Stressing diabetes? The hidden links between insulinotropic peptides and the HPA axis

Abstract

Diabetes mellitus exerts metabolic stress on cells and it provokes a chronic increase in the long-term activity of the hypothalamus-pituitary-adrenocortical (HPA) axis, perhaps thereby contributing to insulin resistance. GLP-1 receptor (GLP-1R) agonists are pleiotropic hormones that not only affect glycaemic and metabolic control, but they also produce many other effects including activation of the HPA axis. In fact, several of the most relevant effects of GLP-1 might involve, at least in part, the modulation of the HPA axis. Thus, the anorectic activity of GLP-1 could be mediated by increasing CRF at the hypothalamic level, while its lipolytic effects could imply a local increase in glucocorticoids and glucocorticoid receptor (GC-R) expression in adipose tissue. Indeed, the potent activation of the HPA axis by GLP-1R agonists occurs within the range of therapeutic doses and with a short latency. Interestingly, the interactions of GLP-1 with the HPA axis may underlie most of the effects of GLP-1 on food intake control, glycaemic metabolism, adipose tissue biology and the responses to stress. Moreover, such activity has been observed in animal models (mice and rats), as well as in normal humans and in type I or type II diabetic patients. Accordingly, better understanding of how GLP-1R agonists modulate the activity of the HPA axis in diabetic subjects, especially obese individuals, will be crucial to design new and more efficient therapies for these patients.

Association of adverse childhood experiences with diabetes in adulthood: results of a cross-sectional epidemiological survey in Singapore

“…Several reasons have been suggested to explain the association of ACEs with the development of diabetes and other chronic physical conditions. ACEs negatively impact neurodevelopment especially that of the hypothalamic-pituitary-adrenal axis, 50 cause an elevated level of triglycerides, free fatty acids and glucose in the blood, 23 and they result in the elevation of inflammatory markers, all of which have been postulated to be involved in the development of chronic illnesses including diabetes. 51 In the older population, that is, those more than 50 years of age, living with household members who were mentally ill or suicidal and emotional abuse were both less likely to have diabetes.…”

“…Suggested pathophysiological mechanisms linking ACEs with diabetes include effects on the hypothalamicpituitary axis [21][22][23] ; metabolic dysregulation, that is, elevated level of triglycerides, free fatty acids, glucose and insulin caused by the chronic stress from ACEs 24 ; elevated levels of inflammatory markers 25 ; and epigenetic changes. 26 27 Psychosocial risk factors have also been proposed as a possible mechanism.…”

Clinical Evidence of Antidepressant Effects of Insulin and Anti-Hyperglycemic Agents and Implications for the Pathophysiology of Depression—A Literature Review

“…GCs are major regulators of energy metabolism, playing key roles in the counter-regulatory responses and metabolic adaptations to the increased energy demand provoked by stress. In general, GCs mobilize energy substrates such as lipids and glucose, increasing their levels in systemic circulation [164]. Physiologically, GCs promote insulin secretion [165]; conversely, insulin activates the HPA axis and leads to an increase in GC levels and corticotropin releasing hormone (CRH) levels [166].…”

Twenty-five years later: How consistent are studies using the Trier Social Stress Test protocol - A Systematic Review of its methodology

“…Such diseases represent the leading cause of death and disability worldwide (WHO, 2019). Diabetes, coronary heart disease, cancer and chronic obstructive pulmonary disease (Dis-Chaves et al, 2016;Matura et al, 2018) have all been associated with increased CORT secretion. In North America, an estimated 25-33% of the adult population live with one or more chronic health conditions (Ward et al, 2012;Branchard et al, 2018), often associated with dysregulations of HPAA activation (Allen, et al, 2014).…”