Original Article

Evaluation of Endothelial Function and Effect of Glycemic Control (Excellent Vs Poor / Fair Control) on Endothelial Function in Uncontrolled Type 2 Diabetes Mellitus

SN Chugh*, Surekha Dabla**, Vinish Jain***, Kiran Chugh****, Jyotsna Sen*****

*Senior Professor of Medicine and Pro Vice-Chancellor, **Associate Professor, Department of Medicine, ***Ex-Resident, Department of Medicine, ****Associate Professor, Department of Biochemistry, *****Professor, Department of Radio-Diagnosis, Pt. B. D. Sharma Post Graduate Institute of Medical Sciences (PGIMS), Rohtak & Pt. B. D. Sharma University of Health Sciences, Rohtak, Haryana, India. Received: 13.04.2009; Revised: 07.07.2009; Accepted: 08.07.2009

Abstract

Objective: To evaluate the endothelial functions before and after glycemic control in type II diabetes mellitus.

Material and Methods: It was an open, randomized and comparative study on 30 patients of type 2 diabetes mellitus. The study was of 12 weeks spread over 5 visits. The initial visit (visit 1) is for screening of patients. Other visits (visits 2 to 5) constituted the follow up of patients. The primary efficacy parameters included blood sugar (fasting and postprandial) done on each visit and glycosylated hemoglobin (HbA1c) done at visits 1 and 5. Based on glycosylated hemoglobin (HbA1c) only poorly controlled and fairly controlled patients were included in the study. Brachial artery flow mediated vasodilatation (FMD) was studied in all these patient at visits 1 and 5 to see the effect of glycemic control on endothelial functions. Results obtained were statistically analyzed with appropriate method.

Results: There was a significant improvement in endothelial functions in patients with fair, good and excellent control of diabetes. During uncontrolled state (HbA1c 10.08 ± 0.48 %) FMD was lowest i.e. 2.88 ± 0.53 at 1st week which improved to 11.94 ± 3.33 at 12th week with control of diabetes (HbA1c 6.74 ± 0.16 %). The FMD in patients who had fair control (HbA1c 8.45 ± 0.30 %) in the beginning was 6.74 ± 2.43 % and after excellent control in these patients FMD rises to 12.81 ± 3.16%.

Conclusion: Our data showed that the endothelial functions improved sequentially with control of diabetes from fair to good to excellent glycemic control.

Introduction

Diabetes mellitus has assumed epidemic proportion in the new millennium. The W.H.O. has projected that global prevalence of type-II diabetes mellitus will tremendously increase to more than double from 135 million in 1995 to 300 million by 2025.1 The American Diabetes Association recently designated type-II diabetes mellitus as a major risk factor for cardiovascular diseases.2 Atherosclerosis which is a precursor for macro-vascular disease involves both functional as well as structural changes in the vasculature. Functional changes involve abnormalities in endothelium, vascular smooth muscle cells and platelet functions.3,4 Endothelial function is the earliest to be affected in this cascade of events leading to atherosclerotic plaque formation.3,5

The metabolic abnormality in type-II diabetes mellitus provokes various molecular mechanisms which contribute to endothelial dysfunction3,4,6,7 due to which vessels are unable to dilate sufficiently in response to appropriate stimuli and ultimately tissue perfusion diminishes gradually. This endothelial dysfunction is followed by structural changes in vasculature and atherosclerotic plaque formation leading onto macrovascular complications.5, 6,8 Endothelial dysfunction is a reversible process9 but uncontrolled diabetes mellitus and unchecked endothelial dysfunction ultimately leads to irreversible structural changes in the vasculature, so by preventing the development of endothelial dysfunction or reversing it after development will prevent or delay the macro-vascular complications. Therefore, early detection of endothelial dysfunction can help in the detection of macrovascular complications which are likely to occur in future in type-II diabetics10,11 and thus help in planning primary and secondary preventive strategy in these patients.8,9

The International Task Force on brachial artery reactivity has endorsed the brachial artery flow-mediated vasodilatation (FMD) as standard test for screening of endothelial dysfunction.12,13 Using this technique several studies conducted during the past decade demonstrated the link between endothelial dysfunction, impaired glucose tolerance and type-II diabetes mellitus.14-17 A recently concluded study on endothelial dysfunction and diabetic foot ulcer risk endorsed that a fundamental defect in endothelial function reflected in flow-mediated dilatation is the basis of microvascular complications in diabetic subjects.18 Scanty literature exists on the effect of glycemic control on endothelial dysfunction in type-II diabetes mellitus. Hence, the present study was conducted to evaluate the endothelial function and effect of glycemic control (excellent vs poor/fair control) on endothelial function in uncontrolled type 2 diabetes mellitus.

Material and Methods

30 patients with uncontrolled type-II diabetes mellitus were included in the study and 10 normal healthy subjects served as controls. The conditions/diseases likely to affect endothelial functions such as coronary artery disease, hypertension, peripheral vascular disease, cerebrovascular disease, chronic illnesses, chronic alcoholism and patients on statin therapy were excluded from the study.

Study design: It was an open, randomized and comparative clinical study.

Duration of study: The total duration of study was 12 weeks. All the patients were advised to follow dietary as well as drug interventions for strict control of diabetes mellitus.

Details of visits: The study comprised of 5 visits.

Visit 1 (Initial visit) was meant for screening the patients for inclusion in the study.

The 2nd, 3rd and 4th visits were follow up visits on the 2nd, 4th and 6th week respectively. Finally the 5th visit was on the 12th week of study.

Parameters of Control

Short-term glycemic control was evaluated by measuring fasting and postprandial blood sugar levels on each visit and long term glycemic control was evaluated by measuring Glycosylated hemoglobin (HbA1c) on the initial and the last visits. The patients included in the study were grouped as per their glycosylated haemoglobin levels in four groups (Table 1).

We only included poorly controlled and fairly controlled diabetics in this study so as to evaluate the effect of glycemic control.

Brachial artery flow mediated vasodilatation (FMD) was studied in all patient after overnight fasting (8 hours) using 7.5 Hz phased array linear transducer. The medial epicondyle was used as anatomical landmark for brachial artery. Flow mediated vasodilatation (FMD) was calculated as:-

Target Parameters

Two target parameters [glycosylated haemoglobin (HbA1c) and brachial artery flow mediated vasodilatation (FMD)] were performed twice i.e. at first visit to establish basal values and thereafter at the 12th week to study the effect of control.

Statistical analysis- Student “t” test was applied for statistical significance. Paired “t” test was used for intra group comparison and unpaired “t” test was used for comparison between groups.

Results

The patients and control included in this study were age and sex matched. The initial endothelial functions in patients and controls are shown in Table 2.

All the patients included in this study had highly significant mean glycosylated haemoglobin (HbA1c) 9.43 ± 0.91% as compared to control i.e. 5.78 ± 0.30% and FMD was significantly reduced to 4.43 ± 2.47% in patients with respect to healthy controls i.e. 13.39 ± 3.09. This fact indicated that endothelial dysfunctions occurred in the patients with uncontrolled diabetes (p<0.001). Endothelial functions evaluated further in two groups (Group I and Group II) are depicted in table 3 and 4 respectively. The patients of Group I (HbA1c 10.08 ± 0.48 %) had lowest FMD e.g. 2.88 ± 0.53 % indicating severe endothelial dysfunction during first visit. The endothelial function improved serially with control of diabetes and FMD reached to 11.94 ± 3.33 % at visit 5 when excellent control was achieved (HbA1c 6.74 ± 0.16%).

Discussion

Endothelial dysfunction appears early as a key event in atherogenesis, long before the structural changes and hyperglycemia is a major determinant factor for reduced flow mediated vasodilatation.3,13,19 The endothelial functions, hence, are likely to improve with control of hyperglycemia.14,16,19 The uncontrolled state of diabetes produces changes in the vascular tone due to reduced nitrous-oxide production and formation of advanced glycation product with the result the vasodilatation of the arteries suffer. This stage is reversible with control of diabetes because structural changes of atherosclerosis have not been still initiated. Endothelial dysfunction is the earliest marker of macrovascular complications and can be assessed by Flow-mediated vasodilatation. Flow-mediated vasodilatation (FMD) in our patients during uncontrolled state (HbA1c 10.08 ± 0.48 %) was 2.88 ± 0.53 at visit 1 which improved to 11.94 ± 3.33 at visit 5 with control of diabetes (HbA1c 6.74 ± 0.16 %). It is a known fact that the endothelial functions improve in parallel with the glycemic control13,16,17 but to what extent is still not known. Based on this concept, the FMD was measured in patients with poor control (group-I), it was 2.88 ± 0.53% at visit 1 which improved to 11.94 ± 3.33 % at visit 5 with excellent control. This fact clearly indicated that improvement in endothelial functions occurred in parallel with the achievement of glycemic control, a fact not highlighted in the literature. This fact further has been highlighted by our findings in group-II. The FMD in patients who had fair control (HbA1c 8.45 ± 0.30 %) in the beginning was 6.74 ± 2.43 % indicating that it was already better as compared to group-I (poor control). It itself strengthens the fact that FMD improves serially with achievement of various stages of control. These patients showed further improvement and FMD rises to 12.81 ± 3.16% equal to excellent control achieved in group-I. Thus, now, we have established that there is scope of improvement in FMD at every stage of control though the literature is silent on this aspect. Finally, we emphasize that excellent control should be the target to achieve maximum improvement in FMD so as to retard or delay the development of macrovascular disease in diabetic patients.

References

1. King H, Rewers M. Global estimates for prevalence of diabetes and impaired glucose tolerance in adults. WHO ad hoc diabetes reporting group. Diabetes Care 1993;16:157-77.
2. American Diabetes association. Standards of medical care for patients with diabetes mellitus (Position Statement).Diabetes Care 2003;26(Suppl. 1):S33–S50.
3. Cohen RA. Dysfunction of vascular endothelium in diabetes mellitus. Circulation 1993;87:67-76.
4. King GL, Kunisahi M, Nihio Y. Biochemical and molecular mechanisms in the development of diabetic vascular complications. Diabetes 1996;45 Suppl 3:S105-8.
5. Ross R. The pathogenesis of atherosclerosis: a perspective for 1990s. Nature 1993;362:801-9.
6. Creager MA, Luscher TF. Diabetes and vascular disease. Circulation 2003;108:1527-32.
7. Hink U, Li H, Mollnau H, Oelze M, Matheis E, Hartmann M, Skatchkov M et al, Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res 2001;88:E14-22.
8. Reddy KG, Nair RN, Sheehan HM, Hodgon J. Evidence that selective endothelial dysfunction may occur in the absenceof angiographic or ultrasound atherosclerosis in patients with risk factors for atherosclerosis. J Am Coll Cardiol 1994;23:833-843.
9. Celemajor DS. Endothelial dysfunction: Does it matter? Is it reversible? J Am Coll Cardiol 1987;30:325-33.
10. Yu HI, Sheu WHH, Lai CJ, Lee WJ, Chen YT. Endothelial dysfunction in type 2 diabetes mellitus subjects with peripheral artery disease. Inter J Cardiol 2001;78:19-25.
11. Bhargava K, Hansa G, Bansal M, Tandon S, Kasliwal RR. Endothelium-dependent brachial artery flow mediated vasodilatation in patients with diabetes mellitus with and without coronary artery disease. J Assoc Physicians India 2003;51:355-8.
12. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, Drexler H et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilatation of the brachial artery: A report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 2002;39:257-65.
13. Patel S, Celermajer DS. Assessment of vascular disease using arterial flow mediated dilatation. Pharmacological Reports. 2006;58(suppl.):3-7.
14. Kawano H, Motoyama T, Hirashima O, Hirai N, Miyao Y, Sakamoto T, Kugiyama K et al. Hyperglycemia rapidly suppresses flow-mediated endothelium-dependent vasodilatation of brachial artery. J Am Coll Cardiol 1999;34:146-54.
15. Manzella D, Grella R, Abbatecola AM, Paolisso G. Repaglinide administration improves brachial reactivity in type 2 diabetic patients. Diabetes Care 2005;28:366-71.
16. Caballero AE, Saouaf R, Lim SC, Hamdy O, Abou EK OP”Connor C Et al. The effects of troglitazone, an insulin-sensitizing agent, on the endothelial function in early and late type 2 diabetes: a placebo controlled randomized clinical trial. Metabolism 2003;52:173-80.
17. Ravikumar R, Deepa R, Shanthi Rani CS, Mohan V. Comparison of carotid intima-media thickness, arterial stiffness and brachial artery flow-mediated vasodilatation in diabetic and non-diabetic subjects (The Chennai Urban Population Study (CUPS No.9). Am J Cardiol 2002;90:702-7.
18. Fryer J, Ellepola W. A Prospective study of endothelial dysfunction and diabetic Foot Ulcer Risk- sponsored by Department of Veterans Affairs-U.S. FDA resources referred as ClinicalTrials.gov Identifier: NCT00013286.2009.
19. Shige H, Ishikawa T, Suzukawa K, Ito T, Nakajima K, Higashi K, Ayaori M et al. Endothelium-dependent flow-mediated vasodilatation in the postprandial state in type 2 diabetes mellitus. Am J Cardiol 1999;84:1272-4.