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Effects of olanzapine on glucose transport, proliferation and survival in C2C12 myoblasts
Giovanni Tulipano1, PierFranco Spano, Daniela Cocchi
1Division of Pharmacology and Toxicology, Department of Biomedical Sciences and Biotechnologies, University of Brescia, Brescia, Italy. tulipano@med.unibs.it
Abstract:
The aim of our study was to investigate the direct effects of atypical antipsychotics on muscle cell functions in order to ascertain the diabetic liability of these drugs. We investigated the effects of olanzapine, clozapine and alpha-methyl-5-hydroxytryptamine on basal glucose uptake and glucose uptake in response to insulin using in vitro cultures of mouse skeletal muscle satellite cells (C2C12). We extended our study to the effects of these compounds on cell proliferation, survival and differentiation into myotubes and on the growth of differentiated myotubes. Olanzapine and alpha-methyl-5-HT stimulated 2-deoxyglucose uptake in C2C12 myoblasts in a dose-dependent manner (minimal effective dose: 2 microM olanzapine and 10 microM alpha-methyl-5-HT). The treatment with clozapine had no effect on glucose transport. Insulin and olanzapine increased the plasma membrane (PM) abundance of glucose transporter GLUT4. We investigated whether protein kinase Akt (PKB) and AMP-dependent kinase may participate in mediating olanzapine effects on glucose transport. Clozapine and olanzapine did not induce DNA laddering in differentiating myoblasts and differentiated myotubes and did not affect myotube growth. Olanzapine-induced glucose disposal in vitro is consistent with the acute lowering of plasma glucose/insulin concentrations that occurs in rats before olanzapine-induced overeating [Albaugh, V.L., Henry, C.R., Bello, N.T., Hajnal, A., Lynch, S.L., Halle, B., Lynch, C.J., 2006. Hormonal and metabolic effects of olanzapine and clozapine related to body weight in rodents. Obesity 14, 36-50].
Insights
Atypical antipsychotics like olanzapine directly impact muscle cell glucose uptake, potentially influencing diabetes risk. Clozapine showed no effect on glucose transport in this study.
Area of Science:
- Pharmacology
- Cell Biology
- Metabolism
Background:
- Atypical antipsychotics are associated with increased diabetes risk.
- The direct cellular mechanisms underlying this risk are not fully understood.
Purpose of the Study:
- To investigate the direct effects of atypical antipsychotics on skeletal muscle cell functions.
- To determine the potential diabetic liability of these drugs at the cellular level.
Main Methods:
- In vitro study using mouse skeletal muscle satellite cells (C2C12).
- Assessed basal and insulin-stimulated glucose uptake (2-deoxyglucose uptake).
- Evaluated effects on cell proliferation, survival, differentiation, and myotube growth.
Main Results:
- Olanzapine and alpha-methyl-5-HT dose-dependently stimulated glucose uptake in C2C12 myoblasts.
- Clozapine did not affect glucose transport.
- Olanzapine increased plasma membrane GLUT4 abundance, suggesting enhanced glucose transport.
- Neither clozapine nor olanzapine affected myoblast/myotube proliferation, survival, or growth.
Conclusions:
- Olanzapine enhances glucose uptake in muscle cells, potentially through GLUT4 translocation.
- These findings provide cellular insights into the metabolic side effects of atypical antipsychotics.
- The observed in vitro effects align with in vivo observations of glucose changes prior to weight gain.
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Glucose Transporters
Facilitated diffusion-glucose transporters (GLUTs) are encoded by the solute-linked carrier (SLC) family 2, subfamily A gene family, or SLC2A. The 14 GLUT protein members are distributed into three classes:
