Hyaluronan accumulates with high-fat feeding and contributes to insulin resistance.
Hyaluronan accumulates with high-fat feeding and contributes to insulin resistance.
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DOI：
10.2337/db12-1502
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发表时间：
2013-06
期刊：
影响因子：
7.7
通讯作者：
Wasserman DH
中科院分区：
文献类型：
--
作者：
Kang L;Lantier L;Kennedy A;Bonner JS;Mayes WH;Bracy DP;Bookbinder LH;Hasty AH;Thompson CB;Wasserman DH
特定细胞外基质（ECM）成分沉积增加是胰岛素抵抗骨骼肌的特征。透明质酸（HA）是ECM的主要成分。对以下假设进行了测试：1）胰岛素抵抗骨骼肌ECM中HA含量增加，2）长效聚乙二醇化人重组PH 20透明质酸酶（PEGPH 20）逆转高脂（HF）饮食诱导的肌肉胰岛素抵抗导致的肌肉ECM中HA减少。我们发现，HF饮食诱导的肥胖（DIO）小鼠的肌肉HA增加，PEGPH 20的治疗，剂量依赖性地减少HA在肌肉ECM中，减少脂肪量，脂肪细胞大小，肝脏和肌肉胰岛素抵抗在DIO小鼠在10 mg/kg。降低肌肉胰岛素抵抗与增加胰岛素信号传导、肌肉血管化和心脏输出到肌肉的百分比相关，而不是与肌肉本身的胰岛素敏感性相关。剂量反应研究表明，PEGPH 20剂量依赖性地增加DIO小鼠的胰岛素敏感性，最低有效剂量为0.01 mg/kg。0.1和1 mg/kg剂量的PEGPH 20将肌肉HA降低至在普通饲料喂养的小鼠中观察到的水平，减少脂肪量，并增加肌肉葡萄糖摄取。这些发现表明ECM HA是治疗胰岛素抵抗的靶点。
Increased deposition of specific extracellular matrix (ECM) components is a characteristic of insulin-resistant skeletal muscle. Hyaluronan (HA) is a major constituent of the ECM. The hypotheses that 1) HA content is increased in the ECM of insulin-resistant skeletal muscle and 2) reduction of HA in the muscle ECM by long-acting pegylated human recombinant PH20 hyaluronidase (PEGPH20) reverses high-fat (HF) diet–induced muscle insulin resistance were tested. We show that muscle HA was increased in HF diet–induced obese (DIO) mice and that treatment of PEGPH20, which dose-dependently reduced HA in muscle ECM, decreased fat mass, adipocyte size, and hepatic and muscle insulin resistance in DIO mice at 10 mg/kg. Reduced muscle insulin resistance was associated with increased insulin signaling, muscle vascularization, and percent cardiac output to muscle rather than insulin sensitization of muscle per se. Dose-response studies revealed that PEGPH20 dose-dependently increased insulin sensitivity in DIO mice with a minimally effective dose of 0.01 mg/kg. PEGPH20 at doses of 0.1 and 1 mg/kg reduced muscle HA to levels seen in chow-fed mice, decreased fat mass, and increased muscle glucose uptake. These findings suggest that ECM HA is a target for treatment of insulin resistance.
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在四种常用的近交小鼠菌株中的体内葡萄糖代谢。
影响因子：
7.7
作者：
Berglund, Eric D.;Li, Candice Y.;Poffenberger, Greg;Ayala, Julio E.;Fueger, Patrick T.;Willis, Shannon E.;Jewell, Marybeth M.;Powers, Alvin C.;Wasserman, David H.
通讯作者：
Wasserman, David H.
影响因子：
33.6
作者：
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通讯作者：
Noble PW
影响因子：
5.8
作者：
Frederiksen, L.;Nielsen, T. L.;Andersen, M.
通讯作者：
Andersen, M.
影响因子：
24.5
作者：
Jacobetz MA;Chan DS;Neesse A;Bapiro TE;Cook N;Frese KK;Feig C;Nakagawa T;Caldwell ME;Zecchini HI;Lolkema MP;Jiang P;Kultti A;Thompson CB;Maneval DC;Jodrell DI;Frost GI;Shepard HM;Skepper JN;Tuveson DA
通讯作者：
Tuveson DA
影响因子：
10.8
作者：
Bookbinder, L. H.;Hofer, A.;Frost, G. I.
通讯作者：
Frost, G. I.