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Alterations in Skeletal Muscle Insulin Signaling DNA Methylation: A Pilot Randomized Controlled Trial of Olanzapine
Kyle J Burghardt1, Paul R Burghardt2, Bradley H Howlett1
1Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.
Abstract:
Antipsychotics are associated with severe metabolic side effects including insulin resistance; however, the mechanisms underlying this side effect are not fully understood. The skeletal muscle plays a critical role in insulin-stimulated glucose uptake, and changes in skeletal muscle DNA methylation by antipsychotics may play a role in the development of insulin resistance. A double-blind, placebo-controlled trial of olanzapine was performed in healthy volunteers. Twelve healthy volunteers were randomized to receive 10 mg/day of olanzapine for 7 days. Participants underwent skeletal muscle biopsies to analyze DNA methylation changes using a candidate gene approach for the insulin signaling pathway. Ninety-seven methylation sites were statistically significant (false discovery rate < 0.05 and beta difference between the groups of ≥10%). Fifty-five sites had increased methylation in the skeletal muscle of olanzapine-treated participants while 42 were decreased. The largest methylation change occurred at a site in the Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha (PPARGC1A) gene, which had 52% lower methylation in the olanzapine group. Antipsychotic treatment in healthy volunteers causes significant changes in skeletal muscle DNA methylation in the insulin signaling pathway. Future work will need to expand on these findings with expression analyses.
Insights
Antipsychotic medications like olanzapine alter DNA methylation in skeletal muscle, potentially contributing to insulin resistance. This study observed significant changes in genes critical for insulin signaling in healthy volunteers.
Area of Science:
- Pharmacology
- Metabolic Disorders
- Epigenetics
Background:
- Antipsychotics can cause severe metabolic side effects, notably insulin resistance.
- The precise mechanisms linking antipsychotic use to insulin resistance remain unclear.
- Skeletal muscle's role in glucose uptake suggests it may be a key site for these metabolic changes.
Purpose of the Study:
- To investigate the impact of olanzapine on skeletal muscle DNA methylation in healthy volunteers.
- To identify specific genes within the insulin signaling pathway affected by antipsychotic treatment.
Main Methods:
- A double-blind, placebo-controlled trial involving 12 healthy volunteers.
- Participants received 10 mg/day olanzapine for 7 days.
- Skeletal muscle biopsies were analyzed for DNA methylation changes using a candidate gene approach.
Main Results:
- Olanzapine treatment led to significant DNA methylation changes in 97 sites within the insulin signaling pathway.
- Fifty-five sites showed increased methylation, while 42 sites exhibited decreased methylation.
- The most substantial change was a 52% decrease in methylation at a site within the PPARGC1A gene.
Conclusions:
- Antipsychotic administration significantly alters skeletal muscle DNA methylation patterns related to insulin signaling.
- These epigenetic modifications may contribute to the development of antipsychotic-induced insulin resistance.
- Further research incorporating gene expression analysis is warranted to elucidate these mechanisms.
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