Letter to the Editor: Hypothalamic-pituitary-adrenal axis dysregulation as a plausible contributor to glycated hemoglobin variability and cardiovascular risk in diabetes mellitus

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.

Key Words: Glycated hemoglobin; HbA1c variability; Hypothalamic-pituitary-adrenal axis; Cortisol; Cardiovascular risk; Diabetes mellitus; Adrenal incidentaloma

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.

TO THE EDITOR

We read with great interest the opinion review by Goyal et al[1] in the World Journal of Diabetes, arguing that visit-to-visit glycated hemoglobin (HbA1c) variability (usually quantified as the standard deviation, coefficient of variation, variability independent of the mean, or average real variability of serial HbA1c measurements[2]) adds cardiovascular risk information beyond mean glycemia, and that organ-protective drug selection should take precedence over HbA1c target optimization alone[1]. Before attributing such variability to glycemic instability or non-adherence, it is important to acknowledge common confounders of both the HbA1c level and its inter-visit fluctuation, including medication changes, dietary shifts, intercurrent illness, weight change, renal disease, anemia, altered erythrocyte lifespan, hemoglobinopathies, and exogenous glucocorticoid exposure. Against this background, we wish to highlight an additional endocrine mechanism that has received insufficient attention: Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis may be a plausible contributor to HbA1c variability, operating through two mechanistically distinct tiers.

Tier 1: Persistent elevation of cortisol and fluctuation of HbA1c

When cortisol dysregulation is sustained, as occurs specifically in mild autonomous cortisol secretion from adrenal incidentalomas or in subclinical Cushing’s syndrome, its effects persist across successive erythrocyte lifespans and may measurably shift the HbA1c average between clinical visits. Mild autonomous cortisol secretion is detectable in up to one-third of patients with adrenal incidentalomas and is characterized by insulin resistance, pancreatic β-cell dysfunction, central obesity, and dyslipidemia, all of which adversely affect glycemic stability[3]. Urinary free cortisol levels in patients with subclinical Cushing’s syndrome are positively correlated with fasting blood glucose and HbA1c[4], and surgical correction of cortisol excess improves glycemic control in the majority of such cases. Visit-to-visit HbA1c variability (the metric the authors correctly identify as an independent predictor of aortic stiffness progression, in-stent restenosis, and major adverse cardiovascular and limb events[5-7]) may therefore partly reflect unrecognized sustained cortisol excess in a subset of patients whose variability is otherwise misattributed to dietary non-adherence or suboptimal medication use.

Tier 2: Chronic psychological stress, overactivity of the HPA axis, and the feedback loop of HbA1c

In type 2 diabetes, chronic hyperglycemia activates the HPA axis through immune-inflammatory pathways: Interleukin-1β, interleukin-6, and tumor necrosis factor-α amplify corticotrophin-releasing hormone signaling, creating a feed-forward loop in which hyperglycemia sustains hypercortisolism and glucocorticoid-driven gluconeogenesis perpetuates hyperglycemia[8]. Chronic psychosocial stress and adverse early-life experience operate through this same axis, promoting sustained elevations in hepatic gluconeogenesis and increasing susceptibility to metabolic syndrome and type 2 diabetes[9]. Because these mechanisms alter the glycemic set point over weeks to months, which corresponds to the timescale of HbA1c synthesis and erythrocyte turnover, they may contribute meaningfully to the inter-visit HbA1c variability the authors discuss, independently of changes in diet, adherence, or pharmacotherapy.

Both tiers are clinically actionable within an HbA1c-centred framework. We propose that HPA axis evaluation, comprising a low-dose overnight dexamethasone suppression test and morning cortisol measurement, should be considered in selected patients with persistent, unexplained visit-to-visit HbA1c variability after common causes have been excluded. This is particularly relevant to patients with adrenal incidentalomas under surveillance, clinical features suggestive of cortisol excess (such as central obesity, resistant hypertension, proximal myopathy, or osteoporosis), or worsening insulin resistance disproportionate to weight gain. In patients with known adrenal adenomas, parallel monitoring of HbA1c variability may serve as a functional indicator of the metabolic significance of cortisol output[4]. More broadly, structured stress-management programs integrated into diabetes care have demonstrated dose-dependent reductions in HbA1c alongside reductions in urinary cortisol in randomized trial evidence[10], reinforcing the clinical utility of addressing HPA axis tone as part of glycemic management.

The authors’ call to move beyond glucocentric target-setting is well founded. Incorporating HPA axis assessment into the evaluation of treatment-resistant or variably controlled diabetes would extend this vision, linking endocrinology, psychosomatic medicine, and cardiovascular prevention into a more integrated clinical paradigm.