Vascular endothelium as a target of beraprost sodium and fenofibrate for antiatherosclerotic therapy in type 2 diabetes mellitus

Diabetes mellitus is an important risk factor for cardiovascular morbidity and mortality. The metabolic abnormalities caused by diabetes mellitus induce vascular endothelial dysfunction that predisposes patients with diabetes mellitus to atherosclerosis. Two mega clinical trials showed that intensive glycemic control does not have favorable effects on reducing macrovascular events although it demonstrated significant reductions in microvascular complications. It is becoming worthwhile to clarify the beneficial effects of tight controls on blood pressure, serum lipids, and postprandial hyperglycemia to prevent atherosclerosis in patients with type 2 diabetes mellitus. Here, we focus on vascular endothelium as a target of the prostaglandin I2 analog beraprost sodium and the peroxisome proliferators-activated receptor alpha activator fenofibrate for the prevention and treatment of atherosclerosis in patients with type 2 diabetes mellitus. Beraprost sodium lowered circulating vascular cell adhesion molecule- 1 (VCAM-1) concentration and prevented the progression of carotid atherosclerosis in type 2 diabetic patients, probably through inhibiting VCAM-1 expression in vascular endothelium. Fenofibrate up-regulated endothelial nitric oxide synthase expression, which may explain its effects to improve endothelium-dependent vasodilatation and to prevent the progression of coronary atherosclerosis. The approaches to target the molecules expressed in vascular endothelium will become important for preventing the atherosclerosis in type 2 diabetes mellitus.     

Cardiovascular disease in diabetic nephropathy patients: cell adhesion molecules as potential markers?

Cardiovascular disease is a major complication of diabetes mellitus, especially for patients with diabetic nephropathy. The underlying factor or pathogenic mechanism that links diabetic nephropathy with cardiovascular disease is not known. The endothelial cell adhesion molecules, intercellular adhesion molecule-1 or vascular cell adhesion molecule-1, play a crucial role in the initiation of atherosclerosis. Levels of both cell adhesion molecules are raised by the diabetic and kidney disease states. This review focuses on these important cell adhesion molecules and their role in the pathogenesis of cardiovascular disease in diabetes and diabetic nephropathy.     

Effects of flavonoid-containing beverages and EGCG on endothelial function

Abnormalities of the vascular endothelium contribute to all stages of atherosclerosis from lesion development to clinical cardiovascular disease events. Recognized risk factors, including diabetes mellitus, hypertension, dyslipidemia, cigarette smoking, and sedentary lifestyle are associated with endothelial dysfunction. A variety of pharmacological and behavioral interventions have been shown to reverse endothelial dysfunction in patients with cardiovascular disease. A large number of epidemiological studies suggest that dietary factors, including increased intake of flavonoid-containing foods and beverages, reduce cardiovascular risk, and recent studies have shown that such beverages have favorable effects on endothelial function. These studies have engendered interest in the development of dietary supplements or drugs that would allow for more convenient and higher dose administration of flavonoids and might prove useful for prevention or treatment of cardiovascular disease. In this paper, we will review the contribution of endothelial dysfunction to the pathogenesis and clinical expression of atherosclerosis and recent data linking flavonoid and EGCG consumption to improved endothelial function and reduced cardiovascular risk.     

Effects of Flavonoid-Containing Beverages and EGCG on Endothelial Function

Abnormalities of the vascular endothelium contribute to all stages of atherosclerosis from lesion development to clinical cardiovascular disease events. Recognized risk factors, including diabetes mellitus, hypertension, dyslipidemia, cigarette smoking, and sedentary lifestyle are associated with endothelial dysfunction. A variety of pharmacological and behavioral interventions have been shown to reverse endothelial dysfunction in patients with cardiovascular disease. A large number of epidemiological studies suggest that dietary factors, including increased intake of flavonoid-containing foods and beverages, reduce cardiovascular risk, and recent studies have shown that such beverages have favorable effects on endothelial function. These studies have engendered interest in the development of dietary supplements or drugs that would allow for more convenient and higher dose administration of flavonoids and might prove useful for prevention or treatment of cardiovascular disease. In this paper, we will review the contribution of endothelial dysfunction to the pathogenesis and clinical expression of atherosclerosis and recent data linking flavonoid and EGCG consumption to improved endothelial function and reduced cardiovascular risk.     

A Multifactorial Approach to Reduce Cardiovascular Disease in Type 2 Diabetes Mellitus: Now More Than Ever

Managing cardiovascular (CV) risk is an important part of caring for patients with type 2 diabetes mellitus, as the disease itself confers CV risk. Many CV risk factors (such as hypertension, dyslipidemia, and obesity) have been found to be more common among individuals with diabetes than in the general population. A growing body of evidence provides guidance for clinicians on how to balance control of hyperglycemia with management of these risk factors. Newer classes of antihyperglycemic agents have been associated with beneficial effects on several CV risk factors; several studies evaluating the effect of these newer diabetic medications on CV outcomes have been published, and several more are in progress. While evidence continues to unfold about the benefits of risk factor control in patients with type 1 diabetes mellitus, this article reviews evidence related to risk-factor control in patients with type 2 diabetes mellitus as well as recent findings on the effect of newer drug classes on CV risk factors and outcomes. Favorably altering CV risk factors appears to improve outcomes, and is more important now than ever before.     

Oral antidiabetic therapy and cardiovascular complications: theoretical problem or clinical evidence?

Theoretical and experimental research data as well as human epidemiological studies on large populations suggest a great difference in influencing cardiovascular processes and alterations among the oral antidiabetic drugs used in the treatment of type II diabetes mellitus. Drugs delaying or inhibiting carbohydrate absorption as well as insulin sensitizers have an unambiguous reducing effect on diabetic cardiovascular complications. Only fluid retention needs precaution during the treatment with thiazolidinedions in patients suffering from heart disease. Among insulin secretizers repaglinid, glibenclamid and glipizide have an ATP-sensitive potassium channel inhibiting effect in the vascular smooth muscle cells, too, reducing hereby vasodilation. Glibenclamide also inhibits ischaemic preconditioning. Therefore, the antidiabetic drug of choice can be decisive in diabetic patients suffering from ischaemic heart diseases or peripheral obliterative disorders. In the case of secondary sulphonylurea resistance and/or severe ischaemic alterations insulin treatment becomes necessary to avoid further cardiovascular complications.     

Relationship of adiposity to subclinical atherosclerosis in obese patients with type 2 diabetes

OBJECTIVE: There is an increased prevalence of macrovascular disease in type 2 diabetes. The pathogenesis has been related to metabolic risk factors, insulin resistance, and obesity. One of the strongest predictors is the presence of subclinical atherosclerosis. This study was designed to examine the relationship between obesity and regional patterns of adiposity, insulin resistance, and five independent measures of subclinical atherosclerosis. RESEARCH METHODS AND PROCEDURES: Fifty-two overweight and obese men and women with type 2 diabetes of relatively short known duration were examined. Measures of subclinical vascular disease were assessment of arterial stiffness by pulse wave velocity, ultrasound measurement of the carotid artery intimal-medial thickness and plaque index, and measurement of the extent of coronary and aortic calcification using electron beam computed tomography. Insulin resistance was measured using the hyperinsulinemic euglycemic clamp. Body composition was measured using DXA and computed tomography. RESULTS: Adiposity was a strong determinant of pulse wave velocity. Carotid intimal-medial thickness was correlated with age, low-density lipoprotein-cholesterol, and hyperglycemia, but not with adiposity. Hyperglycemia and plasma activator inhibitor-1 were significant correlates of the carotid artery plaque index. Coronary calcium scores were significantly correlated with age and interleukin-6 and significantly and negatively correlated to insulin sensitivity index. DISCUSSION: These findings suggest that obesity may play an important role in the early phase of subclinical macrovascular disease related to vessel stiffness, whereas hyperglycemia and insulin resistance in conjunction with other risk factors have important roles in progression from vessel stiffness to atheroma formation in type 2 diabetes.     

Postprandial hyperglycemia on vascular endothelial function: mechanisms and consequences

Vascular endothelial dysfunction precedes atherosclerosis and contributes to cardiovascular disease (CVD), which accounts for one-third of all deaths in the United States. Chronic hyperglycemia, such as that associated with diabetes, is well known to impair vascular function. However, recent evidence demonstrates that acute or postprandial hyperglycemia (PPH) not only exacerbates vascular endothelial dysfunction in individuals with chronic hyperglycemia but also transiently impairs vascular function in healthy individuals. Postprandial hyperglycemia has been shown to better predict future CVD mortality compared with fasting glucose in both diabetic and normoglycemic individuals. Compelling evidence exists suggesting that PPH-mediated insults to the vascular endothelium contribute to CVD, especially in pathophysiologic conditions whereby vascular recovery is compromised. Although the mechanisms by which PPH induces vascular dysfunction is not fully understood, oxidative stress–mediated disruptions in nitric oxide homeostasis are implicated as key events leading to vascular dysfunction associated with PPH. This review aims to highlight the findings of clinical studies using functional indices of vascular function to demonstrate that PPH impairs vascular function. We will also discuss the evidence showing the central involvement of oxidative stress in dysregulating nitric oxide homeostasis and contributing to PPH-mediated vascular endothelial dysfunction. Lastly, this review will identify areas of knowledge that remain limited and will provide recommendations for future investigation to more fully define PPH as an important risk factor for CVD.     

Effect of Extra Virgin Olive Oil and Butter on Endothelial Function in Type 1 Diabetes

Post-prandial hyperglycemia can be relevant in developing early manifestations of atherosclerosis. EVOO (Extra Virgin Olive Oil), rich in saturated fatty acids and commonly used in the Mediterranean diet, seems to control post-prandial hyperglycemia better than butter. Subjects with type 1 diabetes are at higher risk of developing cardiovascular disease and show endothelial dysfunction, an early manifestation of atherosclerosis in the first years of the disease. Our study aims to evaluate whether EVOO and butter influence endothelial function in subjects with type 1 diabetes when added to a single high glycemic index (HGI) meal. In this exploratory cross-over study, 10 subjects with type 1 diabetes and 6 healthy subjects were scheduled to receive two types of HGI meals: one enriched with EVOO and one with butter. Before and after each test meal at different time points, all subjects underwent the evaluation of endothelial function by flow-mediated dilation technique, glucose and lipids measurements, and gastric emptying assessment by ultrasound. Flow-mediated dilation significantly increased after EVOO-enriched meal compared with butter in subjects with type 1 diabetes (two-way-repeated measurements ANOVA, p = 0.007). In patients with type 1 diabetes, the add-on of EVOO to HGI meal improves vascular function compared to butter, which has detrimental effects.     

Role of Fluid Milk in Attenuating Postprandial Hyperglycemia and Hypertriglyceridemia

Postprandial plasma glucose and triglyceride concentrations are predictive of relative cardiovascular disease (CVD) risk, and the pathogenesis of both insulin resistance and atherosclerosis has been attributed to acute states of hyperglycemia and hypertriglyceridemia. Postprandial lipemia and hyperglycemia suppress vascular reactivity and induce endothelial dysfunction. Epidemiological studies suggest that chronically-high consumption of milk and milk products is associated with a reduced risk of type 2 diabetes, metabolic syndrome, and CVD. The addition of dairy products to meals high in carbohydrates and fat may lessen these risks through reductions in postprandial glucose and triglyceride responses. Purported mechanisms include dairy proteins and bioactive compounds, which may explain the inverse relationship between dairy consumption and cardiometabolic diseases. The current review evaluates the available literature describing the relationships between metabolic dysfunction, postprandial metabolism, and vascular dysfunction and discusses the potential role of milk and dairy products in attenuating these impairments.     

Cognitive and motor perturbations in elderly with longstanding diabetes mellitus

Type 2 diabetes mellitus is a chronic disease characterized by insulin resistance; inflammation; oxidative stress; vascular damage; and dysfunction of glucose, protein, and lipid metabolisms. However, comparatively less attention has been paid to neurologic alterations seen in elderly individuals with type 2 diabetes. We review clinical, metabolic, and biochemical aspects of diabetic encephalopathy (DE) and propose that quality of dietary lipids is closely linked to DE. This implies that preventive nutritional interventions may be designed to improve DE.     

Treatment update: thiazolidinediones in combination with metformin for the treatment of type 2 diabetes

Type 2 diabetes mellitus (DM2) is characterized by excessive hepatic gluconeogenesis, increased insulin resistance and a progressive inability of pancreatic beta cells to produce sufficient insulin. DM2 evolves as a progression from normal glucose tolerance, to impaired glucose tolerance (IGT) to frank diabetes mellitus, reflecting the establishment of insulin resistance and beta cell dysfunction. Insulin resistance not only contributes to impaired glycemic control in DM2, but to the development of hypertension, dyslipidemia and endothelial dysfunction. Cardiovascular disease is the primary morbidity for patients with DM2. The onset of insulin resistance and cardiovascular insult likely occurs well before the onset of IGT is detected clinically. Biguanides and thiazolidinediones (TZDs) are two classes of oral agents for the management of DM2 that improve insulin resistance, and thus have potential cardiovascular benefits beyond glycemic control alone. Metformin additionally inhibits hepatic gluconeogenesis. The combined use of two of these agents targets key pathophysiologic defects in DM2. Single pill combinations of rosiglitazone/metformin and pioglitazone/metformin have recently been approved for use in the US and Europe. This article reviews the clinical data behind the use of metformin in combination with TZDs for the management of diabetes, its impact on vascular health, side effects and potential mechanisms of action for combined use.     

Hyperhomocysteinemia in poorly controlled type 2 diabetes patients

Elevated blood level of homocysteine is strongly related to an increased risk for atherosclerosis and cardiovascular disease. The role of homocysteine in Type 2 diabetes vascular complications remains unclear. Our objective was to investigate homocysteine levels in poorly controlled Type 2 diabetic patients, who are at increased risk of vascular complications development. Forty-four Type 2 diabetic patients with no symptoms of any cardiovascular disease were divided into 2 groups: 26 patients with poor metabolic control treated with oral agents (aged 66.8 +/- 5.4 yr, diabetes duration 11.9 +/- 4.1 yr, fasting plasma glucose 13.9 +/- 4.6 mmol/l, HbA1C 9.8 +/- 1.6%), 18 well-matched diabetic patients well-controlled with oral agents (aged 65.8 +/- 4.7 yr, diabetes duration 10.9 +/- 4.2 yr, fasting plasma glucose 7.3 +/- 2.4 mmol/l, HbA1c 6.6 +/- 0.7%). The controls were 12 healthy subjects. Fasting total plasma homocysteine and plasma insulin concentrations were measured. Plasma total homocysteine concentrations were significantly higher in poorly controlled than in well-controlled diabetic patients and controls (17.1 +/- 4.5 vs 8.2 +/- 3.9 and 6.5 +/- 4.9 micromol/l respectively, p < 0.001). Insulinemia showed an inverse correlation with homocysteine levels (8.3 +/- 5.2 vs 14.6 +/- 5.2 and 9.3 +/- 6.1 microlU/ml, p < 0.001; r = -0.32, p < 0.05). HbA1c values correlated positively with homocysteine concentrations in poorly controlled subjects (r = 0.41; p < 0.05). In conclusion, chronic poor metabolic control of Type 2 diabetes is characterized by elevation of plasma homocysteine concentration, which also inversely correlates with endogenous insulin levels. These results may add to the understanding of the increased frequency and mechanisms of vascular damage in diabetes mellitus.     

Pharmacological effects and clinical applications of propionyl-L-carnitine

Propionyl-L-carnitine (PLC) is a naturally occurring derivative of carnitine that plays an important role in the metabolism of both carbohydrates and lipids, leading to an increase of ATP generation. PLC, however, is not only a metabolic drug; it is also a potent antiradical agent and thus may protect tissues from oxidative damage. PLC has been demonstrated to exert a protective effect in different models of both cardiac and endothelial dysfunction, to prevent the progression of atherosclerosis, and, more recently, to improve some of the cardiometabolic alterations that frequently accompany insulin resistance. As a result, most of the clinical trials conducted in humans highlight PLC as a potential treatment option in cardiovascular diseases such as peripheral arterial disease, chronic heart failure, or stable angina, especially when type 2 diabetes mellitus or hyperglycemia (i.e., patients on hemodialysis) are also present. The aim of this review is to summarize the pharmacological effects and possible therapeutic applications of PLC, including the most recent findings to date.     

Nutrition and metabolic syndrome

Sufficient evidence exists in relation to the association in clinical practice between disorders in the metabolism of glucose, lipoproteins, insulin action, arterial hypertension and centrally-distributed obesity. This association is named Metabolic Syndrome. Despite the existence thereof had been questioned by the ADA and EASD, it is a useful tool affording the possibility of identifying individuals at high risk of developing cardiovascular disease. Metabolic syndrome and/or its individual components are associated with a high incidence rate of cardiovascular disease. Obesity and a sedentary lifestyle are underlying risk factors along this syndrome's pathway to disease, changes in living habits therefore being a first-line intervention in the prevention and treatment of insulin resistance, hyperglycemia, aterogenic dyslipemia and arterial hypertension. Weight loss and exercise are the keys to the overall plan, one of the most important non-pharmacological cardiovascular risk reduction strategies however still being diet. Epidemiological studies have found a high intake of simple sugars, of foods having a glycemic index and of diets with a high glycemic load to be associated to insulin resistance, type II diabetes mellitus, hypertriglyceridemia and low HDL-cholesterol figures. Los saturated fat intake in favor of polyunsaturated and monounsaturated fatty acids has been implied in a reduction of the incidence of type II diabetes mellitus and dyslipemia, although the debate is ongoing. Unrefined grain fiber in the diet has been beneficial in reducing the risk of diabetes. Among the diet patterns, the Mediterranean diet has been related to a lower incidence of diabetes and a reduction in the risk of death. Studies for intervention in the prevention of type II diabetes have suggested low-fat diets (reducing saturated and trans-fats), with a high degree of fiber and low glycemic index. Clinical trials have shown diets with small amounts of carbohydrates, low glycemic index and the Mediterranean and DASH diets to be beneficial in reducing aterogenic dyslipemia. There is currently no good evidence for choosing diets with restricted carbohydrates. On the other hand, different guides recommend low-calorie diets with a low content in saturated fats, trans-fats, cholesterol and sugars in favor the eating fruits, green vegetables, unrefined grains and fish.     

Endothelial dysfunction in obesity and insulin resistance: a road to diabetes and heart disease

Obesity, insulin resistance, and endothelial dysfunction closely coexist throughout the natural history of type 2 diabetes. They all can be identified not only in people with type 2 diabetes, but also in various groups at risk for the disease, such as individuals with impaired glucose tolerance, family history of type 2 diabetes, hypertension, dyslipidemia, prior gestational diabetes, or polycystic ovary syndrome. Whereas their evident association cannot fully establish a cause-effect relationship, fascinating mechanisms that bring them closer together than ever before are rapidly emerging. Central or abdominal obesity leads to insulin resistance and endothelial dysfunction through fat-derived metabolic products, hormones, and cytokines. Insulin resistance leads to endothelial dysfunction through the frequent association with traditional cardiovascular risk factors and through some more direct novel mechanisms. Some specific and shared insulin signaling abnormalities in muscle, fat, and endothelial cells, as well as some new genetic and nontraditional factors, may contribute to this interesting association. Some recent clinical studies demonstrate that nonpharmacological and pharmacological strategies targeting obesity and/or insulin resistance ameliorate endothelial function and low-grade inflammation. All these findings have added a new dimension to the association of obesity, insulin resistance, and endothelial dysfunction that may become a key target in the prevention of type 2 diabetes and cardiovascular disease.     

Microvascular dysfunction as an explanation for the metabolic syndrome

The metabolic syndrome is a cluster of mutually related risk factors that confers an increased risk for both type 2 diabetes mellitus and cardiovascular disease. Although the metabolic syndrome seems to have multiple aetiological factors, microvascular dysfunction is a potential explanation for the above-mentioned cluster of multiple metabolic risk factors such as hypertension, insulin resistance and glucose intolerance. Microvascular dysfunction leads not only to increased peripheral vascular resistance and blood pressure, but may also decrease the insulin-mediated glucose uptake in muscles. The different effect on the microcirculation may explain why some antihypertensive drugs (beta-blockers) lead to an increased incidence of type 2 diabetes, whereas others (angiotensin-converting enzyme (ACE) inhibitors) are associated with a decrease of that risk.     

The importance of endothelin-1 for microvascular dysfunction in diabetes

Most of the late diabetic complications such as retinopathy, nephropathy, and neuropathy, have their basis in disturbed microvascular function. Structural and functional changes in the micro-circulation are present in diabetes mellitus irrespective of the organ studied, and the pathogenesis is complex. Endothelial dysfunction, characterized by an imbalance between endothelium-derived vasodilator and vasoconstrictor substances, plays an important role in the pathogenesis of diabetic microangiopathy. Increased circulating levels of endothelin-1 (ET-1), a potent vasoconstrictor peptide, has been found in patients with diabetes, and a positive correlation between plasma ET-1 levels and microangiopathy in patients with type 2 diabetes has been demonstrated. In addition to its direct vasoconstrictor effects, enhanced levels of ET-1 may contribute to endothelial dysfunction through inhibitory effects on nitric oxide (NO) production. Vascular endothelial dysfunction may precede insulin resistance, although the feature of insulin resistance syndrome includes factors that have negative effects on endothelial function. Furthermore, ET-1 induces a reduction in insulin sensitivity and may take part in the development of the metabolic syndrome. In the following, the mechanisms by which ET-1 contributes to the development of diabetic microangiopathy and the potentially beneficial effect of selective ET_A receptor antagonists are discussed.     

Current aspects and future perspectives of pharmacotherapy or type II diabetes

Type II diabetes mellitus is a group of metabolic disorders of fat, carbohydrate and protein metabolism that results from defects in insulin action. It is associated with microvascular and macrovascular disease complications. Goals of therapy in management of type II diabetes mellitus are directed at reducing symptoms of hyperglycemia, reducing the onset and progression of retinopathy, nephropathy and neuropathy complications, intensive therapy of associated cardiovascular risk factors and improving quality and quantity of life. Multidisciplinary teams of health care professions are needed to optimize outcomes in persons with diabetes mellitus. This article will focus on the pharmacotherapeutic agents used in type II diabetes mellitus with or without microvascular and macrovascular disease risk. We will describe also the agents used in prevention of this disense.