ORF25-05 - Does Low Glucose Drive Fatigue in Treated Adrenal Cortisol Insufficiency?

Background:
Adults with adrenal cortisol insufficiency (ACI) often report fatigue, sleep disturbances, cognitive complaints, and reduced quality of life, despite receiving glucocorticoid (GC) therapy. Because GC replacement does not fully mimic cortisol circadian rhythms, and hypoglycemia has been observed in adrenal crises, neuroglycopenia may be an underlying cause of these symptoms. We therefore hypothesized that nocturnal hypoglycemia may be contributing to patient-reported symptoms in ACI.

Methods:
In this single-center, prospective study, the institutional database was screened to identify outpatients with ACI using diagnosis codes. Those with confirmed ACI were included, and those with glucose- or cortisol-altering conditions or medications were excluded. Participants had a FreeStyle Libre 3 continuous glucose monitor (CGM) placed and completed baseline surveys on quality of life, mood, fatigue, and sleep (SF-36, PHQ-9, GAD-7, FACIT-Fatigue, PROMIS Sleep Disturbance, Epworth Sleepiness Scale). They wore the CGM for 14 days and completed daily electronic surveys while continuing usual GC replacement. Data were analyzed with t-tests and linear regression.

Results:
Of 356 patients screened, 125 met eligibility criteria, and 35 were consented and enrolled. Participants included 25 females and 10 males, mean age of 54 ± 17 years and mean body mass index of 26.8 ± 5.4 kg/m2. Seventeen participants had primary- and 18 had secondary-ACI. Mean daily hydrocortisone equivalent dose was 18.8 ± 4.9 mg, divided into 1-4 doses. 14-day CGM wear was achieved by 94% of participants. Mean glucose was 107.2 ± 8.1 mg/dL with 98.9 ± 1.4% of time in range of 70-180 mg/dL and 0.6 ± 0.8% of time below range ( < 70 mg/dL). At least one glucose value < 70 mg/dL occurred in 80% of participants, 23% had values < 54 mg/dL. After excluding likely compression hypoglycemia (≤ 5 minutes), 71% still experienced hypoglycemic episodes, with a mean duration of 21.5 ± 13.0 minutes; most (66.9 ± 0.3%) of these episodes occurred overnight (10 PM–7 AM). Lower average glucose was associated with greater fatigue (p = 0.046) and less energy (p = 0.048) on surveys. Survey results of sleep, mood, and other quality-of-life domains did not significantly differ between participants with and without measured hypoglycemia.

Conclusion:
Most patients with ACI had CGM-detected hypoglycemia but spent ~99% of time in range and less time at low glucose than healthy populations described in the literature. Hypoglycemia, especially overnight, was correlated with more fatigue in these patients, suggesting higher sensitivity to even brief hypoglycemia.

References:
Ben-Shlomo A, Koh M, Kremen SA, Wertheimer J. Cognitive Assessment in Adults with Adrenal Cortisol Insufficiency: Challenges and Opportunities. Endocr Rev. Published online September 3, 2025. doi:10.1210/endrev/bnaf029