Type 2 Diabetes Intensifies Nocturnal and Early Morning Circadian Autonomic Dysregulation After Ischaemic Stroke

Diabetes is a well‐established independent risk factor for stroke, with studies showing higher incidence and mortality rates among affected individuals [1, 2]. It causes a range of complications involving multiple organ systems, among which cardiac autonomic neuropathy (CAN) is well‐recognised yet often underdiagnosed. CAN disrupts autonomic regulation of cardiac function and is associated with an increased risk of cardiovascular events and mortality [3]. However, the circadian profile of autonomic function in diabetic patients during the acute post‐stroke phase remains poorly characterised compared with that in non‐diabetic stroke patients.

Heart rate (HR) and HR variability (HRV) are non‐invasive, valuable tools for assessing cardiac autonomic function and identifying individuals at risk for CAN [4, 5]. Diabetes exerts profound and detrimental effects on the circadian regulation of HR and HRV, primarily through the development of CAN [6, 7]. Elevated resting HR, blunted nocturnal HR dips and a generalised reduction in HRV parameters are consistently observed in individuals with diabetes, reflecting widespread impairment of the autonomic nervous system [8]. Notably, diabetes has been reported with increased frequency among patients presenting with wake‐up stroke [9, 10], which implies that diabetes‐related disturbances in circadian regulation may primarily manifest during sleep or in the early morning hours before awakening.

Chronic hyperglycaemia and longer disease duration have been identified as key drivers of this autonomic dysfunction [11]. Early detection of these abnormalities through accessible tools like 24‐h electrocardiographic (ECG) monitoring and HRV analysis is crucial for risk stratification. However, few studies have employed long‐term ECG monitoring to evaluate the impact of type 2 diabetes on circadian HR and HRV patterns in patients with ischaemic stroke.

In this study, we aimed to investigate the circadian rhythms of HR and HRV in patients with ischaemic stroke using continuous 7‐day ECG monitoring and to assess whether type 2 diabetes and glycaemic control status are associated with alterations in these parameters. By characterising time‐dependent changes in autonomic activity, we sought to clarify the clinical significance of diabetes‐related autonomic dysfunction in the post‐stroke setting. We hypothesised that type 2 diabetes attenuates circadian autonomic fluctuations, particularly during nocturnal and early morning periods when parasympathetic dominance is expected. Understanding these patterns may help identify high‐risk periods for cardiovascular events and guide autonomic‐targeted interventions after stroke.

This study demonstrates that type 2 diabetes disrupts circadian autonomic regulation after ischaemic stroke, particularly during the nocturnal and early morning periods when parasympathetic dominance is physiologically expected. Patients with type 2 diabetes exhibited persistently elevated HRs and markedly reduced HRV across both time‐ and frequency‐domain measures than those without diabetes. Despite maintaining an overall circadian rhythm of HR, they showed blunted autonomic fluctuations, most evident at night and before awakening. Moreover, poorer glycaemic control was associated with greater autonomic dysfunction, supporting a dose–response relationship. Together, these findings support our hypothesis that diabetes is associated with attenuated circadian autonomic flexibility after ischaemic stroke and suggest that nocturnal autonomic dysregulation may merit further investigation as a potential therapeutic target.

Diabetes increases stroke risk through mechanisms such as endothelial dysfunction, arterial stiffness, inflammation and cardiac abnormalities, with impaired nitric oxide signalling and heightened inflammatory activity contributing to atherosclerosis and cardiovascular complications [15]. Beyond these mechanisms, CAN has been independently associated with a higher risk of stroke in a large cohort of adults with type 2 diabetes [16]. CAN is a common yet underdiagnosed complication of diabetes, arising from nerve and vascular damage and leading to impaired HR control and abnormal vascular responses [17]. A reduction in HRV is among the earliest subclinical signs of CAN, typically beginning with parasympathetic impairment before progressing to sympathetic dysfunction [18]. CAN also profoundly disrupts the circadian rhythm of HR and HRV in diabetic patients, as evidenced by a reversal of normal day–night modulation and impaired sympathovagal balance. These alterations in autonomic regulation may contribute to the increased risk of nocturnal arrhythmias and adverse cardiac outcomes—including wake‐up stroke—observed in diabetic patients [9, 10, 12, 19].

Our study showed that ischaemic stroke patients with type 2 diabetes exhibited consistently higher HR and lower HRV indices—particularly SDNN, RMSSD, pNN50 and HF—than those without diabetes, with differences most pronounced during the night and early morning hours. These differences were less evident during the day. Parasympathetic activity typically peaks at night, whereas sympathetic tone dominates during the day. This pattern suggests that parasympathetic dysfunction, rather than heightened sympathetic activity, underlies the autonomic impairment in patients with type 2 diabetes. The blunted nocturnal rise in HRV parameters and attenuated circadian variation across both time‐ and frequency‐domain measures, as confirmed by GAMM analysis, further support this interpretation. These findings align with prior reports, including Yu and Lee [20], which emphasises that parasympathetic dysfunction is an early and central feature of CAN in diabetes. Notably, cholinesterase inhibitor therapy, which enhances parasympathetic activity, has been associated with improved HRV by restoring autonomic balance and a reduced risk of cardiovascular events [21–23]. Given the parasympathetic impairment observed in stroke patients with type 2 diabetes, cholinesterase inhibitors may represent a promising therapeutic option in this high‐risk population.

In our study, although patients with type 2 diabetes exhibited relatively preserved circadian rhythms in both HR and HRV indices, the rhythmicity of HRV indices was notably attenuated, with reduced amplitude and less pronounced oscillations compared with HR. This differential pattern suggests that the regulatory mechanisms governing circadian HR and HRV are differentially vulnerable to diabetic complications. The preservation of circadian rhythmicity in HR and HRV in diabetes may indicate that the central circadian pacemaker in the suprachiasmatic nucleus remains functional, continuing to regulate HR and HRV through neurohumoral outputs and autonomic modulation [24]. Additionally, intrinsic cardiac mechanisms—such as the local molecular clock within cardiomyocytes—may contribute to the persistence of robust HR rhythmicity despite systemic metabolic disturbances [25]. Conversely, HRV is primarily influenced by the dynamic balance and reactivity of the autonomic nervous system, particularly parasympathetic (vagal) and sympathetic tone [26]. CAN, a common complication of diabetes, impairs both branches of the autonomic nervous system and growing evidence suggests that overall autonomic responsiveness is attenuated in diabetic individuals, even during circadian transitions [18]. This may account for the observed flattening of HRV rhythms. Taken together, these findings support the notion that diabetes differentially affects circadian cardiovascular regulation: while central circadian mechanisms governing HR and HRV remain relatively intact, the fine‐tuned autonomic control necessary for generating robust HRV oscillations is compromised, resulting in dampened but persistent circadian HRV patterns.

Although Perciaccante et al. [27] observed increased nighttime LF power in insulin‐resistant individuals with normoglycaemia, impaired fasting glucose or impaired glucose tolerance—suggesting early‐stage sympathetic overactivity—LF power was markedly reduced in patients with diabetes. Similarly, the present study demonstrated consistently lower LF and HF power in patients with type 2 diabetes across the 24‐h period, particularly characterised by blunted nocturnal variation (Figure 3). This reduction likely reflects diminished activity in both sympathetic and parasympathetic branches of the autonomic nervous system, consistent with more advanced stages of CAN, in which autonomic nerve damage impairs the normal modulation of HRV.

Elevated glycaemic levels have been linked to adverse effects on cardiac autonomic function in patients with diabetes. The most significant decline in HRV tends to occur in the early years following a diabetes diagnosis, particularly among those with poor glycaemic control [11]. In the present study, diabetic patients with suboptimal glycaemic control (HbA1c > 7% [53 mmol/mol]) exhibited higher HRs and lower HRV, especially during nighttime and early morning hours, compared to those with better control (HbA1c ≤ 7% [53 mmol/mol]). These time‐dependent differences mirrored those observed between diabetic and non‐diabetic individuals, albeit to a lesser extent, suggesting a dose–response relationship between glycaemic burden and autonomic dysfunction. These findings underscore the importance of avoiding sustained hyperglycaemia to preserve cardiac autonomic function.

Several limitations of this study should be acknowledged. First, it was conducted at a single centre with an ethnically homogeneous population, potentially limiting the generalizability of the findings to other ethnic groups or healthcare systems. In addition, because only patients with ischaemic stroke were included, we were unable to compare diabetic individuals with and without stroke; therefore, the stroke‐specific contribution to circadian autonomic alterations in diabetes could not be directly determined. Second, this was a secondary analysis of data originally collected for a different primary purpose, and the application of additional exclusion criteria may have introduced selection bias. Third, although the ECG patch provided 14 days of continuous monitoring, only the first 7 days were analysed to ensure data consistency, which may have led to underutilisation of the available data. Fourth, despite adjusting for a wide range of clinical and laboratory variables, residual confounding from unmeasured factors such as physical activity, sleep quality, psychological stress or medication adherence cannot be ruled out. Fifth, while HRV is a widely accepted surrogate for autonomic nervous system function, direct autonomic testing was not performed and could have provided more comprehensive physiological insight. Future prospective studies with multiethnic cohorts and direct autonomic testing are needed to confirm these findings and elucidate underlying mechanisms. Finally, pre‐stroke HR and HRV measurements were unavailable, as is common in acute stroke cohorts, and therefore causal attribution of stroke‐related or diabetes‐related changes in autonomic patterns cannot be definitively established. Future prospective, multiethnic studies incorporating direct autonomic testing are warranted.

This study underscores the substantial impact of type 2 diabetes and glycaemic control on circadian autonomic regulation in patients with ischaemic stroke. The observed alterations in HR and HRV reflect early autonomic impairment that may not be apparent through routine clinical evaluation. By leveraging continuous ECG monitoring, our findings provide novel insights into the time‐dependent nature of autonomic dysfunction associated with type 2 diabetes. Continuous autonomic monitoring may help identify nocturnal cardiovascular vulnerability in diabetic stroke patients. Interventions that enhance parasympathetic tone, including optimised glycaemic control and potentially cholinergic modulation, warrant further investigation as strategies to reduce post‐stroke cardiovascular risk. Together, these findings highlight the need for targeted approaches to monitor and manage autonomic function in stroke survivors.

Jiann‐Der Lee conceived and designed the study, curated the data, performed formal analysis and investigation, developed the methodology, supervised the project and draughted the original manuscript. Ya‐Wen Kuo contributed to study conceptualisation, formal analysis, investigation, funding acquisition, project administration and critical revision of the manuscript for important intellectual content. Yen‐Chu Huang and Meng Lee contributed to data curation, formal analysis, methodology development and investigation. Chuan‐Pin Lee contributed to data curation, formal analysis and investigation. Tsong‐Hai Lee contributed to methodology, formal analysis and investigation.

This work was supported by grants from CHING PAO P.D. Charitable Foundation (Grant FCRPF6L0033).

The authors remain fully responsible for the accuracy and integrity of the manuscript. All authors reviewed, edited and approved the final version of the manuscript for submission. Ya‐Wen Kuo is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the analysis. The sponsors played no role in the study design, data collection and analysis or decision to submit the article for publication.

The study was approved by the Institutional Review Board of Chang Gung Memorial Hospital, Chiayi Branch, Taiwan (202101821B0C501). Patients provided written informed consent to participate in this study. All methods were carried out in accordance with relevant guidelines and regulations.

The authors declare no conflicts of interest.

Additional supporting information can be found online in the Supporting Information section.