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ORIGINAL ARTICLE Table of Contents  
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An observational study of the endothelial dysfunction in type 2 diabetes mellitus and its association with risk factors


1 Department of Medicine and Baroda Medical College, Vadodara, Gujarat, India
2 Department of Medicine, Pramukhswami Medical College, Karamsad, Gujarat, India

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Date of Submission15-Dec-2021
Date of Decision11-Feb-2022
Date of Acceptance28-Feb-2022
Date of Web Publication25-Jun-2022
 

  Abstract 


Background: Cardiovascular diseases (CVDs) are the major culprit to cause morbidity in type 2 diabetes mellitus (T2DM) patients. Endothelial dysfunction (ED) precedes the progressed stage of CVD presentation. This study aimed to study the risk factors for ED and identify the modifiable factors for risk reduction and provide caution measures. Materials and Methods: This cross-sectional observational study included 100 adult patients with T2DM on oral hypoglycemic drugs or insulin therapy. Based on glycemic control, type 2 diabetic patients were divided into four groups: Group 1 (poor glycemic control and hemoglobin A1C (HbA1c) >9%), Group 2 (fair glycemic control and HbA1c 8%–8.9%), Group 3 (good glycemic control and HbA1C 7–7.9%), and Group 4 (excellent glycemic control, HbA1C <7%). P < 0.05 was considered statistically significant. Results: Overall, significantly higher glycemic levels (fasting blood glucose, postprandial blood glucose, and HbA1c) and lipid derangements (cholesterol, low-density lipoprotein, and triglyceride) were found in patients with ED as compared to those without ED (P < 0.05). Baseline brachial artery diameter (D1) was into three groups, one group with D1 (≤3.6 mm) with mean flow-mediated dilatation (FMD) of 9.07%, Another group of D1 (3.61 mm to ≤4.30 mm) with mean FMD of 5.26%, and the third group with D1 (>4.41 mm) with mean FMD of 4.58%. There was a statistically significant association seen between baseline brachial artery diameter and FMD (P < 0.05). Multivariate linear regression showed that HbA1c and treatment of both Oral hypoglycemic agents (OHA) and insulin were the significant independent factors affecting the ED with OR of 7.566 (P = 0.0003) and 0.013 (P = 0.011), respectively. Conclusion: In diabetics, the risk of ED is increased with worsening levels of lipid profile and glycemia irrespective of the age and duration of the disease.

Keywords: Endothelial dysfunction, flow-mediated dilation, type 2 diabetes mellitus


How to cite this URL:
Prajapati KV, Gandhi AU, Rathod MM, Patel MH, Patel S, Patel T. An observational study of the endothelial dysfunction in type 2 diabetes mellitus and its association with risk factors. APIK J Int Med [Epub ahead of print] [cited 2022 Oct 6]. Available from: https://www.ajim.in/preprintarticle.asp?id=348291





  Introduction Top


Type 2 diabetes mellitus (T2DM) is a worldwide prevalent, chronic disease with multiorgan involvement. Cardiovascular system disease (CVD) is present in approximately 32.2% of T2DM patients.[1] Globally, CVD is the major culprit to cause morbidity in T2DM patients. The high clinical burden of CVD complications in T2DM patients demands action for joint management of CVD and T2DM. Although strict glycemic control is the first approach to treatment, prevention strategy is the need of the hour. Early development stages of CVD such as endothelial dysfunction (ED) need attention.[1],[2]

ED precedes the progressed stage of CVD presentation.[2] Identification of risk factors leading to ED is of paramount importance so that prevention and correction can be implied in the early stages of ED to lower down rate of CVD, which often results in high morbidity and mortality in advanced cases of DM patients.

ED can be studied with ultrasound, angiography, and immunological methods.[2] Researchers in the recent past have assessed ED in T2DM by brachial artery flow-mediated dilatation (FMD). FMD is a noninvasive, method for the prediction of ED and efficiently evaluates vascular endothelial cells' function. Reduction in FMD is an alarm sign for CVD development. Previous studies have confirmed low FMD in T2DM.[3],[4]

Studies have enumerated risk factors such as smoking, hypertension, and dyslipidemia for ED, but not much effort has been put to investigate the relative association of these factors and glycemic control.[5],[6] A systematic approach to their early recognition will lead to the lower burden of CVD.

Hence, we studied risk factors for ED such as age, gender, smoking, body mass index (BMI), diabetes duration, and dyslipidemia in T2DM and its association with glycemic control. The aim was to identify the modifiable factors for risk reduction and provide caution measures. Our findings would be useful for the high-risk population such as first-degree relatives and early ED patients as they can take precautions and early treatment to timely rectify these identified risk factors for CVD in T2DM.


  Materials and Methods Top


A cross-sectional observational study was conducted over 1 year (November 2018–November 2019) on 100 adult patients with more than 18 years of age who were previously diagnosed cases of T2DM on oral hypoglycemic drugs or insulin therapy or were freshly diagnosed cases of T2DM as per the American diabetes association 2015 diagnostic criteria.[7] Any patient with coronary artery disease, peripheral vascular disease, cerebrovascular disease, hypertension, renal dysfunction, or statin therapy were excluded from the study. Written consent was obtained from all the patients participating in the study after clearly explaining the study procedure.

The sample size for the present study was based on the study of Naka et al.[8] who observed that the flow-mediated dilation was 1.98% ± 1.66%. Taking this value as reference, the minimum required sample size with an estimate to be within 20%, and 5% level of significance is 68 patients. To reduce the margin of error, the total sample size taken is 100.

The demographic and clinical details of the patients were recorded such as age, gender, duration of type 2 diabetes, BMI, waist circumference, addictions, and treatment is taken. All patients underwent investigation which included fasting blood sugar, postprandial blood sugar, hemoglobin A1C (HbA1c) (%), total cholesterol (TC), HDL, low-density lipoprotein (LDL), and triglyceride.

We informed the participants not to smoke, eat or drink anything containing caffeine, or should not take a fatty meal for 12 h before the FMD measurements. The participants were allowed to rest for at least 10 min before the first scan.

Then, we did the ultrasound procedure in the supine position with the use of high-resolution high-frequency Doppler linear vascular probe to measure the arterial diameter of the right brachial artery at a fixed position about 5 cm above the elbow joints. Brachial artery diameter was measured at rest and then during peak reactive hyperemia, for this blood pressure cuff was tied around the forearm which was inflated to 50 mmHg above systolic blood pressure for 5 min, followed by sudden deflation to generate an increase in blood flow in the brachial artery located proximal to the tourniquet. Lumen diameter was measured around 45–80 s after deflation of the cuff.

Percentage increase in lumen diameter during peak reactive hyperemia as compared to basal lumen diameter was labeled as FMD% which is a marker of endothelium-dependent dilation. FMD of <6.0% was taken as the presence of ED in our study.

FMD (%) = ([d2 – d1])/d1) × 100

d1 = Base line brachial artery diameter

d2 = Brachial artery diameter at 1 min postdeflation

The primary outcomes were ED as per FMD and the secondary outcomes were associated factors of ED.

Statistical analysis

The data presentation was done as n (%), mean ± standard deviation, and median values. Mann–Whitney test (for not normally distributed data) and independent t-test (for normally distributed data) were used to compare quantitative variables, and Chi-square test/Fisher's exact test was used to compare qualitative variables. Multivariate logistic regression was used to find out significant risk factors of ED. For statistical significance, P < 0.05 was considered statistically significant.


  Results Top


The mean age of the patients was 54.65 ± 11.82 years; 55.00% of the patients were males. The mean duration of type 2 diabetes was 4.54 ± 3.07 years. The mean BMI and waist circumference was 26.84 ± 4.09 kg/m2 and 93.84 ± 10.59 cm, respectively. The number of alcoholics and smokers was 21.00% and 27.00%, respectively. OHA was taken by 75.56% of patients, Injection insulin by 8.89%, and both by 15.56% of patients [Table 1].
Table 1: Distribution of sociodemographic characteristics

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Compared to patients without ED, patients with ED had comparable age (53.36 ± 11.35 vs. 56.51 ± 12.36, P = 0.19), gender (P = 0.854), mean duration of type 2 diabetes (years) (4.41 ± 3.05 vs. 4.73 ± 3.14, P = 0.62), BMI (P = 0.263), waist (P = 0.707), addiction (smokers, P = 0.377; alcoholics, P = 0.072), and HDL (P = 0.231). Overall, significantly higher glycemic levels (fasting blood glucose [FBG], postprandial blood glucose [PPBG], and HbA1c) and lipid derangements (cholesterol, LDL, and triglyceride[TG]) were found in patients with ED as compared to without ED (P < 0.05) [Table 2].
Table 2: Association of sociodemographic characteristics with endothelial dysfunction

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In the present study, we have divided baseline brachial artery diameter (D1) into three groups, one group with D1 (≤3.6 mm) with mean FMD of 9.07%, another group of D1 (3.61 mm to ≤4.30 mm) with mean FMD of 5.26% and the third group with D1(>4.41 mm) with mean FMD of 4.58%. Hence, as baseline brachial artery diameter increased, mean FMD decreased.

There was a statistically significant association seen between baseline brachial artery diameter and FMD (P < 0.05) [Figure 1].
Figure 1: Association of brachial artery diameter with endothelial dysfunction

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Multivariate linear regression showed that HbA1c and treatment of both OHA and insulin were the significant independent factors affecting the ED with OR of 7.566 (P = 0.0003) and 0.013 (P = 0.011), respectively [Table 3].
Table 3: Multivariate logistic regression to find out significant risk factors of endothelial dysfunction

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  Discussion Top


In the present study, we found ED among more than half of patients. ED presence in the majority implies poor glycemic control in DM; besides doing harm to other organs,[9] affects endothelium in a major way to further worsen the CVD. Hyperglycemia leads to metabolic alterations sustained oxidative stress, in turn resulting imbalance between antioxidant defense and harmful free radicals. Endothelial cell damage results in vasomotor dysfunction, increased endothelial apoptosis, hampering endothelial barrier, and triggering atherogenic response.[10],[11],[12],[13] These are major known alterations, although research on each component of the regulatory mechanism is ongoing.

ED in the present study was assessed by FMD which showed a decrease with the increase in brachial artery diameter. This may be because all parameters captured in FMD are more efficiently measured in major vessels, leading to higher specificity; eliminating factors leading to false results in narrower vessels. Other studies corroborated with our study. Meeking et al.[14] found significant reduction (P < 0.0001) in FMD in diabetic patients compared with control participants (2.4% vs. 6.3%). Rossi et al.[14] found a significant increase in the relative risk of diabetes with each unit decrease of FMD. Wu et al.[15] found FMD significantly decreased (P < 0.05) in DM, and with diabetes progression, FMD level descended. Henry et al.[16] showed DM2 was independently associated with impaired FMD.

FMD measurement holds importance as this parameter detects early ED changes with high specificity and sensitivity.[17]

In our effort to determine the association of ED with the severity of glycemia in the diabetics, we found significantly higher glycemic levels (FBG, PPBG, and HbA1c) among the patients with ED as compared to those without ED (P < 0.05). This clearly implies poor glycemic control to be a significant trigger for ED occurrence in DM patients.

Naka et al.[8] found worse glycemic control was associated with ED. Similar results were shown in other studies with varied global distribution.[15],[18],[19],[20] Contrary to our findings, previously reported data have not shown an association of glycemic control with ED.[21],[22] Conflicting results may be attributed to varied evaluation methods, study designs, therapeutic drugs administered, and heterogeneous study populations.

Among the other variables, we found significantly higher lipid derangements (cholesterol, LDL, and TG) in patients with ED as compared to those without ED (P < 0.05). Lipid derangements lead to endothelial oxidative stress, enhanced inflammatory response, and inhibition of insulin signaling. Moreover, mutual interactions between dyslipidemia, hyperglycemia and insulin resistance have a summative adverse effect for ED development.[11]

This significant association points to the fact that a balanced lipid profile is important in CVD cases of DM. Patients with diabetes mellitus are majorly concerned for controlling blood sugar levels only and often, they are not aware of additive harm that high lipids can do. Hence, findings highlight the need for a balanced diet and lipid levels check-in diabetes mellitus patients.

Other studies[15] showed similar results. Aberra et al.[23] found that higher TGs were associated with increased CVD risk, even at levels previously considered “optimal” (<150 mg/dL). Wu et al.[15] observed endothelium-dependent vasodilation impaired in T2DM patients is associated with hyperlipidemia. Compared to controls, significantly increased (P < 0.05) levels of TC, TG, and LDL-cholesterol were found in the DM2 group. However, a recent study[24] found no significant difference in levels of TG, LDL, and HDL in ED and non-ED groups.

Overall multiple regression showed that HbA1c and treatment of both OHA and insulin were the significant independent factors affecting the ED with OR of 7.566 (P = 0.0003) and 0.013 (P = 0.011), respectively. High HbA1c was associated with ED, which signifies that sustained hyperglycemia further invokes ED which in turn worsens DM. Hence, this vicious cycle of sustained high glucose and ED can be broken by control of sugar levels. Like our findings, Wu et al.[15] showed a negative correlation between impaired endothelial function and HbA1c. However, Koo et al.[24] found no significant difference in HbA1c in ED and non-ED groups.

Our all patients on insulin therapy had ED, unlike recipients of OHA (showed equal distribution of ED and non-AD). Hence, this indirectly reflects patients with ED have worse disease courses requiring higher stepped treatment with are managed by insulin.

However, recent studies with conflicting results (protective role vs. no effect) have come up investigating the role of OHA and insulin in ED.

We failed to note any significant association of demographic variables (age, gender), duration, BMI, and any addictions. Contrary to our results, Naka et al.[8] found decreased endothelial function was independently associated with older age. Sheibani et al.[25] found BMI as a predictor for CVD. A recent study[26] concluded the association of CVD with advanced age, higher BMI, and alcohol addiction.

The significantly higher glycemic levels (FBG, PPBG, and HbA1c) and lipid derangements (cholesterol, LDL, and TG) in patients with ED as compared to without ED implies that to lower down CVD burden on the health-care sector, these modifiable risk factors need preventive measures.

We suggest general changes in lifestyle such as regular exercise, avoid stress, and consume food rich in antioxidants;[27],[28] all these are highly recommended for high-risk populations with a family history of diabetes mellitus. Patients already diagnosed with diabetes mellitus should maintain blood sugar and lipid levels as they are major triggers for ED.

Our study holds strength as we excluded patients with hypertension, so we could assess ED risk factors in isolation without any interference and interplay by high BP in the FAD calculation. Studies in literature have not excluded this major confounding factor while assessing ED.

The limitation of our study is that we were not able to exclusively include freshly diagnosed cases of diabetes, and mean duration of 4.5 years in the rest of the cases would have certainly fogged down the actual result reflection of early ED assessment.

Second, the study had a small sample size which restricted the number of patients in subgroups on detailed data categorization. Hence, on the basis of our findings, we recommend prospective study with large cohort comprising patients with early diabetes and preferably newly diagnosed cases. Moreover, besides FMD, markers of endothelial function such as smooth muscle cell function and large artery stiffness could not be measured to assess common correlates.


  Conclusion Top


Diabetes mellitus predisposes an individual to ED and increases the chances of cardiovascular disease. The risk of ED is increased with worsening levels of lipid profile and glycemia irrespective of the age and duration of the disease. Thus, patients with diabetes must make an effort to restrict sugar and fat consumption and continue with regular exercise and lifestyle modifications for preventing further macrovascular complications.

Ethical clearance

Approval for conducting the study was taken from the Institutional Ethical Committee.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Correspondence Address:
Kesar Vinodbhai Prajapati,
Department of Medicine, Baroda Medical College, Vadodara, Gujarat
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ajim.ajim_128_21



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