Small-molecule inhibitors of PKR improve glucose homeostasis in obese diabetic mice.
Small-molecule inhibitors of PKR improve glucose homeostasis in obese diabetic mice.
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DOI：
10.2337/db13-1019
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发表时间：
2014-02
期刊：
影响因子：
7.7
通讯作者：
Hotamisligil GS
中科院分区：
文献类型：
--
作者：
Nakamura T;Arduini A;Baccaro B;Furuhashi M;Hotamisligil GS
肥胖症和代谢性疾病呈簇状出现，通常具有胰岛素抵抗和2型糖尿病的高风险，并且构成了治疗选择有限的主要全球健康问题。先前的研究表明，双链RNA依赖性激酶PKR在营养/病原体传感界面中起着重要作用，并且作为肥胖症中慢性代谢炎症、胰岛素敏感性和葡萄糖稳态的关键调节剂。最近，病理性PKR激活也在肥胖人群中得到证实，加强了其作为潜在药物靶点的前景。在这里，我们研究使用两种结构不同的小分子PKR抑制剂在治疗胰岛素抵抗和2型糖尿病的细胞和严重肥胖和胰岛素抵抗的小鼠模型。在体外和体内，PKR的抑制降低了应激诱导的Jun NH 2-末端激酶活化和胰岛素受体底物1丝氨酸磷酸化。此外，在建立肥胖和胰岛素抵抗后，用两种PKR抑制剂治疗减少了脂肪组织炎症，改善了胰岛素敏感性，并改善了小鼠的葡萄糖耐受不良。我们的研究结果表明，以PKR为靶点的胰岛素抵抗和2型糖尿病可能是一种有效的治疗策略。
Obesity and metabolic diseases appear as clusters, often featuring high risk for insulin resistance and type 2 diabetes, and constitute a major global health problem with limited treatment options. Previous studies have shown that double-stranded RNA–dependent kinase, PKR, plays an important role in the nutrient/pathogen-sensing interface, and acts as a key modulator of chronic metabolic inflammation, insulin sensitivity, and glucose homeostasis in obesity. Recently, pathological PKR activation was also demonstrated in obese humans, strengthening its prospects as a potential drug target. Here, we investigate the use of two structurally distinct small-molecule inhibitors of PKR in the treatment of insulin resistance and type 2 diabetes in cells and in a mouse model of severe obesity and insulin resistance. Inhibition of PKR reduced stress-induced Jun NH2-terminal kinase activation and insulin receptor substrate 1 serine phosphorylation in vitro and in vivo. In addition, treatment with both PKR inhibitors reduced adipose tissue inflammation, improved insulin sensitivity, and improved glucose intolerance in mice after the establishment of obesity and insulin resistance. Our findings suggest that pharmacologically targeting PKR may be an effective therapeutic strategy for the treatment of insulin resistance and type 2 diabetes.
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DOI：
10.1016/s0006-291x(03)01318-4
发表时间：
2003-08-15
影响因子：
3.1
作者：
Jammi, NV;Whitby, LR;Beal, PA
通讯作者：
Beal, PA
影响因子：
82.9
作者：
Arkan, MC;Hevener, AL;Karin, M
通讯作者：
Karin, M
通过抑制DSRNA依赖性蛋白激酶，在恶病质鼠模型中肌肉萎缩的衰减。
影响因子：
8.8
作者：
Eley, H L;Russell, S T;Tisdale, M J
通讯作者：
Tisdale, M J
影响因子：
29
作者：
Baker RG;Hayden MS;Ghosh S
通讯作者：
Ghosh S
DOI：
10.1073/pnas.0707849104
发表时间：
2008-01-29
影响因子：
11.1
作者：
Wunderlich, F. Thomas;Luedde, Tom;Bruening, Jens C.
通讯作者：
Bruening, Jens C.