Corticotropic axis drive of overnight cortisol secretion is suppressed in adolescents and young adults with type 1 diabetes mellitus

Context: Type 1 diabetes mellitus (T1DM) is a pro-inflammatory stress state, which, with its attendant hyperglycemia, likely disrupts hypothalamo-pituitary-adrenal (HPA) control, further dysregulating glucose homeostasis. Objective: To test the hypothesis that endogenous adrenocorticotropic hormone (ACTH)-cortisol dose-responsive drive, estimated analytically, is significantly accentuated in adolescents and young adults with T1DM compared with healthy individuals. Design, setting, patients, and interventions: This was a pilot study of 11 volunteers with T1DM and 10 controls, ages 16-30 yr, at a medical center. Subjects underwent overnight frequent blood sampling (every 10 min for ACTH and cortisol and every 60 min for blood glucose) from 10 pm to 8 am. T1DM volunteers maintained their home insulin regimen. Main outcomes: Deconvolution analysis and dose-response estimates were the key outcomes. Results: Mean free cortisol, but not ACTH, concentrations were lower in the T1DM group compared with controls (p = 0.012). Non-invasive ACTH-cortisol dose-response estimates revealed that T1DM patients had reduced ACTH efficacy (maximal cortisol secretion, p = 0.009), reduced ACTH potency as quantified by greater EC₅₀ (ACTH concentration driving half-maximal cortisol secretion, p = 0.04), and increased ACTH sensitivity (more positive ACTH-cortisol slope, p = 0.03). Post-hoc gender comparisons indicated that these differences were limited to females. Linear regression in women showed a strong correlation of both ACTH efficacy and EC₅₀ with C-peptide levels (both p < 0.01). Conclusion: Compared with healthy individuals, T1DM patients manifest decreased overnight adrenal responsiveness to endogenous ACTH leading to lower free cortisol concentrations. These findings suggest impaired stress-related adaptations of the HPA axis in T1DM.