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
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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