AKT2 Skeletal Muscle DNA Methylation and Levels in Atypical Antipsychotic-Induced Insulin Resistance
Dass, Sabrina E.
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Atypical antipsychotics (AAPs) are an effective drug in treating mental illness, however studies have shown that a correlation exists between AAPs and the onset of physiological diseases such as diabetes. It has been suggested that insulin resistance from the use of AAPs may be associated with changes in DNA methylation. To prevent diabetes morbidity and mortality in the mentally ill treated with AAPs, an understanding of the tissue-specific epigenetic mechanisms underlying obesity-independent AAP induced insulin resistance is needed. For this study, bipolar subjects treated with AAPs or lithium monotherapy were recruited for a cross-sectional visit to analyze skeletal muscle DNA methylation and insulin resistance. Our results indicated that a change in DNA methylation of the AKT2 gene occurred in those who have been stabilized by AAPs for more than 6 weeks. A significant positive association was found between skeletal muscle DNA methylation and insulin resistance (p=0.0082). Moreover, a significant association was identified between the degree of methylation and whether or not a subject had insulin resistance (p=0.0023). Additionally, an oral glucose tolerance test (OGTT) was performed and a trend was observed in which subjects with impaired glucose tolerance (IGT) had higher methylation at Chr19: 40789824 compared to subjects with normal glucose tolerance (NGT) (p=0.5). Trends were also apparent between AKT2 protein levels and HOMA-IR, insulin resistance cutoffs, and glucose tolerance (p=0.2, 0.9, and 0.6, respectively). These findings have implications for future studies in identifying the epigenetic mechanisms of AAP-induced insulin resistance in a causal or functionally significant manner.