Targeting the ERK signaling pathway as a potential treatment for insulin resistance and type 2 diabetes
Targeting the ERK signaling pathway as a potential treatment for insulin resistance and type 2 diabetes
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DOI：
10.1152/ajpendo.00445.2015
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发表时间：
2016-04-15
影响因子：
5.1
通讯作者：
Kohno, Michiaki
中科院分区：
文献类型：
--
作者：
Ozaki, Kei-ichi;Awazu, Midori;Kohno, Michiaki
细胞外信号调节激酶（ERK）参与了肥胖和2型糖尿病相关的胰岛素抵抗的发生。我们现在已经研究了MEK（ERK激酶）抑制剂（PD 184352和PD 0325901）对ERK通路的药理学靶向作用，用于治疗肥胖相关的胰岛素抵抗的潜力。因此，在作为脂肪细胞肥大模型的长期培养的3 T3-L1脂肪细胞中检查了PD 184352和PD 0325901对脂肪细胞因子表达和脂解活性的影响。瘦素受体缺陷（db/db）小鼠和高脂肪饮食喂养的KKAy小鼠（两者都是2型糖尿病模型）也用PD 184352口服治疗以检查其对糖尿病病症的影响。ERK活性在肥大的3 T3-L1脂肪细胞以及db/db小鼠和高脂饮食喂养的KKAy小鼠的脂肪组织中增加，并且这种增强的ERK信号传导与脂肪细胞因子表达的失调和脂解活性增加相关。通过MEK抑制剂特异性阻断肥大3 T3-L1脂肪细胞中的ERK通路，改善了脂肪细胞因子表达的失调，并抑制了增强的脂解活性。此外，重复口服PD 184352使糖尿病小鼠的高血糖症和高脂血症正常化，并改善胰岛素敏感性和葡萄糖耐量。这些结果表明，ERK通路在脂肪细胞中的持续激活与2型糖尿病的发病机制相关，并且用MEK抑制剂选择性阻断该通路作为治疗胰岛素抵抗和2型糖尿病的有希望的方法值得进一步研究。
Extracellular signal-regulated kinase (ERK) has been implicated in the development of insulin resistance associated with obesity and type 2 diabetes mellitus. We have now examined the potential of pharmacological targeting of the ERK pathway with MEK (ERK kinase) inhibitors (PD184352 and PD0325901) for the treatment of obesity-associated insulin resistance. The effects of PD184352 and PD0325901 on the expression of adipocytokines and lipolysis activity were thus examined in 3T3-L1 adipocytes maintained in long-term culture as a model of adipocyte hypertrophy. Leptin receptor-deficient (db/db) mice and high-fat diet-fed KKAy mice, both of which are models of type 2 diabetes, were also treated orally with PD184352 to examine its effects on the diabetic condition. ERK activity was increased in hypertrophic 3T3-L1 adipocytes as well as in adipose tissue of db/db mice and high-fat diet-fed KKAy mice, and this enhanced ERK signaling was associated with dysregulation of adipocytokine expression and increased lipolysis activity. Specific blockade of the ERK pathway in hypertrophic 3T3-L1 adipocytes by MEK inhibitors ameliorated the dysregulation of adipocytokine expression and suppressed the enhanced lipolysis activity. Furthermore, repeated oral administration of PD184352 normalized hyperglycemia and hyperlipidemia and improved insulin sensitivity and glucose tolerance in the diabetic mice. These results suggest that sustained activation of the ERK pathway in adipocytes is associated with the pathogenesis of type 2 diabetes and that selective blockade of this pathway with MEK inhibitors warrants further study as a promising approach to the treatment of insulin resistance and type 2 diabetes.