title: Olanzapine and aripiprazole differentially affect glucose uptake and energy metabolism in human mononuclear blood cells.
abstract: The use of antipsychotics carries the risk of metabolic side effects, such as weight gain and new onset type-2 diabetes mellitus. The mechanisms of the observed metabolic alterations are not fully understood. We compared the effects of two atypical antipsychotics, one known to favor weight gain (olanzapine), the other not (aripiprazole), on glucose metabolism. Primary human peripheral blood mononuclear cells (PBMC) were isolated and stimulated with olanzapine or aripiprazole for 72 h. Cellular glucose uptake was analyzed in vitro by 18F-FDG uptake. Further measurements comprised mRNA expression of glucose transporter (GLUT) 1 and 3, GLUT1 protein expression, DNA methylation of GLUT1 promoter region, and proteins involved in downstream glucometabolic processes. We observed a 2-fold increase in glucose uptake after stimulation with aripiprazole. In contrast, olanzapine stimulation decreased glucose uptake by 40%, accompanied by downregulation of the cellular energy sensor AMP activated protein kinase (AMPK). GLUT1 protein expression increased, GLUT1 mRNA expression decreased, and GLUT1 promoter was hypermethylated with both antipsychotics. Pyruvat-dehydrogenase (PDH) complex activity decreased with olanzapine only. Our findings suggest that the atypical antipsychotics olanzapine and aripiprazole differentially affect energy metabolism in PBMC. The observed decrease in glucose uptake in olanzapine stimulated PBMC, accompanied by decreased PDH point to a worsening in cellular energy metabolism not compensated by AMKP upregulation. In contrast, aripiprazole stimulation lead to increased glucose uptake, while not affecting PDH complex expression. The observed differences may be involved in the different metabolic profiles observed in aripiprazole and olanzapine treated patients.
authors.affiliation: Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; Department of Cardiology and Angiology, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Stapel
authors.affiliation: Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kotsiari
authors.affiliation: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Scherr
authors.affiliation: Department of Cardiology and Angiology, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Hilfiker-Kleiner
authors.affiliation: Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bleich
authors.affiliation: Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: Helge
authors.initials: H
authors.lastname: Frieling
authors.affiliation: Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Electronic address: kahl.kai@mh-hannover.de.
authors.forename: Kai G
authors.initials: KG
authors.lastname: Kahl
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D015703:Antigens, CD / Q000378:metabolism; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D019175:DNA Methylation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D027342:Excitatory Amino Acid Transporter 2; D005434:Flow Cytometry; D019788:Fluorodeoxyglucose F18; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D051274:Glucose Transporter Type 3 / Q000235:genetics / Q000378:metabolism; D050491:Glutamate Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007658:Ketone Oxidoreductases / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism*; D000077152:Olanzapine; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012337:RNA, Ribosomal, 18S / Q000235:genetics / Q000378:metabolism; D018709:Statistics, Nonparametric
chemical_list: D015703:Antigens, CD; D014150:Antipsychotic Agents; D027342:Excitatory Amino Acid Transporter 2; D051274:Glucose Transporter Type 3; D050491:Glutamate Plasma Membrane Transport Proteins; D012333:RNA, Messenger; D012337:RNA, Ribosomal, 18S; C493397:SLC1A2 protein, human; C495687:SLC2A3 protein, human; D019788:Fluorodeoxyglucose F18; D001569:Benzodiazepines; D000068180:Aripiprazole; D007658:Ketone Oxidoreductases; C053164:pyruvate dehydrogenase (NADP+); D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D005947:Glucose; D000077152:Olanzapine