Serum Uric Acid and HRV in Prediabetes and Diabetes

ABSTRACT IMAGE

INTRODUCTION

There is some really intriguing research out there looking into how hyperuricemia connects with various health issues such as hypertension, heart failure, and other cardiovascular diseases. What’s surprising, though, is that not many studies have delved into its link with diabetes mellitus. Uric acid is the end result of purine metabolism and plays a key role in this whole picture. When hyperuricemia occurs, uric acid can seep into cells and act as both an oxidant and a standalone risk factor for developing type 2 diabetes mellitus (T2DM). This situation creates oxidative stress, which in turn reduces nitric oxide levels, making it harder for tissues to take up insulin and potentially lowering insulin sensitivity.^[1] On top of that, uric acid can trigger the Renin–Angiotensin–Aldosterone System, kicking off a series of harmful changes that lead to vascular dysfunction and inflammation, ultimately resulting in cardiovascular and kidney complications. Moreover,^[2-4] decreased heart rate variability (HRV) is a sign of cardiac autonomic dysfunction (CAD) and is also seen in individuals with type 2 diabetes, although more research is needed in this area.^[5-7] The relationship between uric acid levels and HRV has not been thoroughly investigated in people with pre-diabetes or diabetes. Benichou et al., noted that T2DM is linked to a general decline in HRV among patients. This altered sympathetic and parasympathetic activity is thought to stem from the negative effects of disrupted glucose metabolism, which can lead to cardiac autonomic neuropathy.^[2] Coopmans et al.,^[3] found that both prediabetes and type 2 diabetes are linked to a decrease in HRV. Their study shows that people who have prediabetes might already be experiencing issues with their heart’s automatic functions. In addition, a review by Xiong et al.,^[6] confirmed a positive relationship between uric acid levels and diabetes mellitus.^[3] Van Der Schaft et al.,^[7] suggested that there is a connection between hyperuricemia and the onset of prediabetes and type 2 diabetes.^[4] We were inspired to dive into the connection between serum uric acid (SUA) levels and HRV in individuals with prediabetes and diabetes mellitus, especially given the limited research in Southern India. Understanding the balance between sympathetic and vagal activity, along with changes in SUA levels, could be key in spotting early signs of CAD in diabetes patients, particularly those who are prediabetic. This motivated us to measure SUA levels and HRV in both men and women within these two groups. We also wanted to explore how SUA relates to HRV across both genders in our study.

MATERIALS AND METHODS

The study took place in the Department of Physiology and kicked off after receiving the green light from both the Institutional Ethics Committee and the Institutional Research Committee. We included a total of fifty-six participants, made up of 28 individuals diagnosed with diabetes mellitus and 28 prediabetic individuals, all randomly selected from the diabetic clinic in the Department of Medicine. Each participant provided written consent before joining the study. The HRV analysis was conducted in the Department of Physiology. According to the World Health Organization criteria, all prediabetic individuals in our study had HbA1c levels ranging from 5.7% to 6.4%, while those with diabetes had HbA1c levels of 6.5% or higher. We chose to focus on HbA1c levels instead of plasma glucose levels because they are a more reliable indicator of hyperglycemia. All diabetes patients included in our study received treatment with allopathic medications. Subjects who were on diuretics, lipid-lowering agents, hyper- or hypouricemic agents, antihypertensives, or those with any clinical suspicion of malignancy, acute infectious diseases, acute inflammatory diseases, or renal issues were excluded. In addition, any prediabetic subjects with hyperuricemia were also excluded, ensuring that only those with normal uric acid levels were included for a proper correlation analysis. SUA levels were tested using an auto-analyzer with Vitros uric acid reagent in the Biochemistry laboratory. Normal SUA values were defined as 2.5–7.0 mg/dL for males and 1.5–6.0 mg/dL for females, with levels above 7.0 mg/dL in males and 6.0 mg/dL in females classified as hyperuricemia.^[5] The HRV analysis was performed using PowerLab AD Instruments from Australia.

RESULTS

DISCUSSION

This study reinforces the well-established observation that SUA levels tend to be higher in patients with diabetes mellitus, which is consistent with findings from previous epidemiological and clinical research. Our results show that both HbA1c and SUA levels were notably higher in the diabetes group compared to the prediabetes group [Figures 1a and 1b], aligning with the diagnostic criteria and our understanding of the mechanisms behind diabetes. Interestingly, SUA levels were normal in individuals with prediabetes, hinting at a potential early metabolic imbalance that could precede hyperuricemia and diabetes [Figures 2a and 2b, 3a and 3b]. We also observed a consistent decline in HRV components, such as TP, HF, and LF, in both the diabetic and prediabetic groups, with a more pronounced drop in those with diabetes. This finding is in line with other studies that suggest CAD may be an early complication of diabetes [Figures 4a and 4b, 5a and 5b, 6a and 6b]. The increased LF/HF ratio in the prediabetes group points to a sympathetic-vagal imbalance even before the condition progresses to full-blown diabetes, supporting Coopmans et al.^[3] findings that prediabetes is linked to lower HRV and early signs of autonomic dysregulation. Tables 1 and 2 indicated values based on diabetes and prediabetes groups.

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Figure 1:

Correlation between uric acid and HRV in patients of diabetes. (TF: Total frequency, LF: Low frequency, HF: High frequency, HRV: Heart rate variability)

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Figure 2:

Correlation between uric acid and HRV in female diabetic patient. (TF: Total frequency, LF: Low frequency, HF: High frequency, HRV: Heart rate variability)

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Figure 3:

Correlation between uric acid and HRV in male diabetic patient. (TF: Total frequency, LF: Low frequency, HF: High frequency, HRV: Heart rate variability)

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Figure 4:

Correlation between uric acid and HRV prediabetic individuals. (TF: Total frequency, LF: Low frequency, HF: High frequency, HRV: Heart rate variability)

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Figure 5:

Correlation between uric acid and HRV prediabetic female individuals. (TF: Total frequency, LF: Low frequency, HF: High frequency, HRV: Heart rate variability)

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Figure 6:

Correlation between uric acid and HRV prediabetic male individuals. (TF: Total frequency, LF: Low frequency, HF: High frequency, HRV: Heart rate variability)

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We also observed sex-based differences in autonomic function, with males showing a more severe reduction in HRV compared to females. This aligns with research suggesting that gender can influence autonomic tone, possibly due to the protective effects of estrogen on the cardiovascular system. The higher LF/HF ratio in females indicates sympathetic dominance, likely influenced by hormonal factors, as noted in previous studies. Table 3 indicated values based on diabetes and prediabetes groups

Hyperuricemia, or high levels of uric acid in the blood, triggers oxidative stress through the production of reactive oxygen species (ROS). This process can lead to issues like endothelial dysfunction and inflammation in the blood vessels, as thoroughly discussed by Coopmans et al.^[3] and Xiong et al.^[6] The oxidative environment created here messes with how insulin is secreted and how sensitive our bodies are to it. Matsuoka et al.^[8] pointed out that ROS, which depend on glycation, can actually suppress the expression of insulin genes, while Li et al.^[9] found that increased activity of xanthine oxidase can kickstart diabetes. These factors play a role in the complex relationship between high SUA levels and poor glucose metabolism, suggesting that hyperuricemia is both a result of and a contributor to metabolic issues.^[10]

Our results align with the findings of Bombelli et al.,^[11] who noted that hyperuricemia stands out as an independent risk factor for impaired fasting glucose and metabolic syndrome – both of which can lead to diabetes. In addition, uric acid’s activation of the renin-angiotensin-aldosterone system might worsen problems in the blood vessels and kidneys, increasing cardiovascular risks, as shown in other studies.^[12]

In our research, we found a connection between a higher LF/HF ratio and elevated HbA1c levels, which echoes previous studies, particularly by Benichou et al.^[2] They pointed out that reduced HRV^[13-15] can indicate cardiac autonomic neuropathy, which correlates with glycemic control. The drop in VLF power we observed fits with the work of Usui and Nishida,^[14] who linked VLF to slower recovery after stress, hinting at a reduced ability of the autonomic system to adapt in diabetes.

The relationship between HRV^[2,4] and SUA is quite intriguing, especially when we look at how the LF/HF ratio correlates positively with SUA in men. This suggests that uric acid might play a significant role in disrupting the balance of our autonomic nervous system and contributing to sympatho-vagal dysfunction in diabetes. These findings echo the research by Shen et al.^[15] who highlighted SUA’s link to insulin resistance and autonomic issues, even among those who are not diabetic or are in the prediabetic stage. In addition, pointed out SUA’s connection to islet beta-cell dysfunction, reinforcing the relationship between high uric acid levels and problems with glucose regulation.

The increase in sympathetic activity, indicated by the rising LF/HF ratio alongside SUA levels, could lead to enhanced lipolysis and higher free fatty acid concentrations. This, in turn, may reduce insulin sensitivity and adversely impact heart function and HRV, which is a key aspect of metabolic syndrome.^[13] This chain of events offers a solid explanation for the early signs of autonomic dysfunction that we often see in prediabetes and diabetes, highlighting the need to keep an eye on both SUA and HRV in these groups.^[14,15]

It is also important to consider the differences between sexes, as men showed a more significant drop in HRV. This could be linked to differences in how oxidative stress is managed, hormonal influences, and overall cardiovascular risk. While the small sample size here makes it hard to draw firm conclusions, it certainly points to a vital area for future research that should involve larger studies focused on gender differences.

Our study really highlights the importance of catching cardiac autonomic neuropathy early in people with prediabetes and diabetes. We are using HRV^[2,4] along with SUA as a possible predictive marker. By addressing high uric acid levels and autonomic imbalance early on, we could potentially protect cardiovascular health and enhance metabolic outcomes. What makes this study stand out is how it sheds light on the relationship between SUA, HRV, and gender differences within an Indian population.

This group is seeing a rise in diabetes cases, yet there is not much data on autonomic dysfunction and the role of uric acid. To really confirm our findings and develop personalized prevention strategies, we need more extensive, long-term studies that combine molecular and clinical markers.

CONCLUSION

This study reveals a clear link between serum uric acid levels and lower heart rate variability in people with diabetes mellitus. Interestingly, even those in the prediabetic stage showed early signs of cardiac autonomic dysfunction, despite having normal uric acid levels. These results emphasize the need to assess both serum uric acid and heart rate variability as potential early indicators of autonomic issues in prediabetes and diabetes. This highlights the importance of early detection and intervention to help lower the risk of future cardiovascular problems.