Dysregulation of early gene response to a mixed meal in skeletal muscle in obesity and type 2 diabetes.

Obesity and type 2 diabetes mellitus-induced changes in expression of protein-coding genes in human skeletal muscle were extensively examined at baseline (after an overnight fast). We aimed to compare the early transcriptomic response to a typical single meal in skeletal muscle of metabolically healthy subjects and obese individuals without and with type 2 diabetes. Transcriptomic response (RNA-seq) to a mixed meal (nutritional drink, ~25 kJ/kg of body mass) was examined in the vastus lateralis muscle (1 h after a meal) in 7 healthy subjects and 14 obese individuals without or with type 2 diabetes. In all obese individuals the transcriptome response to a meal was dysregulated (suppressed and altered) and associated with different biological processes compared to healthy control. To search for potential transcription factors regulating transcriptomic response to a meal, the enrichment of transcription factor binding sites in the human skeletal muscle individual promoters was examined. In obese individuals, the transcriptomic response is associated with a different set of transcription factors than that in healthy subjects. In conclusion, metabolic disorders are associated with a defect in the regulation of mixed meal/insulin-mediated gene expression - insulin resistance in terms of gene expression. Importantly, this dysregulation occurs in obese individuals without type 2 diabetes i.e., at the first stage of the development of metabolic disorders.