Insulin-signaling abnormalities in drug-naive first-episode schizophrenia: Transduction protein analyses in extracellular vesicles of putative neuronal origin

Kapogiannis, Dimitrios; Dobrowolny, Henrik; Tran, Joyce; Mustapic, Maja; Frodl, Thomas; Meyer-Lotz, Gabriela; Schiltz, Kolja; Schanze, Denny; Rietschel, Marcella; Bernstein, Hans-Gert und Steiner, Johann (2019): Insulin-signaling abnormalities in drug-naive first-episode schizophrenia: Transduction protein analyses in extracellular vesicles of putative neuronal origin. In: European Psychiatry, Bd. 62: S. 124-129

Abstract

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0924-9338
• Sprache: Englisch