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

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?, 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?, 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? (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.

SUBMITTER: Kapogiannis D

PROVIDER: S-EPMC6941668 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

Kapogiannis Dimitrios D Dobrowolny Henrik H Tran Joyce J Mustapic Maja M Frodl Thomas T Meyer-Lotz Gabriela G Schiltz Kolja K Schanze Denny D Rietschel Marcella M Bernstein Hans-Gert HG Steiner Johann J

European psychiatry : the journal of the Association of European Psychiatrists 20191004

<h4>Background</h4>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.<h4>Methods</h4>To gain insight ...[more]

PMID: 31590015

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Project description:Schizophrenia is a serious neuropsychiatric disorder characterized by disruptions of brain cell metabolism, microstructure, and neurotransmission. All of these processes require coordination of multiple kinase-mediated signaling events. We hypothesize that imbalances in kinase activity propagate through an interconnected network of intracellular signaling with potential to simultaneously contribute to many or all of the observed deficits in schizophrenia. We established a workflow distinguishing schizophrenia-altered kinases in anterior cingulate cortex using a previously published kinome array data set. We compared schizophrenia-altered kinases to haloperidol-altered kinases, and identified systems, functions, and regulators predicted using pathway analyses. We used kinase inhibitors with the kinome array to test hypotheses about imbalance in signaling and conducted preliminary studies of kinase proteins, phosphoproteins, and activity for kinases of interest. We investigated schizophrenia-associated single nucleotide polymorphisms in one of these kinases, AKT, for genotype-dependent changes in AKT protein or activity. Kinome analyses identified new kinases as well as some previously implicated in schizophrenia. These results were not explained by chronic antipsychotic treatment. Kinases identified in our analyses aligned with cytoskeletal arrangement and molecular trafficking. Of the kinases we investigated further, AKT and (unexpectedly) JNK, showed the most dysregulation in the anterior cingulate cortex of schizophrenia subjects. Changes in kinase activity did not correspond to protein or phosphoprotein levels. We also show that AKT single nucleotide polymorphism rs1130214, previously associated with schizophrenia, influenced enzyme activity but not protein or phosphoprotein levels. Our data indicate subtle changes in kinase activity and regulation across an interlinked kinase network, suggesting signaling imbalances underlie the core symptoms of schizophrenia. DISEASE MECHANISMS:A SIGNALING IMBALANCE: A study by US scientists indicates that changes in the activity of key signaling proteins may underlie core symptoms of schizophrenia. Protein kinases mediate the activation of intracellular signaling events and analyses of the kinome, the complete set of protein kinases encoded in the genome, previously revealed significant changes in phosphorylation patterns in postmortem brain tissue from patients with schizophrenia. Based on these findings, Jennifer McGuire at the University of Cincinnati and colleagues investigated the upstream regulation of these proteins. They identified both established and novel proteins associated with schizophrenia in the anterior cingulate cortex, with JNK and AKT activity being the most disrupted in schizophrenia patients. Their findings highlight how subtle changes in the activity of a small number of signaling proteins can propagate and have major consequences for mental health.

Project description:Accumulating evidence suggests that disrupted insulin signaling is involved in bipolar disorder (BD) pathogenesis. Herein, we aimed to directly explore the potential role of neuronal insulin signaling using an innovative technique based on biomarkers derived from plasma extracellular vesicles enriched for neuronal origin (NEVs). We leveraged plasma samples from a randomized, double-blind, placebo-controlled, 12-week clinical trial evaluating infliximab as a treatment of bipolar depression. We isolated NEVs using immunoprecipitation against neuronal marker L1CAM from samples collected at baseline and weeks 2, 6 and 12 (endpoint) and measured NEV biomarkers using immunoassays. We assessed neuronal insulin signaling at its first node (IRS-1) and along the canonical (Akt, GSK-3β, p70S6K) and alternative (ERK1/2, JNK and p38-MAPK) pathways. A subset of participants (n = 27) also underwent whole-brain magnetic resonance imaging (MRI) at baseline and endpoint. Pre-treatment, NEV biomarkers of insulin signaling were independently associated with cognitive function and MRI measures (i.e. hippocampal and ventromedial prefrontal cortex [vmPFC] volumes). In fact, the association between IRS-1 phosphorylation at serine site 312 (pS312-IRS-1), an indicator of insulin resistance, and cognitive dysfunction was mediated by vmPFC volume. In the longitudinal analysis, patients treated with infliximab, a tumor necrosis factor-alpha antagonist with known insulin sensitizing properties, compared to those treated with placebo, had augmented phosphorylation of proteins from the alternative pathway. Infliximab responders had significant increases in phosphorylated JNK levels, relative to infliximab non-responders and placebo responders. In addition, treatment with infliximab resulted in increase in MRI measures of brain volume; treatment-related changes in the dorsolateral prefrontal cortex volume were mediated by changes in biomarkers from the insulin alternative pathway. In conclusion, our findings support the idea that brain insulin signaling is a target for further mechanistic and therapeutic investigations.

Dataset Information

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

Publications

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

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