Impaired regulation of the TNF-alpha converting enzyme/tissue inhibitor of metalloproteinase 3 proteolytic system in skeletal muscle of obese type 2 diabetic patients: a new mechanism of insulin resistance in humans.
Impaired regulation of the TNF-alpha converting enzyme/tissue inhibitor of metalloproteinase 3 proteolytic system in skeletal muscle of obese type 2 diabetic patients: a new mechanism of insulin resistance in humans.
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DOI：
10.1007/s00125-009-1451-3
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发表时间：
2009-10
期刊：
影响因子：
8.2
通讯作者：
Folli, F.
中科院分区：
文献类型：
--
作者：
Monroy, A.;Kamath, S.;Chavez, A. O.;Centonze, V. E.;Veerasamy, M.;Barrentine, A.;Wewer, J. J.;Coletta, D. K.;Jenkinson, C.;Jhingan, R. M.;Smokler, D.;Reyna, S.;Musi, N.;Khokka, R.;Federici, M.;Tripathy, D.;DeFronzo, R. A.;Folli, F.
肥胖和2型糖尿病患者TNF-α水平升高。TNF-α转换酶（TACE）及其抑制剂组织金属蛋白酶3 （TIMP3）在2型糖尿病中的调节作用尚不清楚。我们研究了TACE/TIMP3的调节：(1)在瘦肉和肥胖的正常糖耐量（NGT）个体以及2型糖尿病患者中；(2) NGT患者输脂/生理盐水6小时后；(3)用棕榈酸盐孵育的精瘦NGT个体培养的人肌管。胰岛素敏感性通过血糖钳评估，TACE/TIMP3通过共聚焦显微镜、RT-PCR、western blotting和体外活性测定评估。评价循环TNF-α、TNF-α-受体1 （TNFR1）、TNF-α-受体2 （TNFR2）、IL-6受体（IL-6R）、血管细胞粘附分子（VCAM）和细胞间粘附分子（ICAM）水平。2型糖尿病骨骼肌TIMP3水平降低，TACE酶活性升高。2型糖尿病患者TACE表达升高，TACE、TNF-α、TNFR1、IL-6R水平升高，与胰岛素抵抗呈正相关。对NGT个体进行6小时脂质输注，胰岛素刺激的葡萄糖代谢降低25%，TACE升高，编码TIMP3的基因表达降低，IL-6R释放增加。棕榈酸盐诱导培养肌管中TIMP3显著降低，TACE/TIMP3比值升高。肥胖2型糖尿病患者骨骼肌和脂质诱导的胰岛素抵抗中TACE活性增加。我们认为TACE/TIMP3对TNF-α和IL-6R的膜蛋白水解的失调是肥胖2型糖尿病患者骨骼肌胰岛素抵抗的一个重要因素，其机制是一种新的自分泌/旁分泌机制。
TNF-α levels are increased in obesity and type 2 diabetes. The regulation of TNF-α converting enzyme (TACE) and its inhibitor, tissue inhibitor of metalloproteinase 3 (TIMP3), in human type 2 diabetes is unknown. We examined TACE/TIMP3 regulation: (1) in lean and obese normal glucose tolerant (NGT) individuals and in type 2 diabetes patients; (2) following 6 h of lipid/saline infusion in NGT individuals; and (3) in cultured human myotubes from lean NGT individuals incubated with palmitate. Insulin sensitivity was assessed by a euglycaemic clamp and TACE/TIMP3 was evaluated by confocal microscopy, RT-PCR, western blotting and an in vitro activity assay. Circulating TNF-α, TNF-α-receptor 1 (TNFR1), TNF-α-receptor 2 (TNFR2), IL-6 receptor (IL-6R), vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) levels were evaluated. TIMP3 levels were reduced and TACE enzymatic activity was increased in type 2 diabetes skeletal muscle. TACE expression, and TACE, TNF-α, TNFR1 and IL-6R levels were increased in type 2 diabetes, and positively correlated with insulin resistance. A 6 h lipid infusion into NGT individuals decreased insulin-stimulated glucose metabolism by 25% with increased TACE, decreased expression of the gene encoding TIMP3 and increased IL-6R release. Palmitate induced a dramatic reduction of TIMP3 and increased the TACE/TIMP3 ratio in cultured myotubes. TACE activity was increased in skeletal muscle of obese type 2 diabetes patients and in lipid-induced insulin resistance. We propose that dysregulation of membrane proteolysis by TACE/TIMP3 of TNF-α and IL-6R is an important factor for the development of skeletal muscle insulin resistance in obese type 2 diabetes patients by a novel autocrine/paracrine mechanism.
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DOI：
10.1152/ajpendo.00471.2005
发表时间：
2006-07-01
影响因子：
5.1
作者：
Krogh-Madsen, Rikke;Plomgaard, Peter;Pedersen, Bente K.
通讯作者：
Pedersen, Bente K.
影响因子：
15.9
作者：
FOLLI, F;SAAD, MJA;KAHN, CR
通讯作者：
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影响因子：
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DOI：
10.1152/ajpendo.1999.276.5.e849
发表时间：
1999-05-01
影响因子：
5.1
作者：
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Kirwan, JP
DOI：
10.1016/j.bbrc.2005.01.140
发表时间：
2005-04-01
影响因子：
3.1
作者：
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