Hyperinsulinemia Induces Insulin Resistance in Dorsal Root Ganglion Neurons
Hyperinsulinemia Induces Insulin Resistance in Dorsal Root Ganglion Neurons
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DOI：
10.1210/en.2011-0029
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发表时间：
2011-10-01
期刊：
影响因子：
4.8
通讯作者：
Feldman, Eva L.
中科院分区：
文献类型：
--
作者：
Kim, Bhumsoo;McLean, Lisa L.;Feldman, Eva L.
胰岛素抵抗(IR)是包括2型糖尿病在内的代谢综合征的主要特征。IR的研究主要集中在外周组织，如肌肉和肝脏。然而，对神经元中的IR知之甚少。在这项研究中，我们研究了神经元是否会因高胰岛素血症而发生IR。我们首先使用成年背根神经节神经元作为模型系统来研究胰岛素信号。急性胰岛素治疗导致时间和浓度依赖的信号级联激活，包括胰岛素受体、Akt、p70S6K和糖原合成酶激酶-3β的磷酸化。为模拟高胰岛素血症，细胞用20 nM胰岛素预处理24 h，然后用20 nM胰岛素刺激15分钟。慢性胰岛素治疗导致基础Akt磷酸化增加。更重要的是，慢性胰岛素治疗后的急性胰岛素刺激导致Akt、p70S6K和糖原合成酶-3β的钝化磷酸化。有趣的是，当用磷脂酰肌醇3-激酶途径抑制剂而不是MAPK途径抑制剂处理细胞时，慢性胰岛素治疗并不能阻断急性胰岛素治疗诱导的Akt磷酸化。BKS-db/db组小鼠背根神经节细胞中胰岛素诱导的Akt磷酸化程度低于对照组。这种影响与年龄有关。我们的结果表明，高胰岛素血症通过破坏Akt介导的途径而引起IR。我们还证明了高胰岛素血症增加了线粒体分裂蛋白Dynamin相关蛋白1。我们的结果为糖尿病神经病变的病因学提供了一种新的理论，即与胰岛素依赖组织类似，神经元发展IR，进而不能对胰岛素的神经营养特性做出反应，导致神经元损伤和神经病变的发展。(内分泌学152：3638-3647,2011)
Insulin resistance (IR) is the major feature of metabolic syndrome, including type 2 diabetes. IR studies are mainly focused on peripheral tissues, such as muscle and liver. There is, however, little knowledge about IR in neurons. In this study, we examined whether neurons develop IR in response to hyperinsulinemia. We first examined insulin signaling using adult dorsal root ganglion neurons as a model system. Acute insulin treatment resulted in time- and concentration-dependent activation of the signaling cascade, including phosphorylation of the insulin receptor, Akt, p70S6K, and glycogen synthase kinase-3 beta. To mimic hyperinsulinemia, cells were pretreated with 20 nM insulin for 24 h and then stimulated with 20 nM insulin for 15 min. Chronic insulin treatment resulted in increased basal Akt phosphorylation. More importantly, acute insulin stimulation after chronic insulin treatment resulted in blunted phosphorylation of Akt, p70S6K, and glycogen synthase kinase-3 beta. Interestingly, when the cells were treated with phosphatidylinositol 3-kinase pathway inhibitor, but not MAPK pathway inhibitor, chronic insulin treatment did not block acute insulin treatment-induced Akt phosphorylation. Insulin-induced Akt phosphorylation was lower in dorsal root ganglion neurons from BKS-db/db compared with control BKS-db+ mice. This effect was age dependent. Our results suggest that hyperinsulinemia cause IR by disrupting the Akt-mediated pathway. We also demonstrate that hyperinsulinemia increases the mitochondrial fission protein dynamin-related protein 1. Our results suggest a new theory for the etiology of diabetic neuropathy, i.e. that, similar to insulin dependent tissues, neurons develop IR and, in turn, cannot respond to the neurotrophic properties of insulin, resulting in neuronal injury and the development of neuropathy. (Endocrinology 152: 3638-3647, 2011)