Ilias I, Zabuliene L. Letter to the Editor: Hypothalamic-pituitary-adrenal axis dysregulation as a plausible contributor to glycated hemoglobin variability and cardiovascular risk in diabetes mellitus. World J Diabetes 2026; 17(9): 124386 [DOI: 10.4239/wjd.124386]
Corresponding Author of This Article
Ioannis Ilias, MD, PhD, Director, Department of Endocrinology, Hippocration General Hospital, No. 63 Evrou Street, Athens GR-11521, Greece. iiliasmd@yahoo.com
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Endocrinology & Metabolism
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letter
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Ilias I, Zabuliene L. Letter to the Editor: Hypothalamic-pituitary-adrenal axis dysregulation as a plausible contributor to glycated hemoglobin variability and cardiovascular risk in diabetes mellitus. World J Diabetes 2026; 17(9): 124386 [DOI: 10.4239/wjd.124386]
World J Diabetes. Sep 15, 2026; 17(9): 124386 Published online Sep 15, 2026. doi: 10.4239/wjd.124386
Letter to the Editor: Hypothalamic-pituitary-adrenal axis dysregulation as a plausible contributor to glycated hemoglobin variability and cardiovascular risk in diabetes mellitus
Ioannis Ilias, Lina Zabuliene
Ioannis Ilias, Department of Endocrinology, Hippocration General Hospital, Athens GR-11521, Greece
Lina Zabuliene, Faculty of Medicine, Vilnius University, Vilnius LT-03101, Lithuania
Co-first authors: Ioannis Ilias and Lina Zabuliene.
Author contributions: Ilias I and Zabuliene L contributed to the conception of this letter, performed the literature search, wrote the original draft, and reviewed and edited the manuscript; and both authors have read and approved the final version of the manuscript. Both authors have made crucial and indispensable contributions towards the completion of the project and thus qualify as the co-first authors of the paper.
AI contribution statement: Portions of this manuscript were edited using AI tools solely for language refinement. The authors carefully reviewed and verified all AI-assisted outputs and take full responsibility for the scientific content of the manuscript.
Conflict-of-interest statement: All Authors report no conflict of interest.
Corresponding author: Ioannis Ilias, MD, PhD, Director, Department of Endocrinology, Hippocration General Hospital, No. 63 Evrou Street, Athens GR-11521, Greece. iiliasmd@yahoo.com
Received: June 15, 2026 Revised: July 6, 2026 Accepted: July 17, 2026 Published online: September 15, 2026 Processing time: 79 Days and 3.2 Hours
Abstract
We read with great interest the recent opinion review by Goyal et al on the cardiovascular implications of glycated hemoglobin (HbA1c) beyond its conventional role as a glycemic monitoring tool. This review argues that visit-to-visit HbA1c variability (usually quantified as the standard deviation, coefficient of variation, or variability independent of the mean across serial measurements) provides independent cardiovascular risk information beyond mean glycemia. To this, we would like to add a plausible endocrine mechanism that may partly explain this variability. We propose a two-tier model centered on dysregulation of the hypothalamic-pituitary-adrenal axis. First, sustained cortisol excess, as occurs in mild autonomous cortisol secretion from adrenal incidentalomas or in subclinical Cushing’s syndrome, acts across successive erythrocyte lifespans and may measurably shift mean HbA1c between clinic visits. Second, hyperglycemia-driven hypothalamic-pituitary-adrenal axis hyperactivity, mediated by pro-inflammatory cytokines, establishes a feed-forward loop that further perturbs the glycemic set point. We suggest that unexplained HbA1c variability, after exclusion of common causes such as medication changes, intercurrent illness, anemia, or altered erythrocyte lifespan, could prompt targeted hypothalamic-pituitary-adrenal axis screening in selected patients with additional clinical features of cortisol excess.
Core Tip: The inter-visit variability of glycated hemoglobin independently predicts cardiovascular outcomes in diabetes mellitus, yet its mechanistic determinants remain incompletely characterized. We propose that hypothalamic-pituitary-adrenal axis dysregulation is a plausible, underrecognized contributor, operating through two tiers. One tier involves sustained cortisol excess, as seen in mild autonomous cortisol secretion from adrenal incidentalomas or in subclinical Cushing’s syndrome, shifting mean glycated hemoglobin measurably across consecutive visits. The second tier involves hyperglycemia-driven hypothalamic-pituitary-adrenal hyperactivity, mediated by pro-inflammatory cytokines and perpetuating a feed-forward glycemic loop. Unexplained inter-visit glycated hemoglobin variability, after exclusion of common causes, may warrant targeted hypothalamic-pituitary-adrenal axis evaluation in selected patients.
