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Evidence for impaired glucose metabolism in the striatum, obtained postmortem, from some subjects with schizophrenia.

ABSTRACT: Studies using central nervous system tissue obtained postmortem suggest pathways involved in energy and metabolism contribute to the pathophysiology of schizophrenia; neuroimaging studies suggesting glucose metabolism is particularly affected in the striatum. To gain information on the status of pathways involved in glucose metabolism in the striatum, we measured levels of glucose, pyruvate, acetyl-CoA and lactate as well as the ? subunit of pyruvate dehydrogenase, a rate limiting enzyme, in the postmortem tissue from subjects with schizophrenia and age/sex-matched controls. The subjects with schizophrenia were made up of two subgroups, which could be divided because they either had (muscarinic receptor deficit schizophrenia (MRDS)), or did not have (non-MRDS), a marked deficit in cortical muscarinic receptors. Compared to controls, levels of ? subunit of pyruvate dehydrogenase were lower (? mean=-20%) and levels of pyruvate (? mean=+47%) and lactate (? mean=+15%) were significantly higher in the striatum from subjects with schizophrenia. Notably, in subjects with non-MRDS, striatal levels of ? subunit of pyruvate dehydrogenase were lower (? mean=-29%), whereas levels of pyruvate (? mean=-66%), acetyl-CoA (? mean=-28%) and glucose (? mean=-27%) were higher, whereas levels of lactate (? mean=+17%) were higher in MRDS. Finally, discriminate analyses using levels the ? subunit of pyruvate dehydrogenase and glucose, or better still, ? subunit of pyruvate dehydrogenase and glucose in combination with pyruvate, lactate or acetyl-CoA could separate subjects with non-MRDS from controls with high levels of specificity (up to 93%) and selectivity (up to 91%). Our data show the benefit of being able to study defined subgroups within the syndrome of schizophrenia as such an approach has revealed that changes in glucose metabolism may be a significant contributor to the pathophysiology of non-MRDS.

SUBMITTER: Dean B

PROVIDER: S-EPMC5314134 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Evidence for impaired glucose metabolism in the striatum, obtained postmortem, from some subjects with schizophrenia.

Dean B B Thomas N N Scarr E E Udawela M M

Translational psychiatry 20161115 11

Studies using central nervous system tissue obtained postmortem suggest pathways involved in energy and metabolism contribute to the pathophysiology of schizophrenia; neuroimaging studies suggesting glucose metabolism is particularly affected in the striatum. To gain information on the status of pathways involved in glucose metabolism in the striatum, we measured levels of glucose, pyruvate, acetyl-CoA and lactate as well as the β subunit of pyruvate dehydrogenase, a rate limiting enzyme, in the ...[more]

PMID: 27845781

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Project description:Schizophrenia is a psychiatric disorder which has a lifetime prevalence of ~1%. Multiple candidate mechanisms have been proposed in the pathogenesis of schizophrenia. One such mechanism is the involvement of neuroinflammation. Clinical studies, including neuroimaging, peripheral biomarkers and randomized control trials, have suggested the presence of neuroinflammation in schizophrenia. Many studies have also measured markers of neuroinflammation in postmortem brain samples from schizophrenia patients. The objective of this study was to conduct a systematic search of the literature on neuroinflammation in postmortem brains of schizophrenia patients indexed in MEDLINE, Embase and PsycINFO. Databases were searched up until 20th March 2016 for articles published on postmortem brains in schizophrenia evaluating microglia, astrocytes, glia, cytokines, the arachidonic cascade, substance P and other markers of neuroinflammation. Two independent reviewers extracted the data. Out of 5385 articles yielded by the search, 119 articles were identified that measured neuroinflammatory markers in schizophrenic postmortem brains. Glial fibrillary acidic protein expression was elevated, lower or unchanged in 6, 6 and 21 studies, respectively, and similar results were obtained for glial cell densities. On the other hand, microglial markers were increased, lower or unchanged in schizophrenia in 11, 3 and 8 studies, respectively. Results were variable across all other markers, but SERPINA3 and IFITM were consistently increased in 4 and 5 studies, respectively. Despite the variability, some studies evaluating neuroinflammation in postmortem brains in schizophrenia suggest an increase in microglial activity and other markers such as SERPINA3 and IFITM. Variability across studies is partially explained by multiple factors including brain region evaluated, source of the brain, diagnosis, age at time of death, age of onset and the presence of suicide victims in the cohort.

Project description:OBJECTIVE:The Williams-Beuren syndrome (WS) is associated with impaired glucose metabolism (IGM) early in adulthood. However, the pathophysiology of IGM remains poorly defined, due to the lack of longitudinal studies investigating the contribution of ?-cell dysfunction and impaired insulin sensitivity. This study aimed at assessing incidence of IGM and the underlying mechanisms in WS adults. METHODS:This observational, longitudinal (5-year), cohort study enrolled thirty-one consecutive WS subjects attending a tertiary referral center. An oral glucose tolerance test (OGTT) was performed yearly and used to classify patients as normal or IGM, including impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) and diabetes mellitus (DM), and to calculate surrogate measures of insulin secretion and/or sensitivity. RESULTS:IGM patients were 18 (58.1%, three DM) at baseline and 19 (61.3%, five DM) at end-of-follow-up. However, 13 individuals changed category of glucose homeostasis in both directions during follow-up (8 progressors, 5 regressors) and 18 did not (8 non-progressors, 10 non-regressors). New cases of IGM and DM were 11.1 and 2.53 per 100 persons-year, respectively, and were treated non-pharmacologically. In the whole cohort and, to a higher extent, in progressors, indices of early-phase insulin secretion and insulin sensitivity decreased significantly from baseline to end-of-follow-up, with concurrent reduction of the oral disposition index and insulin secretion-sensitivity index-2 (ISSI-2), compensating insulin secretion for the level of insulin resistance. No baseline measure independently predicted progression, which correlated with change from baseline in ISSI-2. Compared with patients with normal glucose homeostasis, IGT subjects had impaired insulin sensitivity, whereas insulin secretion was reduced only in those with IFG+IGT or DM. CONCLUSIONS:IGM incidence is high in young adults with WS, suggesting the need of early screening and timed intervention. As in classical type 2 diabetes, impaired insulin sensitivity and ?-cell dysfunction contribute, in this sequence, to progression to IGM and DM.

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Evidence for impaired glucose metabolism in the striatum, obtained postmortem, from some subjects with schizophrenia.

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Evidence for impaired glucose metabolism in the striatum, obtained postmortem, from some subjects with schizophrenia.

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