Deletion of cd39/entpd1 results in hepatic insulin resistance.
Deletion of cd39/entpd1 results in hepatic insulin resistance.
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DOI：
10.2337/db07-1265
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发表时间：
2008-09
期刊：
影响因子：
7.7
通讯作者：
Robson, Simon C.
中科院分区：
文献类型：
--
作者：
Enjyoji, Keiichi;Kotani, Ko;Thukral, Chandrashekar;Blumel, Benjamin;Sun, Xiaofeng;Wu, Yan;Imai, Masato;Friedman, David;Csizmadia, Eva;Bleibel, Wissam;Kahn, Barbara B.;Robson, Simon C.
细胞外核苷酸是炎症反应的重要介质，也可能影响代谢稳态。2型嘌呤能（P2）受体结合细胞外核苷酸，并由负责葡萄糖稳态的主要外周组织表达。CD 39/ENTPD 1是主要的血管和免疫细胞胞外酶，其水解胞外核苷酸以调节嘌呤能信号传导。研究设计和方法-我们研究了Cd 39/Entpd 1基因缺失小鼠，以确定细胞外核苷酸浓度的任何相关变化是否影响葡萄糖稳态。CRTTS-Cd 39/Entpd 1-null小鼠葡萄糖耐量受损，胰岛素敏感性降低，血浆胰岛素水平显著升高。高胰岛素-正葡萄糖钳夹研究表明肝脏葡萄糖代谢改变。通过向野生型小鼠注射外源性ATP或胞外ATP酶抑制剂ARL-67156，以及通过体外将肝细胞暴露于胞外核苷酸，在体内模拟这些作用。在Cd 39/Entpd 1-null小鼠中观察到血清白细胞介素-1 β、白细胞介素-6、干扰素-γ和肿瘤坏死因子-α水平升高，与促炎表型一致。在体内注射ATP后，Cd 39/Entpd 1小鼠的胰岛素敏感性受损伴随着肝脏c-Jun NH 2-末端激酶/应激活化蛋白激酶的活化增加。这导致胰岛素受体底物-2的酪氨酸磷酸化减少，胰岛素信号传导受阻。结论-CD 39/Entpd 1是细胞外核苷酸信号转导的调节剂，也影响代谢。Cd 39/Entpd 1的缺失直接和间接影响胰岛素调节和肝脏葡萄糖代谢。细胞外核苷酸作为“代谢因子”，表明炎症和相关代谢紊乱之间的进一步联系。
OBJECTIVE—Extracellular nucleotides are important mediators of inflammatory responses and could also impact metabolic homeostasis. Type 2 purinergic (P2) receptors bind extracellular nucleotides and are expressed by major peripheral tissues responsible for glucose homeostasis. CD39/ENTPD1 is the dominant vascular and immune cell ectoenzyme that hydrolyzes extracellular nucleotides to regulate purinergic signaling. RESEARCH DESIGN AND METHODS—We have studied Cd39/Entpd1-null mice to determine whether any associated changes in extracellular nucleotide concentrations influence glucose homeostasis. RESULTS—Cd39/Entpd1-null mice have impaired glucose tolerance and decreased insulin sensitivity with significantly higher plasma insulin levels. Hyperinsulinemic-euglycemic clamp studies indicate altered hepatic glucose metabolism. These effects are mimicked in vivo by injection into wild-type mice of either exogenous ATP or an ecto-ATPase inhibitor, ARL-67156, and by exposure of hepatocytes to extracellular nucleotides in vitro. Increased serum interleukin-1β, interleukin-6, interferon-γ, and tumor necrosis factor-α levels are observed in Cd39/Entpd1-null mice in keeping with a proinflammatory phenotype. Impaired insulin sensitivity is accompanied by increased activation of hepatic c-Jun NH2-terminal kinase/stress-activated protein kinase in Cd39/Entpd1 mice after injection of ATP in vivo. This results in decreased tyrosine phosphorylation of insulin receptor substrate-2 with impeded insulin signaling. CONCLUSIONS—CD39/Entpd1 is a modulator of extracellular nucleotide signaling and also influences metabolism. Deletion of Cd39/Entpd1 both directly and indirectly impacts insulin regulation and hepatic glucose metabolism. Extracellular nucleotides serve as “metabolokines,” indicating further links between inflammation and associated metabolic derangements.
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影响因子：
4.1
作者：
KOIKE, M;KASHIWAGURA, T;TAKEGUCHI, N
通讯作者：
TAKEGUCHI, N
影响因子：
15.9
作者：
Kotani, K;Peroni, OD;Kahn, BB
通讯作者：
Kahn, BB
影响因子：
16
作者：
Michael, MD;Kulkarni, RN;Kahn, CR
通讯作者：
Kahn, CR
影响因子：
13.5
作者：
Dranoff, JA;Kruglov, EA;Sévigny, J
通讯作者：
Sévigny, J
影响因子：
7.7
作者：
Friedman, David J.;Rennke, Helmut G.;Robson, Simon C.
通讯作者：
Robson, Simon C.