Tschritter Otto, Preissl Hubert, Hennige Anita M, Stumvoll Michael, Porubska Katarina, Frost Rebekka, Marx Hannah, Klösel Benjamin, Lutzenberger Werner, Birbaumer Niels, Häring Hans-Ulrich, Fritsche Andreas
Medizinische Klinik der Universität, University of Tübingen, 72076 Tübingen, Germany.
Proc Natl Acad Sci U S A. 2006 Aug 8;103(32):12103-8. doi: 10.1073/pnas.0604404103. Epub 2006 Jul 28.
Animal studies have shown that the brain is an insulin-responsive organ and that central nervous insulin resistance induces obesity and disturbances in glucose metabolism. In humans, insulin effects in the brain are poorly characterized. We used a magnetoencephalography approach during a two-step hyperinsulinemic euglycemic clamp to (i) assess cerebrocortical insulin effects in humans, (ii) compare these effects between 10 lean and 15 obese subjects, and (iii) test whether the insulin receptor substrate (IRS)-1 Gly972Arg polymorphism in the insulin-signaling cascade modifies these effects. Both spontaneous and stimulated (mismatch negativity) cortical activity were assessed. In lean humans, stimulated cortical activity (P = 0.046) and the beta and theta band of spontaneous cortical activity (P = 0.01 and 0.04) increased with insulin infusion relative to saline. In obese humans, these effects were suppressed. Moreover, the insulin effect on spontaneous cortical activity correlated negatively with body mass index and percent body fat (all r < -0.4; all P < 0.05) and positively with insulin sensitivity of glucose disposal (theta band, r = 0.48, P = 0.017). Furthermore, insulin increased spontaneous cortical activity (beta band) in carriers of wild-type IRS-1, whereas, in carriers of the 972Arg allele, this insulin effect was absent (P = 0.01). We conclude that, in lean humans, insulin modulates cerebrocortical activity, and that these effects are diminished in obese individuals. Moreover, cerebrocortical insulin resistance is found in individuals with the Gly972Arg polymorphism in IRS-1, which is considered a type 2 diabetes risk gene.
动物研究表明，大脑是一个对胰岛素有反应的器官，中枢神经胰岛素抵抗会导致肥胖和葡萄糖代谢紊乱。在人类中，胰岛素在大脑中的作用特征尚不明确。我们在两步高胰岛素正葡萄糖钳夹试验期间采用脑磁图方法，以（i）评估人类大脑皮质胰岛素的作用，（ii）比较10名瘦人和15名肥胖受试者之间的这些作用，以及（iii）测试胰岛素信号级联反应中的胰岛素受体底物（IRS）-1 Gly972Arg多态性是否会改变这些作用。评估了自发和刺激（失配负波）皮质活动。在瘦人中，与输注生理盐水相比，输注胰岛素后刺激皮质活动（P = 0.046）以及自发皮质活动的β和θ波段（P = 0.01和0.04）增加。在肥胖人中，这些作用受到抑制。此外，胰岛素对自发皮质活动的作用与体重指数和体脂百分比呈负相关（所有r < -0.4；所有P < 0.05），与葡萄糖处置的胰岛素敏感性呈正相关（θ波段，r = 0.48，P = 0.017）。此外，胰岛素增加了野生型IRS-1携带者的自发皮质活动（β波段），而在972Arg等位基因携带者中，这种胰岛素作用不存在（P = 0.01）。我们得出结论，在瘦人中，胰岛素调节大脑皮质活动，而在肥胖个体中这些作用减弱。此外，在IRS-1中具有Gly972Arg多态性的个体中发现了大脑皮质胰岛素抵抗，该多态性被认为是2型糖尿病风险基因。
