Stress, glucose metabolism and the HPA axis: Early life adversity-the missing piece of the puzzle?

Abstract

Physiological stress prompts metabolic reactions aimed at increasing glucose supply, to initiate a fight/flight response in a healthy individual. The quality of the first 1000 days of life is a critical period which impacts the overall metabolic trajectory. Exposure to stress in early life increases the risk of developing cardiometabolic disorders. This may be due to epigenetic programming of cardiometabolic and stress response mechanisms. The objective of this study was to investigate both stress induced and baseline glucose levels in different models of early life adversity, in addition to dissecting mechanisms that drive these changes. We determined baseline and stress mediated blood glucose release in 3 different early life adversity models. Furthermore, we administered an escalating cortisol dose to an adversity negative cohort, to dissect the gluconeogenic driving mechanism and checked glucocorticoid driven gene expression to confirm GC-GR binding. Our study showed an impairment of stress response along with sex dependent differences in basal glucose levels in early life adversity models. The human institutionalisation/adoption and mice infection models showed higher baseline glucose levels in females, while the rat maternal deprivated males showed lower baseline glucose levels compared to the control group. Additionally, we established the stress mediated glucose release as a glucocorticoid independent process. Our study proposes a new outlook on potential mechanisms that may drive stress mediated metabolic changes. Additionally, we emphasise quality of early life as the missing piece of the puzzle to get a better understanding of the adult metabolic profile.