Graham Timothy E, Yang Qin, Blüher Matthias, Hammarstedt Ann, Ciaraldi Theodore P, Henry Robert R, Wason Christopher J, Oberbach Andreas, Jansson Per-Anders, Smith Ulf, Kahn Barbara B
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
N Engl J Med. 2006 Jun 15;354(24):2552-63. doi: 10.1056/NEJMoa054862.
Insulin resistance has a causal role in type 2 diabetes. Serum levels of retinol-binding protein 4 (RBP4), a protein secreted by adipocytes, are increased in insulin-resistant states. Experiments in mice suggest that elevated RBP4 levels cause insulin resistance. We sought to determine whether serum RBP4 levels correlate with insulin resistance and change after an intervention that improves insulin sensitivity. We also determined whether elevated serum RBP4 levels are associated with reduced expression of glucose transporter 4 (GLUT4) in adipocytes, an early pathological feature of insulin resistance.
We measured serum RBP4, insulin resistance, and components of the metabolic syndrome in three groups of subjects. Measurements were repeated after exercise training in one group. GLUT4 protein was measured in isolated adipocytes.
Serum RBP4 levels correlated with the magnitude of insulin resistance in subjects with obesity, impaired glucose tolerance, or type 2 diabetes and in nonobese, nondiabetic subjects with a strong family history of type 2 diabetes. Elevated serum RBP4 was associated with components of the metabolic syndrome, including increased body-mass index, waist-to-hip ratio, serum triglyceride levels, and systolic blood pressure and decreased high-density lipoprotein cholesterol levels. Exercise training was associated with a reduction in serum RBP4 levels only in subjects in whom insulin resistance improved. Adipocyte GLUT4 protein and serum RBP4 levels were inversely correlated.
RBP4 is an adipocyte-secreted molecule that is elevated in the serum before the development of frank diabetes and appears to identify insulin resistance and associated cardiovascular risk factors in subjects with varied clinical presentations. These findings provide a rationale for antidiabetic therapies aimed at lowering serum RBP4 levels.
胰岛素抵抗在2型糖尿病的发生中起因果作用。视黄醇结合蛋白4（RBP4）是一种由脂肪细胞分泌的蛋白质，其血清水平在胰岛素抵抗状态下会升高。小鼠实验表明，RBP4水平升高会导致胰岛素抵抗。我们试图确定血清RBP4水平是否与胰岛素抵抗相关，以及在改善胰岛素敏感性的干预后是否会发生变化。我们还确定血清RBP4水平升高是否与脂肪细胞中葡萄糖转运蛋白4（GLUT4）表达降低有关，这是胰岛素抵抗的早期病理特征。
我们测量了三组受试者的血清RBP4、胰岛素抵抗和代谢综合征的组成成分。其中一组在运动训练后重复进行测量。在分离的脂肪细胞中测量GLUT4蛋白。
血清RBP4水平与肥胖、糖耐量受损或2型糖尿病患者以及有2型糖尿病家族史的非肥胖、非糖尿病患者的胰岛素抵抗程度相关。血清RBP4升高与代谢综合征的组成成分有关，包括体重指数增加、腰臀比增加、血清甘油三酯水平升高、收缩压升高以及高密度脂蛋白胆固醇水平降低。运动训练仅在胰岛素抵抗得到改善的受试者中与血清RBP4水平降低有关。脂肪细胞GLUT4蛋白与血清RBP4水平呈负相关。
RBP4是一种由脂肪细胞分泌的分子，在显性糖尿病发生之前血清中水平就会升高，并且似乎可以识别不同临床表现受试者的胰岛素抵抗及相关心血管危险因素。这些发现为旨在降低血清RBP4水平的抗糖尿病治疗提供了理论依据。
