver Ameliorates Insulin Resistance

1Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
2Department of Endocrinology, Diabetes and Geriatric Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita, Akita 010-8543, Japan
3Chugai Research Institute for Medical Science, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
4Project Planning & Coordination Department, Chugai Pharmaceutical Co., Ltd., 2-1-1 Nihonbashi, Muromachi, Chuo-ku, Tokyo 103-8324, Japan

Received 16 June 2015; Revised 26 September 2015; Accepted 29 September 2015

Academic Editor: Raffaella Mastrocola

Copyright © 2016 Atsunori Ueyama et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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.