Dimitrios Kapogiannis1, Henrik Dobrowolny2, Joyce Tran3, Maja Mustapic3, Thomas Frodl4, Gabriela Meyer-Lotz2, Kolja Schiltz5, Denny Schanze6, Marcella Rietschel7, Hans-Gert Bernstein2, Johann Steiner8. 1. Laboratory of Neurosciences, National Institute on Aging / National Institutes of Health (NIA/NIH), Baltimore, MD, USA. Electronic address: kapogiannisd@mail.nih.gov. 2. Department of Psychiatry and Psychotherapy, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany; Laboratory of Translational Psychiatry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany. 3. Laboratory of Neurosciences, National Institute on Aging / National Institutes of Health (NIA/NIH), Baltimore, MD, USA. 4. Department of Psychiatry and Psychotherapy, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany; Center for Behavioral Brain Sciences (CBBS), Magdeburg, Germany; German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany. 5. Department of Psychiatry and Psychotherapy, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany; Department of Forensic Psychiatry, Ludwig-Maximilians-University Munich, Munich, Germany. 6. Institute for Human Genetics, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany. 7. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. 8. Department of Psychiatry and Psychotherapy, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany; Laboratory of Translational Psychiatry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany; Center for Behavioral Brain Sciences (CBBS), Magdeburg, Germany. Electronic address: johann.steiner@med.ovgu.de.
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-GSK3β, 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, GSK3β, 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), GSK3β (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.
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-GSK3β, pS2448-mTOR, pT389-p70S6K and respective total protein levels were determined in plasma nEVs from 48 DNFESpatients 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, GSK3β, 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), GSK3β (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.
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