Journal of Diabetology

ORIGINAL ARTICLES
Year
: 2020  |  Volume : 11  |  Issue : 3  |  Page : 191--197

The relationship between serum triglyceride level and heart rate variability in type 2 diabetes mellitus patients of North Karnataka


Fareedabanu A Balikai1, Neeta Deshpande2, Shivalingappa Javali3, Darshit P Shetty4, Jyoti M Benni5, Varsha Shindhe1, Kamaruddin Jaalam6, Nitin Kapoor7,  
1 Department of Physiology, USM-KLE International Medical Programme, Belgaum, Karnataka, India
2 Department of Medicine, USM-KLE International Medical Programme, Belgaum, Karnataka, India
3 Department of Community Medicine, USM-KLE International Medical Programme, Belgaum, Karnataka, India
4 Department of Obstetrics and Gynaecology, USM-KLE International Medical Programme, Belgaum, Karnataka, India
5 Department of Pharmacology, USM-KLE International Medical Programme, Belgaum, Karnataka, India
6 Department of Physiology, USM-KLE International Medical Programme, Belgaum, Karnataka, India; Department of anaesthesia and critical care medicine, School of Medical sciences, PPSP USM Kubang kerian, Malaysia and USM-KLE International Medical Programme, Belgaum, India
7 Department of Endocrinology, Diabetes and Metabolism, CMC Vellore, Vellore, Tamil Nadu, India

Correspondence Address:
Dr. Fareedabanu A Balikai
Department of Physiology, USM-KLE International Medical Programme, USMKLE, Nehru Nagar, Belgaum, Karnataka.
India

Abstract

Context: Diabetes mellitus is associated with an increased risk of mortality and morbidity from cardiovascular disease (CVD), which is mainly because of dyslipidemias. Several researchers have suggested that increased serum lipid fractions such as low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) were linked to decreased heart rate variability (HRV). Until now no papers have studied the association between serum triglyceride (TG) values and HRV. Aims: The objective of this study was to evaluate the relationship between serum TG levels and HRV in patients with type 2 diabetes mellitus. Materials and Methods: The study included 120 patients with type 2 diabetes mellitus (both male and female) of the age group 35–65 years, who visited Belgaum Diabetes Centre. They were selected by simple random sampling and recruited into the study. The patients were divided into three groups depending on the duration of diabetes. The study duration was 6 months. One-minute HRV was analyzed during deep breathing and defined as the difference between the shortest and the longest heart rate interval measured by Lead II electrocardiographic recording during six cycles of deep breathing using an electrocardiograph (BPL Cardiart 6208 BPL Medical Technologies Pvt Ltd, Bannerghatta Road, Bangalore, India). Kubios HRV Standard (version 3.0, Department of Applied Physics, University of Eastern Finland, Kuopio, Finland) software tool was used to analyze HRV. Fasting serum TG of all the patients (5mL of venous blood) was analyzed using semiautomatic analyzer (Transasia Erba Chem –5 Plu, Transasia Bio-Medicals, Andheri east, Mumbai, Maharashtra, India). Data were analyzed by using Statistical Package for the Social Sciences (SPSS 20.0 version, IBM Bangalore, Karnataka, India) software program, version 20.0. One-way analysis of variance (ANOVA) followed by Tukey’s multiple post hoc tests was used for comparison and Karl Pearson’s correlation coefficient was used to test the correlation between serum TG values and HRV in the three groups. The statistical significance was set at 5% level (P < 0.05). Results: No significant difference was observed in the TG levels (P > 0.05) between the three groups of patients with type 2 diabetes mellitus. The TG levels were significant and negative correlation was observed with HRV (r = 0.6141, P = <0.001) at 5% level of significance in all the three groups. Conclusion: From this study, we conclude that the hypertriglyceridemia in patients with type 2 diabetes mellitus could affect HRV. Further studies are needed to prospectively validate the impact of this novel finding.



How to cite this article:
Balikai FA, Deshpande N, Javali S, Shetty DP, Benni JM, Shindhe V, Jaalam K, Kapoor N. The relationship between serum triglyceride level and heart rate variability in type 2 diabetes mellitus patients of North Karnataka.J Diabetol 2020;11:191-197


How to cite this URL:
Balikai FA, Deshpande N, Javali S, Shetty DP, Benni JM, Shindhe V, Jaalam K, Kapoor N. The relationship between serum triglyceride level and heart rate variability in type 2 diabetes mellitus patients of North Karnataka. J Diabetol [serial online] 2020 [cited 2020 Oct 30 ];11:191-197
Available from: https://www.journalofdiabetology.org/text.asp?2020/11/3/191/294054


Full Text



 Key Message:



Hypertriglyceridemia in patients with type 2 diabetes mellitus is very hazardous and is negatively associated with HRV.

 Introduction



Diabetes mellitus (DM) is a hereditary, chronic endocrine, and metabolic disorder, which leads to increased mortality worldwide.[1] India, a developing Asian country with fast industrialization and adopting a modern lifestyle changes, is facing a serious problem in having the major number of people with increase in incidence of diabetes,[2],[3] which is estimated to reach 80 million by the year 2030.[4],[5] Diabetes is associated with an increased risk of mortality and morbidity from cardiovascular diseases (CVD) which is mainly because of atherogenic dyslipidemias, which is characterized by raised triglycerides (TGs), low high-density lipoprotein (HDL), and high small dense low-density lipoprotein (LDL) particles. The lipid abnormalities are common in DM, because insulin resistance or deficiency affects the key enzymes and pathways in lipid metabolism.[6] Approximately 70%–97% of adults with type 2 diabetes have one or more lipid abnormalities.[7] Abnormal serum lipids contribute to the risk of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM) and assessment of the serum lipid levels in people with diabetes is now considered as a standard of the diabetes care.[8] Abnormal lipid profiles and lipoprotein oxidation are more common in diabetes and are elevated with a poor glycemic control. It is well recognized that patients with diabetes and dyslipidemia have an excess risk of cardiovascular morbidity and mortality because the lipid particles in these patients are more atherogenic than in general population.[9] The main step in the direction of reducing the risk of CVD related with diabetes is detection and treatment of dyslipidemia.[10] According to the American Diabetes Association (ADA) guidelines, LDL-cholesterol (LDL-C) lowering is the first priority, lowering TG level is the second priority, and raising levels of HDL-cholesterol (HDL-C) is the third priority.[11]

Heart rate variability (HRV) has gained an importance in recent years as a noninvasive technique. It has been used in various fields of health and disease via its time- and frequency-domain analysis and used to explore the autonomic nervous system (ANS).[12],[13] In the presence of cardiac autonomic neuropathy, patients with diabetes with or without CVD have a decreased HRV related to increased mortality risk.[14] HRV is a measure of the imbalance between sympathetic and parasympathetic autonomic activity, and its decrease is a sign of dominance of sympathetic activity.[15] It is well known that decreased HRV leads to increased cardiovascular risk, particularly to an increased arrhythmic risk both in CVD patients and healthy subjects. Decreased HRV and sympathovagal imbalance have been reported to be associated with increased cardiovascular mortality. The sympathovagal imbalance is considered as the main pathophysiological basis for metabolic disorders in DM.[16],[17],[18] Several studies on the relationship between plasma lipid fractions and HRV have provided less consistent results. Previous studies have suggested that increased serum lipid fractions such as LDL-C and total cholesterol (TC) were linked to a decreased HRV, although there are still some conflicting results.[19],[20]

The link between hyperlipidemia and depressed HRV is not very well studied. The possible hypothesis linking the association between TGs and HRV could be medicated by the role of catecholamines. Epinephrine and norepinephrine are not only known to increase heart rate but also increase the lipolysis and free fatty-acid production, thereby increasing their hepatic uptake. The blunting in the sympathetic response due to cardiac autonomic neuropathy may alter this pathway in addition to reducing the heart rate. Hence, changes in the catecholamine response in cardiac autonomic neuropathy may be an important link explaining the association between these two clinical variables.

So far, no association has been definitively established between serum TG values and HRV. Hence, this study was undertaken to identify and correlate the relationship between serum TG levels and HRV in patients with type 2 diabetes.

 Materials and Methods



The subjects enrolled in this study were patients with T2DM who were visiting the Belgaum Diabetes Centre, Maruti Galli, Belagavi. Approximately 120 patients with T2DM (both male and female) of age between 35 and 65 years visiting from different places of north Karnataka, with a history of diabetes for more than a month to more than 10 years, were randomly selected and examined for dyslipidemias. Patients with type 1 diabetes, young-onset diabetes, and gestational diabetes mellitus (GDM) patients were excluded from the study. Ethical clearance was obtained for the study from the institutional ethical committee of USM-KLE International Medical Programme, Belagavi. The aim of the study was explained to all the participants and an informed written consent was obtained in vernacular languages. They were selected by simple random sampling and recruited into the study. The study duration was 6 months. Patients were classified into three different groups based on the duration of the diabetes as follows:

Group 1: Patients with T2DM with duration less than 5 years.

Group 2: Patients with T2DM with duration 5–10 years.

Group 3: Patients with T2DM with duration more than 10 years.

HRV was measured using a simple bedside test of 1-min HRV during forced deep breathing.[21] The test was performed using an electrocardiograph (ECG) (BPL Cardiart 6208). The subjects had to lie down quietly in a supine posture and Lead II of the ECG machine was connected to record the heart rate. After obtaining a basal heart rate record, the patients were instructed to breathe deeply at 6‒8 breaths/min (for one respiratory cycle, the time taken will be 10s, 5-s inspiration and 5-s expiration). Lead II was then recorded continuously at a paper speed of 25mm/s for 1min. The maximum variation in heart rate produced was calculated by measuring the differences between minimum heart rate on inspiration and maximum on expiration. The HRV was measured using Kubios HRV (version 3.0) software tool, which analyzes HRV in time domain, frequency domain, and nonlinear indices.

Basal fasting lipid levels of all the patients were noted from their previous reports (if performed within the last 3 months, or else fresh values were obtained). The blood sample was collected after ensuring 12h of overnight fasting. TC, TG, and HDL-C levels were estimated in serum. TC and TG levels were estimated by enzymatic colorimetric method, whereas HDL level was estimated by direct enzymatic liquid method. LDL-C was calculated using the Friedewald formula (LDL-C [mg/dL] = non-HDL-C – TG/5).[22] All the parameters were analyzed on semiautomatic analyzer (Transasia Erba Chem –5 Plus). “As per standard international guidelines, a serum triglyceride value more than 200mg/dL was considered as hypertriglyceridemia.”

Statistical analysis

The data were analyzed by using Statistical Package for the Social Sciences (SPSS) software program, version 20.0. The Kolmogorov–Smirnov one-sample test was applied to assess the normality of all variables and found that all variables data followed a normal distribution. Then, the parametric tests, that is, one-way analysis of variance (ANOVA) followed by Tukey’s multiple post hoc tests for comparison and Karl Pearson’s correlation coefficient, was performed to see the correlation between serum TG values and HRV in the three groups. The statistical significance was set at 5% level (P < 0.05).

 Ethical Clearance



Ethical approval for this study (USM-KLE/IEC/08-2017-02) was provided by the Institutional Ethics Committee, USM-KLE International Medical Programme, Belgaum, Karnataka, on 01 August 2017.

 Results



Male and female were equally distributed in all the three groups (χ2 = 2.4001, P = 0.3011). But the mean age was found significantly higher in Group 3 compared to Groups 1 and 2. The least mean age was found in Group 1 (F = 13.3115, P < 0.05). However, no significant difference was observed in the mean BMI score of all the three groups [Table 1]. Of 120 patients, 44 patients were on insulin, 66 patients on antihypertensive, 27 patients on hypolipidemic drugs, 11 patients on aspirin/clopidogrel, and 5 patents had a history of ischemic heart disease.{Table 1}

A declining trend was observed in both serum TG and HRV across the three groups. No statistical difference was observed between the mean serum TG and HRV values of all the three groups (P > 0.05) [Table 2] and [Table 3]. A strong negative correlation was seen between TG and HRV/mean RR interval (P < 0.001) [Table 4] and [Figure 1][Figure 2][Figure 3][Figure 4].{Table 2} {Table 3} {Table 4} {Figure 1} {Figure 2} {Figure 3} {Figure 4}

 Discussion



This study showed hypertriglyceridemia in all the three groups which was consistent with previous studies,[23] where significantly higher mean serum levels of TC, TG, and LDL-C were noted in patients with T2DM, which are well-known risk factors for CVDs among patients, when compared to the healthy controls. Hypertriglyceridemia is usually associated with reduced HDL-C, which is also a prominent feature of plasma lipid abnormalities seen in individuals with diabetes.[24] The cluster of lipid abnormalities associated with T2DM is defined by a high concentration of TG and small dense LDL and a low concentration of HDL-C.[25] The major abnormalities with the respect to the dyslipidemia in T2DM include increased number of TG-rich particles, increased postprandial concentrations of TG-rich particles, increased number of LDL particles, small dense LDL particles, decreased HDL particle numbers, and several changes in particle composition of HDL.[26]

Our study also showed a significant negative correlation between hypertriglyceridemia and HRV. More recent data have confirmed the significant correlation between CAD mortality and increasing plasma TG concentration. Hypertriglyceridemia can lead to the development of atherosclerosis by a number of mechanisms. One of these is involving a change in HDL metabolism.[27] It is well documented that a high HDL-C level is cardioprotective and low HDL-C levels are widespread in patients with type 2 diabetes, and this appears to be associated with the increased mortality and morbidity in coronary heart disease (CHD). In addition, low HDL-C levels are commonly escorted by elevated TG levels, and the combination appears to be the most severe combination for hastening vascular damage.[28] Dyslipidemia may be an important factor for the development of autonomic dysfunction, and data regarding correlations between serum lipids and HRV are controversial.[19],[20] A study by Ali et al.[29] showed that dyslipidemia might cause disturbed ANS activity as evidenced by the significant decrease in all time-domain indices including mean normal to normal interval (NN), Standard deviation of NN intervals, measured in milli seconds (SDNN), and Root mean square of successive RR interval differences, measured in Milli seconds (RMSSD) in the dyslipidemic group. In addition, there was significant decrease in frequency-domain indices such as total power (TP), high-frequency (HF), very-low-frequency (VLF), and Relative power of the high-frequency band (0.15–0.4Hz) in normal units (HFnu) and significant elevation in low-frequency (LF), Relative power of the low-frequency band (0.04–0.15Hz) in normal units (LFnu) and ratio of LF-to-HF power in percentage (LF-HF) ratio in the dyslipidemic group was observed. Most studies have revealed that decreased HRV, as a strong predictor for CHD, was associated with hypercholesterolemia.[30],[31]

Dyslipidemia is a metabolic abnormality, which is frequently associated with DM. It plays a vital role in the pathogeunesis of developing complications of T2DM. Abnormalities in lipid metabolism have been described in patients with diabetes accompanied by an increased risk of cardiovascular arteriosclerosis. In addition, abnormality in the level of each of the major lipids has been independently related with increased risk of CVD.[32] The lipid abnormalities are more prevalent in diabetes, because insulin resistance or deficiency affects the key enzymes of lipid metabolism pathways. Numerous studies have shown that insulin plays a vital role in liver apolipoprotein production and regulates the enzymatic activity of lipoprotein lipase and cholesterol ester transport protein, which causes dyslipidemia in DM. In addition, insulin deficiency increases mobilization of free fatty acid from adipose tissue and reduces the activity of hepatic lipase and numerous steps in the production of biologically active lipoprotein lipase.[33],[34],[35] The possible mechanism responsible for hypertriglyceridemia may be due to increased hepatic production of very low density lipoprotein (VLDL) via lipogenesis as well as decreased apolipoproteins B degradation, resulting in low HDL-C, increased apolipoproteins B synthesis, small dense LDL-particles, and delayed clearance of TG-rich lipoproteins.[36],[37]

The increase in cardiovascular morbidity and mortality rates in diabetes appears to relate to the synergism of hyperglycemia with other cardiovascular risk factors. Poor glycemic control and hypertriglyceridemia are significant biochemical abnormalities in patients with T2DM. Persistent hyperglycemia causes increased intracellular glucose. This leads to the formation of advanced glycosylation end products, which bind to a cell surface receptor, via the nonenzymatic glycosylation of intra- and extracellular proteins, leading to cross-linking of proteins, accelerated atherosclerosis, and altered extracellular matrix composition. This eventually causes endothelial cell dysfunction, contributing further to atherosclerosis.[38] It may be observed that all these studies including our study emphasize that the abnormal lipid levels are associated with decreased HRV. Therefore, good glycemic control can prevent development and progression of lipid abnormalities among patients with DM. Therefore, improving glycemic control might substantially reduce the risk of dyslipidemia, and hence the cardiovascular events in patients with T2DM.

Early diagnosis and treatment is a hallmark of quality care. From this study, we conclude that the hypertriglyceridemia in patients with T2DM is very hazardous as it increases the incidence of cardiovascular abnormality which is indicated by decrease in HRV. Therefore, there is an urgent need for screening and therapeutic intervention for dyslipidemia to minimize the risk for atherogenic cardiovascular disorder and cerebrovascular accident in patients with T2DM.

Limitation of the study

The potential limitation of the study was that it was performed in a single hospital often seeing higher risk patients; it could be subjected to a bias inherent of this type of study. Further research based on prospective studies is needed to study the correlation between serum TG and HRV values in different hospital setups.

Recommendations

Early management of dyslipidemia and improvement of glycemic control are helpful in reducing the incidence of CVD among patients with T2DM. The awareness of patients with diabetes about their high risk of having dyslipidemia complications and the importance of having routine screening for their lipids profile should be maintained and implemented by developing effective strategies by healthcare providers and decision makers in the country. Measurement of 1-min HRV can be included as one of the screening tests to identify the complications associated with diabetes such as autonomic neuropathy.

Acknowledgement

First and foremost we would like to extend our heartfelt gratitude to Universiti Sains Malaysia (USM), Kubang Kerian, Malaysia for approving and granting this study. We would like to extend our kind regards to our beloved director Dr. H.B. Rajshekhar for his continuous support during the study. We would like to thank all the staff of Belgaum Diabetes Centre, Belagavi for their sustained support in acquisition of data. Last but not the least we would also like to mention a special thanks to all the patients who have generously given their consent and time to participate in this study.

Financial support and sponsorship

Received Grant from School of Medical sciences, PPSP USM Kubang kerian, Malaysia

Conflicts of interest

There are no conflicts of interest.

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