Insulin-signaling abnormalities in drug-naive first-episode schizophrenia: Transduction protein analyses in extracellular vesicles of putative neuronal origin
Insulin-signaling abnormalities in drug-naive first-episode schizophrenia: Transduction protein analyses in extracellular vesicles of putative neuronal origin
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DOI：
10.1016/j.eurpsy.2019.08.012
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发表时间：
2019-10-01
影响因子：
7.8
通讯作者：
Steiner, Johann
中科院分区：
文献类型：
--
作者：
Kapogiannis, Dimitrios;Dobrowolny, Henrik;Steiner, Johann
背景：代谢综合征和胰岛素敏感性受损可能是非典型抗精神病药物的副作用。然而，使用胰岛素抵抗的稳态模型评估(HOMA-IR)或口服葡萄糖耐量试验(OGTT)对外周胰岛素抵抗的研究表明，在药物初治的首发精神分裂症(DNFES)中已经存在糖代谢异常。我们假设DNFES中存在神经胰岛素信号的损伤。方法：为了深入了解体内的神经胰岛素信号，我们分析了外周血中富含神经元来源的细胞外小泡(NEVS)。结果：48例DNFES患者和健康对照组隔夜禁食后，血浆中磷酸化胰岛素信号转导丝氨酸-苏氨酸激酶pS312-IRS-1、Py-IRS-1、PS473-AKT、PS9-GSK3β、pS2448-mTOR、pT389-p70S6K及其相应的总蛋白水平均呈下降趋势(p=0.071；这种情况可能增强了IRS-1信号转导)。对下游丝氨酸苏氨酸激酶(AKT、GSK3β、mTOR、p70S6K)的探索性综合分析显示，与对照组相比，DNFES的磷酸化/总蛋白比率更低(p=0.013)，证实了通路激活的减少。HOC后试验特别显示mTOR的磷酸化比率降低(p=0.027)。P70S6K(p=0.029)、GSK3β(p=0.039)和趋势水平的AKT(p=0.061)的磷酸化比率与胰岛素血水平显示出诊断相关的统计交互作用。AKT的磷酸化比率与PANSS-G和PANSS-TOTAL评分呈负相关，其他比率呈现类似的趋势。结论：这些发现支持DNFES的神经元胰岛素抵抗假说，尽管样本量较小。DNFES中pS312-IRS-1降低的反直觉趋势可能是适应性反馈机制的结果。观察到的胰岛素信号变化可能具有临床意义，因为它们与较高的PANSS评分有关。(C)2019爱思唯尔·马森SAS。版权所有。
Background: Metabolic syndrome and impaired insulin sensitivity may occur as side effects of atypical antipsychotic drugs. However, studies of peripheral insulin resistance using the homeostatic model assessment of insulin resistance (HOMA-IR) or oral glucose tolerance tests (OGTT) suggest that abnormal glucose metabolism is already present in drug-naive first-episode schizophrenia (DNFES). We hypothesized impairments of neuronal insulin signaling in DNFES.Methods: To gain insight into neuronal insulin-signaling in vivo, we analyzed peripheral blood extracellular vesicles enriched for neuronal origin (nEVs). Phosphorylated insulin signal transduction serine-threonine kinases pS312-IRS-1, pY-IRS-1, pS473-AKT, pS9-GSK3 beta, pS2448-mTOR, pT389-p70S6K and respective total protein levels were determined in plasma nEVs from 48 DNFES patients and healthy matched controls after overnight fasting.Results: Upstream pS312-IRS-1 was reduced at trend level (p = 0.071; this condition may amplify IRS-1 signaling). Exploratory omnibus analysis of downstream serine-threonine kinases (AKT, GSK3 beta, mTOR, p70S6K) revealed lower phosphorylated/total protein ratios in DNFES vs. controls (p = 0.013), confirming decreased pathway activation. Post-hoc-tests indicated in particular a reduced phosphorylation ratio of mTOR (p = 0.027). Phosphorylation ratios of p70S6K (p = 0.029), GSK3 beta (p = 0.039), and at trend level AKT (p = 0.061), showed diagnosis-dependent statistical interactions with insulin blood levels. The phosphorylation ratio of AKT correlated inversely with PANSS-G and PANSS-total scores, and other ratios showed similar trends.Conclusion: These findings support the hypothesis of neuronal insulin resistance in DNFES, small sample sizes notwithstanding. The counterintuitive trend towards reduced pS312-IRS-1 in DNFES may result from adaptive feedback mechanisms. The observed changes in insulin signaling could be clinically meaningful as suggested by their association with higher PANSS scores. (C) 2019 Elsevier Masson SAS. All rights reserved.