Insulin-signaling abnormalities in drug-naïve 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-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.

Oxidative-Antioxidant Imbalance and Impaired Glucose Metabolism in Schizophrenia

“…Studies confirm the occurrence of disorders of glucose homeostasis at the early stages of the disease, such as elevated fasting glucose and insulin, and reduced glucose tolerance [44]. This dysfunction may be associated with neuronal insulin resistance [45]. Glucose is the primary source of energy for the brain and is metabolized to ATP during glycolysis, the electron transport chain (ETC), and included in the tricarboxylic acid cycle (TCA) as presented in Figure 1.…”

“…Modern theories slightly differ from the classical explanations, and assume that in schizophrenic patients, absorption of glucose into brain cells is impaired. That can be associated, (among others), with the wrong concentration of glucose transporters, i.e., GLUT1 and GLUT3, or neuronal insulin resistance [45]. Our preliminary studies on a group of 40 patients with the first episode of psychosis (manuscript in preparation) with the use of magnetic resonance spectroscopy (MRS) showed, that the strongest relationship between the metabolites, i.e., GLU + GLN + GSH 3.7 with positive symptom P scale was observed in a cingulate cortex.…”

Extracellular vesicles in patients in the acute phase of psychosis and after clinical improvement: an explorative study

“…In theory, EVs could also be used as therapeutic vehicles, as evidence indicates that their membrane proteins can guide them to specific recipient cells (Van Niel, D'Angelo & Raposo, 2018;Yanez-Mo et al, 2015). To our knowledge, there are only four published studies on psychosis and EVs: one based on brain biopsies (Banigan et al, 2013), a case report involving cerebrospinal fluid (CSF) analysis (Mobarrez et al, 2013), and two studies showing altered insulin signaling in L1 cell adhesion molecule (L1CAM) positive EVs in patients with schizophrenia (Kapogiannis et al, 2019a;Wijtenburg et al, 2019).…”

Analysis of Circulating Exosomes Reveals a Peripheral Signature of Astrocytic Pathology in Schizophrenia

“…Du et al validated several distinct miRNAs in serum exosomes, including 11 that could distinguish between the schizophrenia and the control groups (Du et al, 2019). Finally, Kapogiannis et al reported altered expression of proteins relevant to insulin signaling in plasma derived neuronal exosomes from drug naïve first episode schizophrenia patients, suggesting that altered insulin signaling precedes antipsychotic exposure in schizophrenia (Kapogiannis et al, 2019).…”