Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity
Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity
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DOI：
10.1074/jbc.m311113200
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发表时间：
2004-03-26
影响因子：
4.8
通讯作者：
Scherer, PE
中科院分区：
文献类型：
--
作者：
Pajvani, UB;Hawkins, M;Scherer, PE
脂联素是一种脂肪细胞特异性分泌蛋白，在血清中以相对低分子量（LMW）的六聚体和较大的高分子量（HMW）的多聚体结构循环。该蛋白的血清水平与全身胰岛素敏感性相关。全长蛋白质通过改善胰岛素敏感性影响肝脏再生，脂联素的蛋白水解片段刺激肌肉中的β氧化。在这里，我们表明，这两种低聚物形式（高分子量与低分子量）之间的比例，而不是绝对量，是决定胰岛素敏感性的关键。我们定义了一个新的指数，SA，可以计算为HMW/（HMW + LMW）的比值。db/db小鼠尽管总脂联素水平相似，但与野生型同窝小鼠相比，SA值降低，II型糖尿病患者与胰岛素敏感个体相比也是如此。此外，SA改善与过氧化物酶体增殖物激活受体-γ激动剂治疗（噻唑烷二酮; TZD）在小鼠和人类。我们证明，在一些2型糖尿病队列SA的变化作为TZD治疗期间获得的胰岛素敏感性改善的定量指标，而总血清脂联素水平的变化在个体水平上并不相关。S-A（Δ S（A））的急性改变与肝脏胰岛素敏感性的改善密切相关，作为TZD治疗后肌肉胰岛素敏感性改善的指标相关性较低，进一步强调了既往钳夹研究的结论，即肝脏是全长蛋白的主要作用部位。这些观察结果表明，高分子量脂联素复合物是这种蛋白质的活性形式，我们在体内直接证明了其以剂量依赖性方式抑制血清葡萄糖水平的能力。
Adiponectin is an adipocyte-specific secretory protein that circulates in serum as a hexamer of relatively low molecular weight (LMW) and a larger multimeric structure of high molecular weight (HMW). Serum levels of the protein correlate with systemic insulin sensitivity. The full-length protein affects hepatic gluconeogenesis through improved insulin sensitivity, and a proteolytic fragment of adiponectin stimulates beta oxidation in muscle. Here, we show that the ratio, and not the absolute amounts, between these two oligomeric forms ( HMW to LMW) is critical in determining insulin sensitivity. We define a new index, SA, that can be calculated as the ratio of HMW/(HMW + LMW). db/db mice, despite similar total adiponectin levels, display decreased SA values compared with wild type littermates, as do type II diabetic patients compared with insulin-sensitive individuals. Furthermore, SA improves with peroxisome proliferator-activated receptor-gamma agonist treatment ( thiazolidinedione; TZD) in mice and humans. We demonstrate that changes in SA in a number of type 2 diabetic cohorts serve as a quantitative indicator of improvements in insulin sensitivity obtained during TZD treatment, whereas changes in total serum adiponectin levels do not correlate well at the individual level. Acute alterations in S-A (DeltaS(A)) are strongly correlated with improvements in hepatic insulin sensitivity and are less relevant as an indicator of improved muscle insulin sensitivity in response to TZD treatment, further underscoring the conclusions from previous clamp studies that suggested that the liver is the primary site of action for the full-length protein. These observations suggest that the HMW adiponectin complex is the active form of this protein, which we directly demonstrate in vivo by its ability to depress serum glucose levels in a dose-dependent manner.