Atherosclerosis In Diabetic Subjects Research Articles

Prevalence of Elevated Non-HDL Cholesterol among Patients with Diabetes in An Iranian Population


 
 
 Background and Aims: Non-high density lipoprotein cholesterol (non-
 HDL-C), which reflects all cholesterol present in potentially atherogenic lipoprotein particles, might be a useful marker of atherosclerosis in diabetic subjects. In the present study, we evaluated the prevalence of high non-HDL-C in patients with dyslipidemia in diabetic and non-diabetic subjects following LDL-C assessment as the first goal of therapy. Materials and Methods: A data set of 2142 individuals was included in the study. All values of lipid profile were compared between non-diabetic and diabetic groups and the prevalence of dyslipidemia was evaluated in two groups.
 Results and Conclusions: According to the results, 48% of patients with diabetes achieved combined LDL-C ≤2.5 mmol/L and non-HDL ≤3.3 mmol/L targets, and 58.2% of diabetic patients achieved LDL-C goal while only 50.2% attained non-HDL-C goal. Also, the results indicated that non-HDL-C significantly heightened in patients with diabetes. Therefore, non-HDL-C needs to be calculated as a routine assessment in patients with diabetes.
 
 

Arterial stiffness and matrix metalloproteinases: A correlation study in hypertensive type 2 diabetic subjects

Matrix metalloproteinases (MMP’s) and tribbles 3 human homolog (Trb3) are implicated in atherosclerosis. Changes in the concentration of these biomolecules signal the risk of atherosclerosis in type 2 subjects (T2DM), with or without hypertension (HT), at an early stage. Our aim was to assess the relation between noninvasive arterial stiffness indices and circulating levels of MMP2, MMP9 and Trb3. The study included 144 participants divided into 4 groups: T2DM > 5 years + HT, DM + HT (n = 55), T2DM < 2 years, DM (n = 28), HT (n = 31), and healthy controls (HC) (n = 30). Anthropometric measurements and blood biochemistry profiles were established using standard protocols. MMP2, MMP9 and Trb3 were estimated using ELISA. Pulse wave velocities (PWV) and arterial stiffness indices (ASI) were measured using PeriScopeTM. Results were analysed using SPSS 21. MMP2, average Brachial Stiffness Index (ba ASI) (Pearson’s r = 0.235, p = 0.005) and Ankle-Brachial Index (ABI) (Pearson’s r = 0.225, p = 0.007) were positively correlated. Average Ankle ASI (Ank ASI) was positively correlated to Trb3 (Pearson’s r = 0.184, p = 0.028), but negatively to MMP9 (Pearson’s r = − 0.184, p = 0.027). In multiple linear regression, MMP2 influenced ba ASI [adjusted R2 = 0.038; F (3) = 2.862, p = 0.039] and ABI [adjusted R2 = 0.033; F (3) = 2.642, p = 0.052]. MMP9 influenced Ank ASI [adjusted R2 = 0.058; F (3) = 3.912, p = 0.01]. Arterial stiffness indices and matrix metalloproteinases conform early risk of atherosclerosis in diabetic subjects.

Влияние вариабельности гликемии на риск развития сердечно-сосудистых осложнений при сахарном диабете

A growing body of evidences indicates the role of increased glucose variability (GV) as an independent cardiovascular risk factor in diabetes. It has been shown that high GV is associated with coronary and carotid atherosclerosis in diabetic subjects. The impact of enhanced glycemic fluctuations on vascular wall is mediated through non-enzymatic glycation, oxidative stress, activation of inflammatory pathways, and endothelial dysfunction. Thus, the effects of high GV exacerbate the influence of chronic hyperglycemia. The FinnDiane study established existence of a relationship between glycated hemoglobin (HbA1c) variability and cardiovascular events (myocardial infarction, coronary artery procedure including by-pass surgery or angioplasty, stroke, limb amputation because of ischemia, or a peripheral artery procedure) in patients with type 1 diabetes. In ADVANCE study visit-to-visit HbA1c and fasting glucose variability was associated with cardiovascular events in type 2 diabetic subjects; moreover, HbA1c variability was associated with all-cause mortality. In Verona Diabetes Study, fasting GV was predictor of cardiovascular mortality in elderly patients with type 2 diabetes. In-hospital glycemic excursions in patients with acute myocardial infarction and in diabetic patients undergoing percutaneous coronary intervention predict the risk of adverse cardiac events. The episodes of hypoglycemia in diabetic patients with high GV may contribute to an increased risk of arrhythmias, myocardial ischemia and infarction, and stroke. The data presented give support to notion that GV could be considered a new therapeutic target in patients with diabetes and cardiovascular disease.

Liraglutide improves carotid intima-media thickness in patients with type 2 diabetes and non-alcoholic fatty liver disease: an 8-month prospective pilot study

Objective: To explore the effects of the glucagon-like peptide-1 receptor analogue liraglutide on subclinical atherosclerosis in diabetic subjects with non-alcoholic fatty liver disease (NAFLD).Research design and methods: In this 8-month prospective study, 29 subjects with type 2 diabetes (T2DM) and NAFLD (16 men and 13 women, mean age: 61 ± 10 years) were matched for age and gender with 29 subjects with T2DM without NAFLD (16 men and 13 women, mean age: 61 ± 8 years). Liraglutide 0.6 mg/day for 2 weeks, followed by 1.2 mg/day, was given in addition to metformin.Main outcome measures: Anthropometric variables, glucometabolic parameters and carotid intima-media thickness (IMT) using B-mode real-time ultrasound were assessed at baseline and 4 and 8 months.Results: Glycated hemoglobin reduced significantly in both groups. No significant changes were found in body weight, waist circumference and lipids. Carotid IMT decreased significantly in the T2DM patients with NAFLD (from 0.96 ± 0.27 to 0.82 ± 0.17 to 0.85 ± 0.12 mm, p = 0.0325), but not in the T2DM patients without NAFLD (from 0.91 ± 0.23 to 0.88 ± 0.17 to 0.85 ± 0.15 mm, p = 0.4473).Conclusion: Eight months of liraglutide use in patients with T2DM and NAFLD significantly reduced carotid IMT, a surrogate marker of atherosclerosis, independently of glucometabolic changes.

Diabetes Mellitus and Vascular Endothelial Dysfunction: Current Perspectives

Patients with diabetes mellitus (DM) have a high prevalence of coronary artery disease (CAD), as diabetes is implicated in the formation of atherosclerotic plaque. Endothelial dysfunction is one of the precursor key steps in the development of atherosclerosis in diabetic subjects. Decreased nitric oxide (NO) production, increased oxidative stress and impaired function of endothelial progenitor cells are the main mechanisms involved in the accelerated atherosclerotic process observed in type 2 DM patients. Therapeutic approaches including classic agents such as statins, angiotensinconverting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), antioxidants and novel agents such as tetrahydrobiopterin (BH4), asymmetric dimethylarginine (ADMA) and homocysteine (tHcy), have been implicated in order to ameliorate endothelial function of diabetic patients.

Plasma fibrinogen in patients with type 2 diabetes mellitus with and without macrovascular disease and its relationship with endothelial function, carotid intima media thickness and dyslipidemia

Plasma fibrinogen is higher in diabetic subjects, but it is not clear whether its levels differ in patients with or without existing macrovascular disease (MVD) and whether it has any relationship with endothelial function as determined by flow mediated dilatation (FMD), carotid intima media thickness (CIMT) and lipids. To study plasma fibrinogen levels and their relationship with endothelial functions, CIMT and dyslipidemia in type 2 diabetic patients with and without macrovascular disease, twenty six diabetic subjects and thirteen matched healthy controls were recruited for the study. Subjects were divided into group I—with MVD, group II—without MVD and group III—healthy controls. Fasting blood was analyzed and radiological studies were performed. Statistical analysis was done to find any correlation between study parameters. Plasma fibrinogen was significantly higher in diabetic subjects as compared to controls. Plasma fibrinogen was significantly higher in group I as compared to group II. Plasma fibrinogen levels correlated significantly with CIMT and FMD in diabetic subjects. No significant correlation was found between plasma fibrinogen and glycemic parameters, insulin or lipids. Plasma fibrinogen levels increased progressively from controls to diabetic subjects without MVD and to those with MVD and is an independent risk factor for atherosclerosis in diabetic subjects.

Fructated apolipoprotein A-I showed severe structural modification and loss of beneficial functions in lipid-free and lipid-bound state with acceleration of atherosclerosis and senescence

Non-enzymatic glycation of serum apolipoproteins is a main feature of diabetes mellitus under hyperglycemia. Advanced glycation end products are implicated in the development of aging and metabolic syndrome, including premature atherosclerosis in diabetic subjects. ApoA-I is the principal protein constituent of HDL. In this study, glycated human apoA-I (gA-I) by fructation was characterized on functional and structural correlations in lipid-free and lipid-bound states. The gA-I showed more spontaneous multimeric band formation up to pentamer and exhibited slower elution profile with more degraded fragments from fast protein liquid chromatography. The gA-I showed modified secondary structure from fluorescence and circular dichroism analysis. Reconstituted high-density lipoprotein (rHDL) containing the gA-I had less content of phospholipid with a much smaller particle size than those of rHDL-containing nA-I (nA-I-rHDL). The rHDL containing gA-I (gA-I-rHDL) consisted of less molecular number of apoA-I than nA-I-rHDL with decreased α-helical content. Treatment of the gA-I-rHDL induced more atherogenic process in macrophage cell and premature senescence in human dermal fibroblast cell. Conclusively, fructose-mediated apoA-I glycation resulted in severe loss of several beneficial functions of apoA-I and HDL regarding anti-senescence and anti-atherosclerosis activities due to a lack of anti-oxidant activity with increased susceptibility of protein degradation and structural modification.

High glucose up-regulates lipopolysaccharide-stimulated inflammatory cytokine production via c-jun N-terminal kinase in the monocytic cell line THP-1

Diabetic subjects are susceptible to atherosclerosis. It has been postulated that inflammation plays a crucial role in atherogenesis. Since previous studies suggested persistent low-grade infection by Gram-negative bacteria such as Chlamydia spp. and/or periodontal infection is associated with increased atherogenesis among diabetic subjects, we hypothesized that macrophages under hyperglycemia respond to lipopolysaccharide (LPS) challenge in a more exaggerated manner than under normal glucose conditions. Therefore, we examined cytokine productivity and associated signal transduction molecules in LPS-stimulated the monocytic cell line THP-1, under conditions of hyperglycemia. Differentiated THP-1 cells were cultured under normal and high glucose conditions without fetal bovine serum, and were stimulated with Escherichia coli LPS in the presence of LPS binding protein. Following stimulation, activated signal transduction molecules were detected by protein microarray and confirmed thereafter. Results indicated that c-jun N-terminal kinase (JNK) was highly-phosphorylated at high glucose concentrations, and this was confirmed by Western-immunoblotting. Tumor necrosis factor-alpha and monocyte chemo-attractant protein-1 production were significantly enhanced under these conditions. SP600125, a selective inhibitor of JNK, dose-dependently suppressed the production of these cytokine. Therefore, we suggest that this may be one of the mechanisms by which sub-clinical infection by Gram-negative bacteria promotes atherosclerosis in diabetic subjects.

Heavy alcohol intake, homocysteine and Type 2 diabetes

Although moderate alcohol intake is associated with reduced risk of atherosclerotic disease in both the general population and in diabetic patients, a recent report suggests that heavy alcohol intake facilitates the development of atherosclerosis exclusively in diabetic individuals. We studied cross-sectionally the effects of the interaction between ethanol consumption category and the prevalence of diabetes on plasma total homocysteine (tHcy), a risk factor for atherosclerotic disease, in middle-aged men. Heavy drinking was associated with elevated tHcy levels only in diabetic subjects but not in non-diabetic subjects. Plasma tHcy of heavy drinkers (average ethanol consumption > 30 ml/day) was higher than that of abstainers in the diabetic subgroup (10.25 +/- 3.39 vs. 8.88 +/- 1.94 micromol/l, P < 0.05), whereas tHcy levels in heavy drinkers were comparable with that of abstainers in the non-diabetic subgroup (9.36 +/- 2.52 vs. 9.12 +/- 2.10 micromol/l, NS). In a two-factor anova, significant interaction was observed on the effects of ethanol consumption category and diabetes prevalence on tHcy levels (P < 0.01). Confounding factors including folate, vitamin B(12), creatinine, age or cigarette smoking did not contribute to the interaction. These findings may partly explain the reported association between heavy drinking and atherosclerosis in diabetic subjects.

Morphologic findings of coronary atherosclerotic plaques in diabetics: a postmortem study.

Coronary atherosclerotic plaque composition of diabetic subjects and localization of receptor for advanced glycation end products (RAGE) and its ligands have not been extensively studied. Hearts from diabetic subjects and age, race, and sex-matched nondiabetic subjects dying suddenly were examined. Coronary arteries were dissected and lesions were evaluated for plaque burden, necrotic core size, and inflammatory infiltrate. The expression of RAGE, the RAGE-binding protein (S100-A12, EN-RAGE), and cell death (apoptosis) were also determined. Lesions from type II diabetic subjects had larger mean necrotic cores (P=0.01) and greater total and distal plaque load (P<0.001) than nondiabetic subjects. Necrotic core size correlated positively with diabetic status, independent of other risk factors. Intimal staining for macrophages, T-cells, and HLA-DR was also significantly greater in diabetic subjects (P=0.03, P=0.003, and P<0.0001), respectively. The association of increased macrophage infiltrate was independent of cholesterol levels and patient age. Expression of RAGE and EN-RAGE was significantly greater in diabetic subjects (P=0.004) and was associated with apoptotic smooth muscle cells and macrophages. In sudden coronary death, inflammation and necrotic core size play a greater role in the progression of atherosclerosis in diabetic subjects. The expression of RAGE and EN-RAGE may further compromise cell survival and promote plaque destabilization.

The pulse wave velocity as an early indicator of atherosclerosis in diabetic subjects.

The arterial pulse wave velocity was measured in 87 healthy individuals and in 52 diabetic patients who did not have clinical evidence of atherosclerosis or hypertension. A significant increase in the pulse wave velocity was found in the diabetic subjects. This increase was not correlated with the duration of their illness as judged from clinical history. It is very likely that the high values of pulse wave velocity were indicative of an incipient process of diffuse atherosclerosis and that the measurement of the pulse wave velocity brought this into evidence earlier than the classic signs and symptoms. Serial measurements of the pulse wave velocity in diabetic subjects may permit early detection of atherosclerosis in these patients.

CHOLESTEROL CONTENT OF BLOOD IN DIABETIC PATIENTS FED DIETS RICH IN FAT

During recent years there has been increasing interest in the blood lipids in patients with diabetes mellitus, chiefly because of the uncertain relationship between dietary fat, hypercholesteremia and the frequent development of atherosclerosis in diabetic subjects. It has been repeatedly demonstrated that atherosclerosis can be produced in rabbits by feeding large amounts of cholesterol. It is also well known that many diabetic patients have hypercholesteremia, that arteriosclerosis develops at a relatively early age in many diabetic patients and that this complication accounts for most of the incapacitation and fatality from this disease. The cause of a high cholesterol content of the blood and of vascular disease in diabetic patients has naturally been the subject of much investigation. Before the advent of insulin it was necessary for all patients with diabetes except those with mild involvement to live on a high fat-low carbohydrate diet. Since 1922, with the use of insulin,