Perspective - Journal of Diabetology (2024) Volume 8, Issue 3

Attenuation of Endothelial Dysfunction In Diabetes Mellitus: An Integral Characteristic of Anti-Diabetic Medications

Article type: Perspective
Homepage URL: https://www.alliedacademies.org/journal-diabetology/
Journal short name: J Diabetol
Volume: 8
Issue: 3
PDF No: 209
Citation: Freeman D J. Exploring Diabetes Complications: Causes and Preventive Strategies. J Diabetol. 2024;8(3):209
*Correspondence to: Dilys J. Freeman, Department of Renal Transplantation, Institute of Organ Transplantation, Xi'an Jiaotong University, China. E-mail: valenchidi@gmail.com

Received: 26-Apr-2024, Manuscript No. AADY-24-132296; Editor assigned: 28-Apr-2024, PreQC No. AADY-27-126045 (PQ); Reviewed: 12-May-2024, QC No. AADY-24-126045; Revised: 17- May-2024, Manuscript No. AADY-24-126045 (R); Published: 22- May-2024, DOI:10.35841/AADY-8.3.209

ABSTRACT

The complications of diabetes mellitus have incapacitated many patients especially in poor income countries. Diabetes mellitus is an endocrine disease but its far- reaching complications arise from cardiovascular derangements. The cardiovascular complications usually stem from endothelial dysfunction which culminates in atherosclerosis. Progressively, atherosclerosis results in micro-vascular and macro-vascular complications.

Key words: Diabetes, endothelial dysfunction, biomarkers, anti-diabetic drugs, C-reactive protein, Intercellular Adhesion Molecule.

Methods

Literature searches were carried out in Google , Pubmed and Medline using the following key words: diabetes mellitus, endothelial dysfunction, biomarkers, anti-diabetic drugs, c-reactive protein, intercellular adhesion molecule.

Summary

The aim of the review is to evaluate the  mechanisms responsible for endothelial dysfunction in diabetes. Endothelial dysfunction may arise from one or combination of these molecular mechanisms:

• decreased nitric oxide synthesis,
• activation of protein kinase C,
• activity of advanced glycation end-products (AGE),
• activation of tumor necrosis factor- α, iv) defective insulin signaling and so on.

The biomarkers of endothelial dysfunction were also explored and they include C-reactive protein (CRP), micro-albuminuria, asymmetric dimethylarginine (ADMA), Toll- like receptors and others . The review also evaluated the effectiveness of anti-diabetic medications in modulating the biomarkers of endothelial dysfunction  in diabetic patients.

  Current Statistics on Type 2 Diabetes Mellitus

Diabetes mellitus has reached an alarming proportion and the current projection is that of approximately 700 million persons worldwide being affected by the metabolic disorder in 2045 [1]. In  Nigeria, a systematic review by Uloko, et al [2], reported a pooled prevalence of 5.7% which is progressively higher compared to 1.5% and 1.9% reported for males and females respectively in 1988 [3] . The increasing prevalence of diabetes also portends a corresponding rise in the microvascular and macrovascular complications. This has necessitated the review of cardiovascular endothelial dysfunction  in diabetes mellitus and the extent to which anti-diabetic drugs can ameliorate the pathophysiological abnormality..  

Biology of Vascular Endothelium

Vascular endothelium refers to the intima of blood vessels.  It is a  monolayer of endothelial cells which constitutes the innermost linings of blood vessels- arteries ,veins and capillaries [4]. Vascular endothelium was thought to be a mere barrier in several decades ago. However, with recent understanding, the endothelium was noted to possess some complex structural and chemical entities bonded together for several functions. Glycocalyx and vinculin make up the main structural complexes of the endothelium [4]. The glycocalyx is composed of glycosaminoglycans and proteoglycans lining the vascular lumen. The glycocalyx functions in regulation of vascular permeability and in transduction of fluid shearing forces [5, 6]. Shear stress from turbulent blood flow ultimately results in endothelial injury and release of the embedded chemical mediators [7]. Vinculin is located mainly at the adherens junction and also contribute to the endothelial barrier integrity [8] .

 The endothelium  is also considered as an endocrine organ since it secretes some chemical mediators such as nitric oxide, thromboxane and prostacyclin [9]. These signaling molecules may exhibit autocrine or paracrine characteristics.  

Endothelial dysfunction refers to the loss of the functional and physical properties of the endothelium. The dysfunction leads to a vasoconstrictive, prothrombotic and pro-inflammatory sequalae [10].The complications of cardiovascular diseases are related to the disruption of the normal endothelium.

Diabetes and Endothelial Dysfunction

Diabetes mellitus is an endocrine disease caused by relative or absolute insulin deficiency manifesting with chronic hyperglycemia[11]. Though diabetes mellitus is regarded as an endocrine disease, the manifestations of the complications are related to the endothelial disruptions of the blood vessels in the retina, nephrons, body extremities and the heart.

How does Diabetes Mellitus cause Endothelial Dysfunction (Mechanisms)

Proper understanding of the molecular mechanisms of endothelial dysfunction in diabetes may give rise to therapeutic and preventive approaches in the management of complications of diabetes. So adequate understanding of the mechanisms is very crucial. The mechanisms include:

• Decreased Nitric oxide synthesis: Insulin enhances nitric oxide synthase (NOS) activity through the protein kinase B (AKt) pathway [12]. Thus, in conditions of insulin deficiency or resistance, NO synthesis is reduced [ 13]. The eNOS  is the predominant form of NOS in the  normal endothelium but with the onset of endothelial damage, inducible forms  become prevalent [14]. There is an interplay between NADPH oxidases and eNOS which results in reduction of NO by consumption of NO but not by inhbition of eNOS activity [15] .
• Activation of Diacylglycerol (DAG) -Protein Kinase C (PKC): Chronic hyperglycemia results in increased synthesis of diacyl glycerol (DAG) [16 ]. Dihydroxyacetone phosphate is an intermediate compound produced from glycolysis which is subsequently converted to glycerol-3-phosphate. Diacylglycerol is eventually synthesized from glycerol-3-phosphate[16]. Diacylglycerol activates protein kinase C, a catalytic factor implicated in diabetic vascular complications [17]. Protein Kinase C increases vascular permeability, cellular growth and apoptosis and leucocyte aggregation which contribute to endothelial dysfunction [17].
• Role of Tumor Necrosis Factor alpha (TNFα): The cytokine is a homotrimeric protein with a molecular weight of 17 kDa and is produced from immunological cells such as T-lympocytes and macrophages [18]. Insulin resistance in type 2 DM and endothelial dysfunction is associated with increased TNFα [19]. TNF may cause elaboration of intracellular adhesion molecule (ICAM) and Vascular cell adhesion molecule (VCAM) with adherence of monocytes [20].
• Formation of Advanced Glycation End-products (AGEs). Chronic hyperglycemia results in glycosylation of structural components of the endothelium. The outcome of the glycosylation is increased oxidative stress, cytokines and transcription factors and atherosclerosis [21, 22] .
• Defective  insulin signaling: Insulin is an anabolic and bioactive hormone and has a causes vasodilatory effect via eNOS activity [23]. Thus insulin resistance in type 2 DM impairs insulin function as well NO synthesis which gives rise to endothelial dysfunction.

Biomarkers of Endothelial Dysfunction in T2dm

The vascular endothelium harbours some multiple chemical mediators which are released into the blood stream when there is disruption or damage to the vessels. Therefore, the biochemical markers become elevated in patients with marked endothelial dysfunction. The biomarkers  include plasminogen activator inhibitor-1 (PAI-1),  von Willebrand factor (vWF), C- reactive protein (CRP), cellular adhesion molecules (VCAM, ICAM), endothelin -1, selectins (P- & S-), nitric oxide  and microalbuminuria [23, 24].

1. C-reactive protein (CRP) is an acute phase reactant produced in the liver via the activity of some cytokines such as tumor necrosis factor-α , interleukin- 1 & 6 (26]. Singh and co-researchers [27] showed that a small percentage of CRP is synthesized from the endothelial cells of blood vessels. Researchers have shown that the endothelial cells of human aorta and coronary arteries were able to synthesize CRP, IL- 6 and IL-1 but not TNF are stimulators of its synthesis [28][29]. C-reactive protein has a pro- atherogenic potential thus, the serum concentration is increased in cardiovascular diseases such as diabetes. High sensitivity CRP is a strong independent predictor of vascular dysfunction [30,31].

The alteration in adipokine function as it occurs in insulin resistant states stimulate CRP production in the liver as well as from the vessels. IL-6 is the main regulator of CRP production by up-regulating transcriptional factors especially C/EBPβ and C/EBP delta [32]. CRP can cause the inhibition of NO production and enhance the formation of adhesion molecules and platelet activator inhibitor.

Kanmani et al [33] has also demonstrated  a positive association between CRP and incident T2DM in a Korean cohort especially in those ≥ 50 years. In addition to T2DM, obesity and hypertension were also identifiable risk factors.

2. Plasminogen Activator Inhibitor-1 (PAI-1) and von Willebrand factor : Increased serum levels of PAI-1  depict impairment of the endothelium and is prominent in atherosclerotic cardiovascular diseases such as diabetes [34].  In a follow- up community study by Meig et al, [35] platelet activating inhibitor (PAI-1) and von Willebrand factor (vWF) which are endothelial  markers were shown to increase the risk of incident diabetes. Endothelial dysfunction was also noted to be an independent predictor of type 2 diabetes. Plasma level of  vWF  has strong significant positive correlation with glycated hemoglobin (HbA1C) and  PAI-1 in patients type 2 diabetes [36].   
3. Intercellular Adhesion Molecule (ICAM-1): ICAM -1 is one of the biological entities noted in vascular endothelial dysfunction which is secreted by endothelial cells, leukocytes and other inflammatory cells [37]. Studies have demonstrated increased expression of ICAM-1 in patients with DM nephropathy [38, 39]. Siddiqui et al [40] have reported that ICAM-1 and VCAM-1 are elevated endothelial markers in patients with gestational diabetes rendering the patients prone to future vascular complications of diabetes. This finding necessitates adequate follow-up of women with gestational diabetes.
4. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase and elevated serum level is observed in type 2 diabetes, stroke, hypertension, chronic kidney disease [41]. ADMA is obtained by methylation of arginine residues in intracellular proteins through the activity of protein arginine N-methyltransferases [42]. ADMA level was measured with high pressure liquid chromatography among 25 patients with metabolic syndrome and 20 healthy subjects[43]. The difference between the two groups was statistically significant(p<0.05).

A meta analysis of ten studies by Liu et al [44] showed significantly higher difference between ADMA levels in diabetic patients with DM microvascular complications compared to DM patients without complications (p<0.05).The authors concluded that ADMA may contribute to the pathogenesis of  DM micro complications. Therapeutic agents with a tendency to lower ADMA levels may prevent the development of diabetic retinopathy. Microalbuminuria, a marker of nephropathy may correlate positively with ADMA levels (45). 

5. Toll like receptors (TLRs): These include mainly TLR 2 and 4. Mudaliar et al (46) observed a maximal upregulation of TLR4 and other inflammatory cytokines such as NF-Kb, IL-8 and ICAM-1 with fluctuating glucose concentration though TLR2 remained unchanged.
6. Soluble E-selectin: E- Selectin, a glycoprotein with molecular weight of 115 kDa is one of the cellular adhesion molecules and a potential marker of endothelial dysfunction[47]. It is also referred to as CD62 antigen-like family member E(CD62E) or leukocyte –endothelial  cell adhesion molecule -2

The main source of E-selectin is the vascular endothelium [49] . The marker can be elevated in patients with overt diabetes or in those with risk factors for diabetes. In a prospective study by Meigs et al [50], the levels of E-selectin, Vascular cell adhesion molecule( VCAM) and Intercellular adhesion molecule (ICAM),were significantly elevated in women who eventually developed diabetes compared to those who did not.

Generally, several factors such as infection, hyperglycemia, oxidative stress, malignancy and age can interfere with endothelial function [51].

Measurement of Endothelial Function 

Non-invasive and invasive methods are used to measure endothelial functions [52, 53]

Non-invasive methods include: i. Ultrasound flow mediated dilatation ii. Pulse wave analysis applanation tonometry with inhaled salbutamol.iii. Flow mediated dilatation using MRI. iv. Pulse contour analysis digital photoplethysmography. This is represented in table 1.

Invasive methods include: i. Intra-arterial acetylcholine or endothelin infusion and strain guage plethysmography. ii. Intravascular ultrasound studies of epicardial coronary arteries. This is represented in table 1.

Endothelial function can be assessed by digital reactive hyperemia index (RHI). RHI is measured using pulse amplitude tonometry which is a non-invasive method. The lower RHI is correlated with traditional cardiovascular risk factors such as diabetes, obesity, dyslipidemia and smoking [54].

Anti-Diabetic Drugs and Attenuation of Endothelial Dysfunction

The ability of any anti-diabetic medication to attenuate vascular endothelial dysfunction determines the extent to which such a drug can mitigate the development and progression of microvascular and macrovascular complications

Metformin

This is one of the oldest anti-diabetic medications which has been approved by some guidelines as first line. The improvement in vascular endothelial dysfunction is related to the activating AMPK pathway which enhances the activity of eNOS. The effect is by enhancing the phosphorylation and activity of eNOS and consequent NO serum level.

Kim et al [57] and Vignozzi et al  have demonstrated that metformin at a dose of 300mg/kg/ day given to  high fat- fed- laboratory animals was able to restore the transcription of  penile endothelial NO synthase and increased NO production compared to  untreated controls.

de Jager et al (59), using a  2,050 mg mean dose of metformin for a follow up period of 4.3 years of 390 T2DM patients demonstrated a statistically significant decrease in vWF, sVCAM, t-PA, PAI-1, sICAM-1  by 11%, 5%, 15%,21%, 5% respectively compared to placebo. In the trial, metformin treatment was associated with less weight gain (p<0.001), better glycemic control (p <0.0001) and reduced insulin requirement (< 0.0001). The authors concluded that improvement in endothelial function may not be related to the better glycemic profile and weight reduction obtained with metformin.

The relationship between endothelial dysfunction and advanced glycation end-products (AGEs) is established. Metformin inhibits formation of AGEs and AGE induced inflammatory cascade (60). This may be one of the mechanisms for the improvement of endothelial function by metformin.

GLUCAGON LIKE PEPTIDE ( GLP-1)AGONISTS

1. Exanetide This is a typical glucagon like -1 (GLP-1)agonist. The effect on endothelial dysfunction is attributed to the inhibition of monocyte chemotactic-protein -1 and vascular cell adhesion molecule-1 expression (61). In a comparative study of the attenuation potential of exenatide and metformin, the reactive hyperemia index (RHI) were found to be similar (0.31±0.70 vs 0.13±0.24, p>0.05). The protective effect of exenatide can be reversed by the pre-treatment with glibenclamide which is a potent inhibitor of K _ATP channels( flow mediated dilatation before and after ischemia-reperfusion were 12.0± 2.2 and 3.2± 2.1 respectively, p< 0.001)

 A significant improvement in coronary endothelial function has been demonstrated using coronary flow velocity reserve after 12 months of exanetide therapy in newly diagnosed T2DM patients. The finding was shown by Wei et al [64] who further suggested the up-regulation of e NOS by exanetide via the AMPK/PI3 K-Akt/eNOS pathway as the possible mechanism.

 In addition to the effect of exanetide on glucose and lipids, the vasodilatory effect which is attributed to improved postprandial endothelial function has also been reported[65].

Liraglutide

The finding from Liraglutide Effect and Action: Evaluation of  Cardiovascular  Outcome Results ( LEADER) trial has supported the cardioprotective role of  liraglutide with significant reduction in non-fatal myocardial infarction and non-fatal stroke( 66). Lin et al [67] have demonstrated that liraglutide attenuates some biomarkers of endothelial dysfunction including tumor necrosis factor  alpha (TNF-α ), plasminogen activator inhibitor.

Liraglutide  also inhibits ICAM-1, VCAM-1, C-reactive protein, IL-6(68, 69). The  mechanisms responsible for the effect of liraglutide on endothelial dysfunction are:

1. amelioration of endoplasmic reticulum stress and JNK activation.
2. Nitric oxide synthase activation in endothelial cells which is mediated by insulin(70)

Semaglutide:  One of the most recent GLP-1 receptor agonist  with  good  cardiovascular safety. Hussain et al [71] in the PIONEER-6 trial demonstrated non-inferiority  of oral semaglutide to placebo in terms of cardiovascular outcomes (hazard ratio, 0.79; 95% CI, 0.57 to 1.11). The  hazard ratio was similar to that obtained with subcutaneous semaglutide in SUSTAIN -6 trial ( 72) though, the cardiovascular events were higher in the latter.

DPP4 INHIBITORS

Aini et al,(73) administered Vildagliptin at a dose of 50mg/kg/day  to non- diabetic, APO E deficient mice fed with western diet for 20weeks or 8 weeks. The rate of atherogenesis as determined using Sudan IV stain was reduced ( p<0.05) likewise vascular adhesion molecule-1 and macrophage infiltration  into atheromatous plaque (p<0.05,p =0.05) respectively.

DPP4 inhibitor is thought to exhibit its effect on atherosclerosis by enhancing GLP-1 signalling and inhibition of macrophage- induced inflammation and smooth muscle proliferation[74].  Mita  et al (75) in a study of 142 insulin treated  patients with type 2 diabetes reported that sitagliptin treatment  attenuated the progression of carotid  intima media thickness compared to the 140 subjects in the control group who were not on sitagliptin.( 0.029 vs 0.024mm, p=0.005).  In comparison with high dose metformin, vildagliptin did not show significant differences in flow mediated dilatation even though there was significant improvement in Hb A1C(P<0.01)[76].

The inconsistencies in the effect of DPP4 inhibitors and GLP-1R agonists on endothelial function have been attributed to the differences in the study patterns as well as in type of vascular bed studied [77]. A study which involved 40 patients aged 68.7± 9.4 years  with uncontrolled DM and coronary artery disease who were started on sitagliptin showed a better improvement in the reactive hyperemia peripheral tonometry index (RHI) compared to the control group (62.4 ±59.2%  vs 15.9±  22.0%), p<0.01) [78]. 

On the contrary, Hage et al, [79] in Beta –cell function in patients with Glucose Abnormalities  and Acute Myocardial infarction (BEGAMI) trial have equally demonstrated no improvement in RHI in 31 T2M or IGT patients on 100mg of sitagliptin compared to placebo group( 1.57 vs 1.60).

Some specific sitagliptin studies/trials are tabulated in Table 2.

SGLT-2 INHIBITORS

The outcome of EMPA- REG (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose) study showed that the clinical effect of Empagliflozin therapy is beyond glucose lowering but it can also reduce the rates of cardiovascular events, hospital admissions for heart failure, kidney function deterioration [80]. Canagliflozin in a separate study was shown to have similar effects as empagliflozin [81].

Does improvement in the endothelial function contribute to better cardiovascular outcomes? A multicentre study which measured the effect of empagliflozin on endothelial function in 117 diabetic patients using hyperemia peripheral arterial tonometry index (RHI) showed no significant improvement after 24 weeks of taking empaglifozin compared to placebo [82]. Therefore, the improved CVD outcome noted with empagliflozin may not be related to improved endothelial function. The improvement in HbA1C, FBG and BMI were significant( p= 0.11, p=0.007, p=0.002 respectively) [82].

EMPA-REG OUTCOME findings showed that empagliflozin has cardio-protective effects which are not only related to the lowering of blood glucose levels [83]. The cardio-pretection has been attributed to the modulation of endothelial function and cardiovascular hemodynamics such as reduction in left ventricular mass and inhibition of cardiac fibrosis[ 83].

Park et al,[84] have also shown that empagliflozin treatment was able to restore the endothelial function in mesenteric artery of Obese ZSF rat as depicted by activation of endothelium  relaxation and attenuation of acetylcholine- mediated endothelial contractile responses. Such empagliflozin- related endothelial relaxation has been demonstrated by Stephen et al [85] and Oelze et al,[86] in streptozotocin induced diabetic rats and Zucker diabetic- fatty rats respectively.

INSULIN

Exogenous insulin  has been demonstrated to reduce the rate of atherosclerosis in insulin resistant and mildly diabetic Apo E^-/- mice that are fed with high fat diet. The suggested mechanism is by decreasing the serum levels of inflammatory cytokines [87].

Insulin  stimulates the production of NO, which has vasodilatory property from the vascular endothelium through activation of endothelial NO synthase (eNOS) [88]. The process involves PI3K and direct phosphorylation of e NOS by protein kinase (PKB)

Insulin resistance, the hallmark of pathogenesis of type 2 DM is associated with endothelial dysfunction and has been linked to the establishment of inbalance between Nitric oxide( NO), a vasodilator and Enothelin-1( ET1), a vasoconstrictor [89]. The key pathways involved are Phosphatidylinositol 3- kinase- NO (PIK3-NO) and Mitogen activated protein kinase-ET1 (MAPK-ET1)  respectively [90].

 Acute infusion of insulin in obese T2DM patients reduces the expression of Toll like receptors to significant proportions compared to controls who received dextrose infusion.  Toll-like receptors- 1, 2, 4  are notable markers of endothelial dysfunction [91].  Westerbacka et al, [92] have shown that both insulin glargine and regular human insulin potentiate acetylcholine-induced endothelium dependent vasodilation in vivo in normal human subjects.

THIAZOLIDINEDIONES

Thiazolidinediones are insulin sensitizers and acts through the peroxisome proliferator-activated receptor-gamma [93]. They ameliorate insulin resistance and chronic hyperglycemia which are prominent features of T2DM.  These pathologic processes establish endothelial dysfunction and progression of atherosclerosis especially, in combination with other cardiovascular diseases such as hypertension, dyslipidemia and cigarette smoking. The cardiovascular benefits of thiazolidinediones are related to decreasing dyslipidemia, endothelial dysfunction, inflammation, pro-coagulant potential and increasing adiponectin [94]. Rosiglitazone has also been shown to improve endothelial function in addition to its glucose lowering capacity [95]. 

 Pioglitazone treatment at a dose of 15mg daily given to 107 subjects with impaired fasting glucose (who are first degree relatives of T2DM patients)  for 12 weeks caused an elevation of NO concentration by 14.60μg/l compared to 1.60μg/l in the control group [96].

Despite these benefits, the use of thiazolidinediones should be in selected patients bearing in mind the outcome of Prospective Pioglitazone Clinical Trial in Macrovascular Events which increased the incidence of peripheral edema and hospitalization for congestive heart failure [97].

CONCLUSION

Endothelial dysfunction is integral to cardiovascular morbidity and mortality in diabetic patients. Therefore, attention should not only be focused on blood glucose lowering in the management of patients with diabetes rather, the extent of endothelial dysfunction as evidenced by biochemical markers should be emphasized. The newer anti-diabetic medications have demonstrated  greater efficacies in attenuating endothelial dysfunction. It is therefore, imperative to incorporate these drugs in the regimens for new and old patients with diabetes in order to improve their cardiovascular integrity and avert further complications. Future therapeutic measures in patients with diabetes mellitus will likely explore the effects of such therapy on the endothelium since dysfunctional endothelium predisposes to cardiovascular sequalae.

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