1 Introduction

Parkinson's disease (PD) is the second most prevalent and fastest-growing neurological disorder globally, characterized by progressive motor symptoms such as bradykinesia, muscle rigidity, and tremor, which severely impair quality of life and impose significant societal and economic burdens [1]. In 2019, PD affected over 10 million individuals worldwide [2]. The disease's primary pathology involves the irreversible loss of dopaminergic neurons in the substantia nigra pars compacta, and to date, no curative treatment exists, underscoring the critical need for effective primary prevention strategies.

Current risk factors for PD, such as advanced age, male gender, and genetic predisposition, are largely nonmodifiable [3]. Although modifiable environmental factors, such as exposure to air pollutants, have been implicated in PD risk, intervention strategies remain complex and challenging to implement [3]. Thus, identifying new modifiable risk factors that can be targeted for early intervention is of paramount importance. Notably, the higher incidence of PD in males compared to females suggests potential sex-specific mechanisms warranting further investigation.

Emerging evidence indicates that hyperglycemia, a marker of metabolic stress, plays a role in various adverse outcomes, including cardiovascular diseases and neurodegenerative disorders [4-6]. However, traditional glycemic metrics, such as fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c), provide limited insights into acute and chronic glycemic interplay. To address this gap, the stress hyperglycemia ratio (SHR) has been introduced as a novel marker that integrates acute glycemic changes (admission glucose) and chronic glycemic status (HbA1c) [7]. Studies have linked elevated SHR to increased risks of cardiovascular events and mortality, even in nondiabetic individuals [8-10]. Despite these findings, the potential relationship between SHR and PD risk remains unexplored, especially in the context of sex-specific and diabetes-specific differences.

This study aimed to investigate the association between SHR and the risk of developing PD, leveraging the UK Biobank's large prospective cohort. By stratifying analyses by sex and diabetes status, we seek to elucidate whether SHR serves as a significant predictor of PD and explore potential mechanisms underlying sex-specific vulnerability to metabolic stress.

2 Method

3 Results

3.1 Baseline Characteristics of the Study Population

A total of 406,271 participants (53.8% female, median age 58 [50, 63] years) were included in this study, with 2837 incident PD cases identified over an average follow-up period of 9 (standard deviation 2.2) years. The study flowchart is provided in Figure 1. Table S1 presents the baseline characteristics stratified by sex. Among male participants, 1801 developed PD, while 1036 cases were observed in females. Across both sexes, participants who developed PD were older and had higher rates of comorbidities, including hypertension, diabetes, stroke, and hyperlipidemia, compared to those who did not. Additionally, a higher proportion of current alcohol consumers was observed in the PD group, alongside elevated FPG and HbA1c levels.

3.2 Relationship Between SHR and PD

Table 1 details the associations between SHR and PD stratified by sex.

TABLE 1. Cox regression models for the association between SHR and PD.

Quantiles of the SHR	Women				Men
	Model 1		Model 2		Model 1		Model 2
	HR (95% CI)	p	HR (95% CI)	p	HR (95% CI)	p	HR (95% CI)	p
T1	Ref		Ref		Ref		Ref
T2	0.87 (0.75–1.01)	0.061	0.86 (0.72–1.03)	0.093	1 (0.89–1.12)	0.945	0.98 (0.85–1.12)	0.751
T3	0.96 (0.83–1.12)	0.627	0.92 (0.76–1.1)	0.341	1.17 (1.04–1.3)	0.006	1.2 (1.06–1.37)	0.004
Continuous
SHR	0.99 (0.63–1.58)	0.982	0.81 (0.45–1.43)	0.458	1.57 (1.16–2.12)	0.003	1.65 (1.17–2.32)	0.004

• Note: Model 1 age, Ethnic background, Townsend Deprivation Index. Model 2: age, Ethnic background, Townsend Deprivation Index, BMI, smoking status, alcohol consumption, physical activity (MET hours/week), hypertension, stroke, high cholesterol, sleep duration, and C-reactive protein levels.
• Abbreviations: CI, confidence interval; HR, hazard ratio.

In females, after adjustment for model 1 covariates, neither the second tertile (T2: HR 0.87 [95% CI: 0.75–1.01]) nor the third tertile (T3: HR 0.96 [95% CI: 0.83–1.12]) of SHR was associated with PD risk compared to the first tertile (T1). Adjusting for Model 2 covariates yielded similar results, with T2 (HR 0.86 [95% CI: 0.72–1.03]) and T3 (HR 0.92 [95% CI: 0.76–1.1]) remaining nonsignificant. When SHR was analyzed as a continuous variable, no significant association was observed (Model 1: HR 0.99 [95% CI: 0.63–1.58]; Model 2: HR 0.81 [95% CI: 0.45–1.43]).

In males, after Model 1 adjustment, T2 was not significantly associated with PD risk (HR 1.00 [95% CI: 0.89–1.12]), but T3 was linked to an increased risk of PD (HR 1.17 [95% CI: 1.04–1.30]). In Model 2, T2 remained nonsignificant (HR 0.98 [95% CI: 0.85–1.12]), while T3 was still associated with an elevated PD risk (HR 1.20 [95% CI: 1.06–1.37]). When analyzed as a continuous variable, SHR was positively associated with PD risk (Model 1: HR 1.57 [95% CI: 1.16–2.12]; Model 2: HR 1.65 [95% CI: 1.17–2.32]).

Sensitivity analyses, excluding participants diagnosed with PD within the first 2 years of follow-up (n = 1414, 63.4% men), confirmed the findings in males, with T3 remaining significantly associated with PD risk (HR 1.21 [95% CI: 1.06–1.38]) and SHR as a continuous variable showing a consistent association (HR 1.66 [95% CI: 1.17–2.35]) (Table S2).

Kaplan–Meier survival analyses illustrating event-free survival across SHR tertiles are presented in Figure 2.

Restricted cubic spline Cox regression analyses revealed that the association between SHR and PD risk was nonlinear in men (p for nonlinearity = 0.018), with a U-shaped curve suggesting increased risk at both lower and higher ends of SHR distribution (Figure 3B). In contrast, no significant association or nonlinearity was observed in women (p for nonlinearity = 0.833, Figure 3A). These findings suggest that the relationship between SHR and PD risk in men may not follow a simple linear trend, highlighting the complexity of metabolic stress responses in neurodegeneration.

4 Discussion

This study aimed to explore the association between the SHR and the risk of PD, with a particular focus on sex- and diabetes-specific factors. Our findings revealed a significant association between elevated SHR and an increased risk of PD in men, particularly those without diabetes, but not in women, men with prediabetes, or men with diabetes. These results highlight the complex interplay of metabolic stress in PD pathogenesis and underscore the need to investigate sex-specific mechanisms and the modifying effects of glucose metabolism status.

SHR is a novel marker that integrates both FPG and HbA1c to provide a more comprehensive measure of an individual's glycemic status, reflecting both acute and long-term glycemic control [15]. Elevated SHR signifies an acute state of metabolic stress, which is thought to be linked to various adverse outcomes, including cardiovascular disease, stroke [16, 17], and now, as demonstrated in this study, neurodegenerative diseases such as PD. While much of the literature has focused on chronic metabolic conditions like diabetes and their links to PD [18, 19], our findings suggest that acute metabolic stress, as indicated by a high SHR, may also play a significant role in the development of PD. This is an important step in understanding how fluctuations in blood glucose may affect the brain, potentially through inflammatory pathways, oxidative stress, or other mechanisms that influence neuronal health.

A striking finding in our study was the marked difference in the association between SHR and PD risk between men and women. While elevated SHR was associated with an increased risk of PD in men, this association was not observed in women. Several factors may contribute to these sex-specific differences.

First, there are well-documented differences in the neurobiological effects of sex hormones on the brain. Estrogen, a hormone that is more prominent in women, has been shown to have neuroprotective effects [20]. It is thought to reduce oxidative stress, modulate mitochondrial function, and enhance neuronal survival [21, 22], all of which could counteract the potentially harmful effects of elevated SHR on the brain. In contrast, men have lower levels of estrogen and may therefore be more susceptible to the harmful effects of metabolic stress on the brain. This might explain why we observed an association between SHR and PD risk in men but not in women.

Second, men and women may experience different patterns of metabolic disease and glycemic dysregulation. Men are more likely to develop metabolic syndrome, including central obesity and higher levels of visceral fat, which have been linked to systemic inflammation and oxidative stress [23, 24]. These metabolic disturbances could exacerbate the neurotoxic effects of elevated blood glucose levels, making men more vulnerable to the development of PD. In contrast, women tend to have a more protective fat distribution pattern and may be less prone to the systemic inflammation that exacerbates PD risk [25]. These biological differences may explain why SHR is a significant predictor of PD in men but not in women.

Third, lifestyle factors may also differ between the sexes and contribute to the observed differences. Men may have higher exposure to environmental toxins, engage in more physically demanding occupations, all of which may amplify the effects of metabolic stress on the brain [26-28]. Women, on the other hand, may benefit from a combination of lifestyle factors that mitigate these risks, such as lower alcohol consumption, greater health awareness, and better management of chronic conditions [29]. However, this hypothesis requires further investigation through more detailed lifestyle and environmental exposure data.

Furthermore, our restricted cubic spline analyses revealed a U-shaped association between SHR and PD risk in men, indicating that both relatively low and high SHR values may confer increased risk. This nonlinear pattern suggests that not only hyperglycemia but potentially relative hypoglycemia or other stress-induced glycemic instability may adversely affect neurological outcomes. This complexity underscores the need to consider SHR as a dynamic marker rather than a strictly linear predictor, and further mechanistic studies are warranted to elucidate how both extremes of glycemic stress influence PD pathogenesis.

Our study also investigated the relationship between SHR and PD risk in individuals with and without diabetes, revealing another important aspect of this relationship. In nondiabetic men, elevated SHR was associated with an increased risk of PD, while no significant association was observed in men with prediabetes or diabetes. Similarly, in women, SHR was not associated with PD risk regardless of their diabetes status, including prediabetes.

In nondiabetic men, elevated SHR may represent a transient but significant metabolic disruption, indicating a heightened acute response to stressors such as inflammation, hyperglycemia, or other metabolic disturbances. Nondiabetic individuals, particularly those without a history of chronic glycemic dysregulation, may experience a stronger acute inflammatory response to elevated glucose levels, which could contribute to the acceleration of neurodegenerative processes [30]. This suggests that the effects of SHR might be most pronounced in individuals without underlying chronic conditions like prediabetes or diabetes, where acute metabolic stress may have a more significant impact on brain function.

On the other hand, diabetic men, who are chronically exposed to higher levels of glucose and insulin resistance, may experience a desensitization of their neural tissues to the acute effects of elevated glucose levels [31]. Chronic hyperglycemia in diabetes could lead to a prolonged inflammatory state, which may not have the same acute impact on neuronal health as a transient spike in glucose [32, 33]. Similarly, in men with prediabetes, the intermediate state of glycemic impairment might not trigger the same acute metabolic stress response as seen in nondiabetic individuals, nor the chronic adaptation seen in diabetes, potentially explaining the lack of association with PD risk [34].

Recent studies have proposed that glucose metabolism abnormalities observed in patients with PD may not simply reflect systemic insulin resistance or chronic hyperglycemia, but rather arise from distinct pathophysiological processes within the central nervous system [35, 36]. For example, impairments in mitochondrial function, neuroinflammation, and altered dopamine–glucose coupling in the brain may independently drive central insulin resistance in PD, even in the absence of systemic metabolic disorders. This central dysregulation may partly explain why SHR, which primarily reflects acute peripheral glycemic stress, shows limited association with PD risk in individuals with established diabetes. In these individuals, chronic hyperglycemia may have already triggered long-term neuroadaptations or neuronal injury, potentially obscuring the added effect of transient glycemic excursions captured by SHR. Therefore, the lack of statistical significance in diabetic subgroups does not necessarily negate a pathophysiological link between glucose dysregulation and PD, but may instead reflect distinct temporal and mechanistic patterns of metabolic involvement in neurodegeneration.

These findings underscore the complex relationship between chronic metabolic conditions and acute metabolic stress. In individuals with diabetes, the body's adaptive mechanisms to long-term glucose fluctuations may reduce the impact of acute metabolic disturbances [37]. In individuals with prediabetes, the transitional glycemic state may mute the effects of SHR, while in those without diabetes, the absence of such adaptation may heighten susceptibility to the neurodegenerative effects of stress hyperglycemia, making SHR a more potent risk marker for PD in these populations.

The relationship between SHR and PD that we observed in men, particularly nondiabetic men, underscores the potential role of metabolic stress in PD pathogenesis. Chronic and acute disturbances in glucose metabolism may contribute to neurodegeneration through several potential mechanisms. Elevated glucose levels are known to induce inflammation, oxidative stress, and mitochondrial dysfunction—all of which are implicated in the development and progression of neurodegenerative diseases like PD [38, 39].

This study has several notable strengths. First, the large sample size and the use of a well-characterized cohort from the UK Biobank enabled robust analyses with comprehensive adjustment for potential confounders. Second, the sex-stratified and subgroup analyses added depth to the findings, uncovering nuanced associations that might be overlooked in a generalized analysis. Finally, the use of SHR, a novel and clinically relevant marker that integrates acute and chronic glycemic measures, adds a unique perspective to the study of PD risk factors.

However, several limitations should be acknowledged. First, the observational nature of this study precludes causal inference, and residual confounding cannot be ruled out despite comprehensive adjustments. Second, SHR was calculated using a single measurement of fasting glucose and HbA1c at baseline, which may not reflect glycemic variability over time. Third, while we stratified participants by glycemic status using ADA-defined cutoffs, the prediabetes definition did not include impaired glucose tolerance (IGT) due to the lack of oral glucose tolerance test (OGTT) data in the UK Biobank. This may have led to misclassification of individuals with isolated IGT, potentially underestimating associations within the prediabetes subgroup. Fourth, the study population consisted predominantly of individuals of European descent, which may limit the generalizability of our findings to other ethnic groups. Future studies incorporating OGTT measurements and more diverse populations are warranted.

5 Conclusion

In conclusion, this study provides evidence that elevated SHR is associated with an increased risk of PD in men, particularly in nondiabetic men, but not in women, prediabetic individuals, or diabetic individuals. These findings highlight the importance of considering sex- and diabetes-specific metabolic factors in PD research. While the study adds a novel perspective on PD risk, further studies are needed to validate these findings in diverse populations and to investigate the underlying mechanisms. Understanding the role of metabolic stress in PD development may pave the way for targeted prevention strategies and early interventions.

Author Contributions

H.Z., Y.M., X.Z., and W.X. designed the study and initial analysis plan. H.Z. and Y.M. contributed to the statistical analysis and wrote the draft of the manuscript. H.Z., Y.M., X.Z., W.X., and W.S. contributed to revision of the manuscript. All authors mentioned above made substantial contributions to the content of the paper.

Disclosure

The authors have nothing to report.

Ethics Statement

The UK Biobank was established with ethical clearance from the North West Multi-Centre Research Ethics Committee (reference: 21/NW/0157).

Consent

Written informed consent have been provided by all participants.

Conflicts of Interest

The authors declare no conflicts of interest.