Exploring underlying mechanisms driving the onset of stress-induced insulin resistance

[摘要] ENGLISH ABSTRACT: Physical and psychological stressors trigger activation of the hypothalamo-pituitary-adrenocortical(HPA) axis that leads to enhanced secretion of glucocorticoids e.g. cortisol. Moreover, chronic activationof this pathway may elevate oxidative stress that is linked to the onset of insulin resistance andcardiovascular diseases (CVD). Our laboratory previously found that oxidative stress increasesfluxthrough metabolic circuits such as the hexosamine biosynthetic pathway (HBP), in effect increasing itsmodification of target proteins post-transcriptionally with O-GlcNAc moeities. This in turn may alterprotein function and contribute to the onset of myocardial insulin resistance and impaired contractilefunction. Since the underlying mechanisms linking chronic stress to cardiometabolic pathophysiologyare poorly understood, we hypothesised that cortisol elicits myocardial oxidative stress, HBP activation,and decreased glucose uptake (due to attenuated glucose transport functionality) with detrimentaloutcomes, i.e. insulin resistance and apoptosis. To investigate this hypothesis we established an in vitro model using HL-1 cardiomyocytes, with whichwe evaluated the degree of O-GlcNAcylation and oxidative stress in response to a range of time-dosetreatments with dexamethasone (synthetic glucocorticoid). Glucose transporter 4 (GLUT4) translocationto the sarcolemma was also assessed. In agreement with the literature, results suggest that GLUT4translocation is significantly decreased subsequent to dexamethasone treatment. Although no significant differences were observed with regards to oxidative stress or O-GlcNAcylation, the data show thatdexamethasone increased the latter with a maximal effect after two hours exposure to the 10-6 M dose.Although our results were not conclusive, the data suggest a potential novel link between dexamethasoneexposure, HBP activation and decreased GLUT4 translocation. Based on ourfindings we proposethat detrimental effects of chronic stress on the heart may be mediated by increased HBPflux. Giventhat glucocorticoid excess and GLUT4 dysregulation have been associated with insulin resistance (andrelated metabolic derangements and diseases), these results provide new targets for potential therapeuticagents.

[发布机构] Stellenbosch University