Gastrectomy promoted diabetes remission involves the molecular clock and epigenetic mechanisms in a rat model of lean type 2 diabetes.

Bariatric surgery results in type 2 diabetes (T2D) improvement. To identify mechanisms associated with gastrectomy-promoted T2D remission in lean individuals, we performed pathophysiological, behavioural and molecular (liver transcriptome, metabolome and lipidome) investigations in the Goto-Kakizaki (GK) model of spontaneously-occurring non-obese T2D following vertical sleeve gastrectomy (VSG) or sham operation. VSG resulted in sustained reduction in hyperglycemia and changes in nycthemeral feeding patterns and activity. Liver transcriptome and lipidome profiling pointed to changes in the expression of genes involved in inflammation, PPAR signalling and fatty acid metabolism, and in the regulation of phosphatidylcholine and lysophosphatidylethanolamine classes. Deeper analysis revealed altered expression of genes involved in histone methylation and co-ordinately differential transcription of key regulators of the molecular clock (Clock, Arntl/Bmal1, Per1, Per2, Per3). In addition to previously reported changes in bile acid metabolism and gut microbiome in this model of VSG, our findings underline the multiple biological mechanisms associated with diabetes remission following VSG and suggest a contribution of chronobiology and epigenetic processes in the long-term therapeutic consequences of VSG in the context of polygenic non-obese T2D.