Inhibition of MEK1 Signaling Pathway in the Liver Ameliorates Insulin Resistance
Autor: | Masao Matsuo, Marii Yamamoto, Minako Takeda, Takehisa Kitazawa, Tohru Hirayama, Nobuhiro Ban, Tatsuhiko Iwase, Masanori Fukazawa, Hiroyasu Muramatsu, Yuka Kawashima, Tatsuo Yata, Yuichiro Yamada, Atsunori Ueyama, Youichi Kushima, Masaki Hoshino, Yoshiki Kawabe |
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Jazyk: | angličtina |
Rok vydání: | 2016 |
Předmět: |
Blood Glucose
Male MAPK/ERK pathway Endocrinology Diabetes and Metabolism medicine.medical_treatment MAP Kinase Kinase 1 lcsh:Diseases of the endocrine glands. Clinical endocrinology Mice 0302 clinical medicine Endocrinology Coumarins Insulin Phosphorylation RNA Small Interfering Glucose tolerance test medicine.diagnostic_test Kinase Glucose clamp technique Liver 030220 oncology & carcinogenesis Benzamides Signal transduction Signal Transduction Research Article medicine.medical_specialty Article Subject 030209 endocrinology & metabolism Biology Adenoviridae Diabetes Mellitus Experimental 03 medical and health sciences Insulin resistance Internal medicine Oxazines medicine Animals Hypoglycemic Agents Protein kinase A lcsh:RC648-665 Body Weight Glucose Tolerance Test medicine.disease Diet Disease Models Animal Glucose Diabetes Mellitus Type 2 Glucose Clamp Technique Insulin Resistance |
Zdroj: | Journal of Diabetes Research, Vol 2016 (2016) Journal of Diabetes Research |
ISSN: | 2314-6753 2314-6745 |
Popis: | 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 indb/dbmice. A hyperinsulinemic-euglycemic clamp test showed increased glucose infusion rate (GIR) indb/dbmice 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-mediatedMek1shRNA expression, we confirmed that blood glucose levels are reduced by suppression of MEK1 expression in the liver ofdb/dbmice. Taken together, these results suggested that the MEK signaling pathway could be a novel therapeutic target for novel antidiabetic agents. |
Databáze: | OpenAIRE |
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