Impaired glycolytic response in peripheral blood mononuclear cells of first-onset antipsychotic-naive schizophrenia patients

Abstract

Little is known about the biological mechanisms underpinning the pathology of schizophrenia. We have analysed the proteome of stimulated and unstimulated peripheral blood mononuclear cells (PBMCs) from schizophrenia patients and controls as a potential model of altered cellular signaling using liquid-chromatography mass spectrometry proteomic profiling. PBMCs from patients and controls were stimulated for 72 h in vitro using staphylococcal enterotoxin B. In total, 18 differentially expressed proteins between first-onset, antipsychotic-naive patients and controls in the unstimulated and stimulated conditions were identified. Remarkably, eight of these proteins were associated with the glycolytic pathway and patient-control differences were more prominent in stimulated compared with unstimulated PBMCs. None of these proteins were altered in chronically ill antipsychotic-treated patients. Non-linear multivariate statistical analysis showed that small subsets of these proteins could be used as a signal for distinguishing first-onset patients from controls with high precision. Functional analysis of PBMCs did not reveal any difference in the glycolytic rate between patients and controls despite increased levels of lactate and the glucose transporter-1, and decreased levels of the insulin receptor in patients. In addition, subjects showed increased serum levels of insulin, consistent with the idea that some schizophrenia patients are insulin resistant. These results show that schizophrenia patients respond differently to PBMC activation and this is manifested at disease onset and may be modulated by antipsychotic treatment. The glycolytic protein signature associated with this effect could therefore be of diagnostic and prognostic value. Moreover, these results highlight the importance of using cells for functional discovery and show that it may not be sufficient to measure protein expression levels in static states.

Metformin attenuates olanzapine-induced hepatic, but not peripheral insulin resistance

“…In humans, the use of higherrange therapeutic doses of Met is unlikely to be of consequence unless elimination of Met is compromised (i.e., renal failure). That said, serious mental illnesses such as schizophrenia and bipolar disorder have been associated with mitochondrial dysfunction and increased lactate levels (Halim et al 2008, Regenold et al 2009, Herberth et al 2011, which raises the unexplored possibility that our patients may require more judicious dosing of Met to obtain maximal benefits. Translation of findings from rodents to clinic may, however, be complicated by genetic factors mediating metabolism and therapeutic action of Met (Shu et al 2007).…”

Transcriptional regulation of neurodevelopmental and metabolic pathways by NPAS3

“…However, schizophrenia has been repeatedly associated with an increased predisposition to metabolic dysfunction and type II diabetes in medication-naïve individuals (50). Studies suggest glycolytic dysfunction (51,52), mitochondrial failure, and oxidative stress (53) may be innate metabolic pathologies in schizophrenia and bipolar disorder.…”

Biomarkers in schizophrenia: A focus on blood based diagnostics and theranostics

“…In a study where PBMC were stimulated ex vivo with staphylococcal enterotoxin B, eight out of total of 18 proteins examined were differentially expressed in cells from people with Sz who were first onset and drugnaive Sz compared to controls. These proteins belonged to the glycolytic pathway [110] , indicating that impaired glycolytic response could be a potential early stage of diagnostic biomarker for Sz. Mitochondrial complex Ⅰ, the first enzyme in the mitochondrial respiratory chain for the oxidation of glucose, was found to have increased activity in the platelets from people with Sz [108] and to have higher mRNA levels in blood from people with Sz [111,113] .…”