Effects of chronic intermittent hypobaric hypoxia on expression and promoter region methylation of key enzyme genes related to glucose metabolism in diabetic mice

Abstract

BackgroundChronic intermittent hypobaric hypoxia (CIHH) can effectively alleviate type 2 diabetes mellitus (T2DM). In this process, the underlying mechanism in its association with the epigenetic regulation of DNA methylation in the promoter regions of glucose metabolism key enzyme genes remains unclear yet.ObjectiveTo investigate the effects of CIHH on expression and promoter region methylation of key enzyme genes related to glucose metabolism in diabetes mice, and to explore the underlying mechanism by which CIHH regulates glucose metabolism.MethodsForty C57BL/6J male mice were divided randomly into a normobaric normoxic control (NN/CON) group, a chronic intermittent hypobaric hypoxia intervention control (CIHH/CON) group, a normobaric normoxic diabetic model (NN/DM) group, and a chronic intermittent hypobaric hypoxia intervention diabetic model (CIHH/DM) group. The mice in the NN/DM and the CIHH/DM groups were fed for 7 weeks with high-fat and high-sugar diet. Subsequently, these mice were intraperitoneally injected consecutively with 50 mmol·L−1 streptozotocin (STZ) for 5 d at a dose of 40 mg·kg−1 (body weight) per day to create T2DM model mice. The mice in the CIHH/DM and the CIHH/CON groups were intervened by simulating hypobaric hypoxia at 5000 m altitude for 6 h per day, while the mice in the NN/DM and the NN/CON groups were always placed in a normobaric normoxic environment. All mice were continuously treated for 4 weeks, and blood glucose were monitored during this period. After the CIHH intervention experiment, the glucose tolerance and insulin sensitivity of mice were evaluated. A set of indicators involved in key glycolytic enzymes glucokinase (GK) and pyruvate kinase (PK), as well as key gluconeogenic enzymes phosphoenolpyruvate carboxyl kinase (PEPCK) and glucose-6-phosphatase (G6P) were measured in the liver of mice, including enzyme activity, relative mRNA expression level, and DNA methylation level in the gene promoter regions.ResultsCompared with the mice in the NN/DM group, the blood glucose levels of the mice in the CIHH/DM group decreased after the 25th day of the CIHH intervention (P0.05), and their correlations with mRNA expression levels were also not statistically significant (P>0.05).ConclusionCIHH intervention may reduce blood glucose level, improve glucose tolerance, alleviate insulin resistance, and regulate the key enzyme activities of glucose metabolism and the relative mRNA expression of their corresponding genes in T2DM mice, but the above phenomena are not related to the DNA methylation levels in the promoter regions of these key enzymes.

Keywords

• chronic intermittent hypobaric hypoxia intervention
• diabetes mellitus
• glucose metabolism
• key enzyme
• dna methylation