Background: Chronic cortisol elevation, from prolonged stress, Cushing's syndrome, or therapeutic glucocorticoids, disrupts glucose homeostasis by impairing insulin signalling and enhancing hepatic glucose production, yet integrated hormonal mechanisms remain incompletely characterized 1,2. Objective: This work aims to systematically review how chronic hypercortisolism affects: (I) peripheral insulin sensitivity; (II) compensatory glucagon secretion and hepatic sensitivity; and (III) fasting glycaemia maintenance in adult populations 2,3. Methods: Systematic search (MEDLINE, Scopus, 2014–2025) of human studies reporting chronic cortisol/glucocorticoid exposure (endogenous or iatrogenic) and fasting metabolic outcomes. Inclusion criteria: adults (≥18 years) with measurements of fasting glycaemia, hepatic glucose production, insulin sensitivity, glucagon levels, or counterregulatory responses. Exclusion criteria: paediatric studies, pregnancy/lactation, animal/in vitro models, or studies lacking fasting measures or cortisol/glucagon data 4. Thirteen peer-reviewed articles were synthesized. Results: Chronic excess of cortisol consistently impairs peripheral insulin sensitivity through post-receptor signalling defects and enhanced lipolysis, reducing insulin-dependent glucose uptake by skeletal muscle and adipose tissue 1,4. Simultaneously, cortisol attenuates insulin's suppression of glucagon and increases hepatic glucagon receptor sensitivity, amplifying hepatic glucose production and gluconeogenesis 3. These dual defects, diminished insulin efficacy combined with exaggerated glucagon actions, sustain fasting hyperglycaemia 2. Central neural dysregulation and disrupted circadian feedback loops further destabilize basal glucose control, particularly in populations with obesity or prediabetes 3,5.Conclusions: Chronic hypercortisolism triggers coordinated insulin–glucagon axis imbalance, impairing fasting glycaemia maintenance through combined peripheral resistance and enhanced hepatic glucose output 1. Targeting hypothalamic–pituitary–adrenal (HPA) axis modulation and stress reduction may prevent glucocorticoid-related dysglycemia 2. Standardized prospective cohort studies with detailed biomarker kinetics and longitudinal follow-up are essential to establish glucocorticoid-induced prediabetes risk profiles and evidence-based intervention strategies 4,5.
Nogueira et al. (Fri,) studied this question.