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The metabolic syndrome consists of a constellation of clinical and biochemical risk factors that cluster together and heighten the risk for atherogenesis, cardiovascular diseases, and diabetes. Established risk cardiovascular factors like hypertension, atherogenic dyslipidaemia, and glucose intolerance occur in the setting of insulin resistance and central adiposity, with genetic and environmental influences modulating the ultimate risk. Chronic insults to the endothelium take its toll in the form of silent as well as clinically evident cardiovascular events. The cellular and vascular accompaniments have shed some light into the underlying pathophysiology. Heightened, low-grade inflammatory processes as well as a continuum of vascular insults ranging from early endothelial derangements to advanced atherosclerosis have been examined. In recent years there has been an explosion of basic and clinical knowledge related to the metabolic syndrome. Although dyslipidaemia is considered a traditional risk component for the syndrome, its qualitative aspects, genetically determined subfractions, and variation in proatherogenic tendency have generated renewed interest and debate. New targets within the dyslipidaemic spectrum that have differing clinical relevance are being evaluated. The effect of heredity, lifestyle changes, pharmacotherapeutic agents, and supplements is being investigated. Further research into the impact of dyslipidemia and inflammation as both pathophysiologic risk factors and objects for targeted therapy in the metabolic syndrome should deepen our understanding and unravel answers to the underlying dynamics in this global epidemic.
Acta Diabetol 2009 Mar
PMID:The therapeutic modulation of atherogenic dyslipidemia and inflammatory markers in the metabolic syndrome: what is the clinical relevance? 1892 58

A cross-sectional descriptive study was done on patients recently entered into the National Diabetes Registry in Eritrea where the prevalence was estimated to be 2.2% based on patient information in 2004. Of the 627 patients with diabetes, two thirds were type 2. Although type 1 had poorer control (42.9%) than type 2 (29.9%), some of the risk factors such as cholesterol (43.4 vs. 28.2%), triglyceride (23.4 vs. 12.8%), hypertension (55.2 vs. 12.7%) as well as BMI and waist/hip ratio were higher in type 2 than type 1. More than one-third (41.2%) of patients with type 2 compared to type 1 (19.5%) had complications, the commonest being retinopathy (33%) followed by foot ulcers (14%) and neuropathy (4%). Many of the diabetic patients demonstrated the presence of the metabolic syndrome components such as hypertension, obesity and dyslipidemia. The authors conclude that diabetes registry is invaluable in providing evidence-based prevention and control of the disease.
Acta Diabetol 2010 Mar
PMID:Profile of patients with diabetes in Eritrea: results of first phase registry analyses. 1918 40

The secondary occurrence of type 2 diabetes with various hormonal diseases (e.g. pituitary, adrenal and/or thyroid diseases) is a recurrent observation. Indeed, impaired glucose tolerance (IGT) and overt diabetes mellitus are frequently associated with acromegaly and hypercortisolism (Cushing syndrome). The increased cardiovascular morbidity and mortality associated with acromegaly and Cushing syndrome may partly be a consequence of increased insulin resistance that normally accompanies hormone excess. Acromegalic patients are insulin resistant, both in the liver and in the periphery, displaying hyperinsulinemia and increased glucose turnover in the basal post-absorptive states. The prevalence of diabetes mellitus and that of IGT in acromegaly is reported to range 16-56%, whereas the degree of glucose tolerance seems correlated with circulating growth hormone (GH) levels, age, and disease duration. Moreover, a family history of diabetes and concomitant presence of arterial hypertension have been found to predispose to diabetes as well. GH has physiological effects on glucose metabolism, stimulating gluconeogenesis and lipolysis, which results in increased blood glucose and free fatty acid levels. Conversely, insulin-like growth factor 1 (IGF-I) enhances insulin sensitivity primarily on skeletal muscles. However, in acromegaly, increased IGF-I levels are unable to counteract the insulin-resistance status determined by GH excess. Therapy with somatostatin analogues (SSAs) induce control of GH and IGF-I excess in the majority of patients, but their inhibitory effect on pancreatic insulin secretion might complicate the overall effect of this treatment on glucose tolerance. Hypercortisolism produces visceral obesity, insulin resistance, and dyslipidemia that together with hypertension, hypercoagulability, and ventricular morphologic and functional abnormalities increase cardiovascular risk, and persist up to 5 years after resolution of hypercortisolism. Hypercortisolism leads to hyperglycaemia and reduced glucose tolerance, determines insulin resistance, stimulates hepatic gluconeogenesis and glicogenolisis. In Cushing syndrome the prevalence of diabetes varies between 20 and 50%, but probably this prevalence is underestimated, as not always an oral glucose tolerance test is performed in the presence of an apparently normal fasting glycaemia. Again, disease duration, rather than hormone levels, seems to be the major determinant in the occurrence of systemic complications in Cushing syndrome. Due to the impact they have on mortality and morbidity in both acromegaly and Cushing syndrome, these complications should be treated aggressively. In patients with neuroendocrine tumours (NETs) the occurrence of altered glucose tolerance may be due to a decreased insulin secretion, like it happens in patients who underwent pancreatic surgery and in those with pheochromocytoma, or to an altered counterbalance between hormones, such as in patients with glucagonoma and somatostatinoma. Moreover, SSAs represent a valid therapeutic choice in the symptomatic treatment of NETs, and also in this case the medical therapy of the primary disease, may have a significant impact on the prevalence of glucose metabolism imbalance. In thyroid disorders, an abnormal glucose tolerance may be principally encountered in hyperthyroidism. The pathogenesis is complex and scant data on prevalence and severity are found in the literature. Adequate treatment for glucose imbalance is mandatory in these peculiar patients in line with the American Diabetes Association and the European Association for the Study of Diabetes consensus statement. In particular, since traditional insulins have two features that may complicate therapy (absorption profiles, delayed onset of action and peak activity), the new insulin analogues could be of particular interest in the management of the secondary diabetes associated with endocrinopathies, considering the frailty of these patients. Indeed, it has been demonstrated that insulin glargine, given once daily, reduces the risk of hypoglycaemia compared with other formulations, and can facilitate a more aggressive insulin treatment in this class of patients.
Acta Diabetol 2009 Jun
PMID:Secondary diabetes associated with principal endocrinopathies: the impact of new treatment modalities. 1932 13

Microvascular complications are an important cause of morbidity in diabetic patients and can be detected in a significant number of patients at the time of diabetes diagnosis. However, little is known about the alterations in the microvasculature previous to the clinical manifestation of diabetes mellitus type 2. To obtain more insights into the early microvascular deterioration resulting from prediabetes, morphological and functional microvascular parameters were monitored using intravital fluorescence microscopy through a dorsal skin-fold chamber preparation in the uncoupling promotor-driven diphtheria toxin A chain (UCP1/DTA) mice. At the age of 12 weeks, the UCP1/DTA-mice were characterized by impaired glucose tolerance with concurrent unchanged fasting glucose, as well as dyslipidemia, hyperinsulinemia, hypertension and obesity. Prediabetic mice displayed combined hypertriglyceridemia and hypercholesterinemia. Associated with these prediabetic metabolic alterations, we demonstrate that microvascular density showed a dramatic decrease due to a reduction in perfused small vessels. A reduction in vascular density combined with unaltered blood flow in single vessels resulted in impaired tissue perfusion. Endothelial dysfunction with subsequently increased microvascular permeability and leukocyte-endothelium interactions were found. Our results of profound microvascular alterations at stages of normal fasting glucose underline the importance of early screening for prediabetes and associated microvascular complications.
Acta Diabetol 2010 Dec
PMID:Early microvascular complications of prediabetes in mice with impaired glucose tolerance and dyslipidemia. 1936 64

Diabetic nephropathy is the leading cause of chronic renal disease and a major cause of cardiovascular mortality. Diabetic nephropathy has been categorized into stages: microalbuminuria and macroalbuminuria. The cut-off values of micro- and macroalbuminuria are arbitrary and their values have been questioned. Subjects in the upper-normal range of albuminuria seem to be at high risk of progression to micro- or macroalbuminuria and they also had a higher blood pressure than normoalbuminuric subjects in the lower normoalbuminuria range. Diabetic nephropathy screening is made by measuring albumin in spot urine. If abnormal, it should be confirmed in two out three samples collected in a three to six-months interval. Additionally, it is recommended that glomerular filtration rate be routinely estimated for appropriate screening of nephropathy, because some patients present a decreased glomerular filtration rate when urine albumin values are in the normal range. The two main risk factors for diabetic nephropathy are hyperglycemia and arterial hypertension, but the genetic susceptibility in both type 1 and type 2 diabetes is of great importance. Other risk factors are smoking, dyslipidemia, proteinuria, glomerular hyperfiltration and dietary factors. Nephropathy is pathologically characterized in individuals with type 1 diabetes by thickening of glomerular and tubular basal membranes, with progressive mesangial expansion (diffuse or nodular) leading to progressive reduction of glomerular filtration surface. Concurrent interstitial morphological alterations and hyalinization of afferent and efferent glomerular arterioles also occur. Podocytes abnormalities also appear to be involved in the glomerulosclerosis process. In patients with type 2 diabetes, renal lesions are heterogeneous and more complex than in individuals with type 1 diabetes. Treatment of diabetic nephropathy is based on a multiple risk factor approach, and the goal is retarding the development or progression of the disease and to decrease the subject's increased risk of cardiovascular disease. Achieving the best metabolic control, treating hypertension (<130/80 mmHg) and dyslipidemia (LDL cholesterol <100 mg/dl), using drugs that block the renin-angiotensin-aldosterone system, are effective strategies for preventing the development of microalbuminuria, delaying the progression to more advanced stages of nephropathy and reducing cardiovascular mortality in patients with diabetes.
Diabetol Metab Syndr 2009 Sep 21
PMID:Diabetic nephropathy. 1982 47

Dyslipidemia is an important etiologic factor in the development of cardiovascular disease (CVD), which is a leading cause of death worldwide. As CVD begins in childhood, and as dyslipidemia is an important risk factor for CVD, screening and treatment of dyslipidemia in adolescents and children becomes an important health matter. This review deals with issues related to screening, diagnosis and treatment of dyslipidemia in children and adolescents.
Diabetol Metab Syndr 2009 Dec 08
PMID:Management of dyslipidemia in children. 1999 41

Even using intensive statin monotherapy, many patients fail to achieve all the desired lipid goals and remain at high residual risk of cardiovascular events. In view of the still unproven decisively intensive "statin as monotherapy" strategy and "residual risk" concept, it is logical to ask whether other strategies, particularly fibrate/statin combination therapy, could be more beneficial and safer. A clear benefit of fibrate monotherapy did emerge previously among patients with atherogenic dyslipidemia (particularly high triglycerides and low high density lipoprotein cholesterol [HDL-C]) typically present in the metabolic syndrome and type 2 diabetes. In contrast, in patients without atherogenic dyslipidemia this favorable effect was not demonstrated. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study investigated whether combination therapy with a statin plus a fibrate, as compared with statin monotherapy, would reduce the risk of cardiovascular disease in patients with type 2 diabetes mellitus. However, relevant patients with atherogenic dyslipidemia represented less than 17 percent of the ACCORD Lipid population (941 out of 5518 patients). In this prespecified subgroup, the patients benefited from fenofibrate therapy in addition to simvastatin similar to the previous "fibrate's as monotherapy" trials: the primary outcome rate was 12.4% in the fenofibrate group, versus 17.3% in the placebo group (28% crude HR reduction, CI less than 1, e.g. statistically significant findings). Among all other 4548 patients without atherogenic dyslipidemia such rates were 10.1% in both fenofibrate and placebo study groups. Authors concluded that in the overall cohort of patients the combination of fenofibrate and simvastatin did not reduce the rate of the cardiovascular events as compared with simvastatin alone. Thus, their results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the general patients with type 2 diabetes. A recent large meta-analysis regarding effects of fibrates on cardiovascular outcomes noted greater effect sizes in trials that recorded a higher mean baseline triglyceride concentration (p = 0.030). As expected, in a so called "general population", reflecting a blend of effects in patients with and without atherogenic dyslipidemia, a mean "diluted" effect of fibrate therapy was reduced, but still producing a significant 10% relative risk (RR) decrease in major cardiovascular events (p = 0.048) and a 13% RR reduction for coronary events (p < 0.0001). It should be pinpointed that the epidemiological characteristics of the ACCORD Lipid study depart from those seen in real clinical practice: among people with type 2 diabetes, there is a high prevalence of atherogenic dyslipidemia and metabolic syndrome. For example, an analysis of NHANES III data in adults aged >or=50 years showed that approximately 86% of patients with type 2 diabetes also had the metabolic syndrome. Therefore, an important finding of ACCORD Lipid study was the observation that fibrates may lead to cardiovascular risk reduction in patients with atherogenic dyslipidemia not only as monotherapy but in combination with statins as well. In conclusion, in patients with atherogenic dyslipidemia (high triglycerides and low HDL-C, fibrates -- either as monotherapy or combined with statins - were associated with reduced risk of cardiovascular events. In patients without dyslipidemia this favorable effect - as expected - was absent.
Cardiovasc Diabetol 2010 Jun 15
PMID:"If it ain't broke, don't fix it": a commentary on the positive-negative results of the ACCORD Lipid study. 2055 Jun 59

Overweight and obesity in youth is a worldwide public health problem. Overweight and obesity in childhood and adolescents have a substantial effect upon many systems, resulting in clinical conditions such as metabolic syndrome, early atherosclerosis, dyslipidemia, hypertension and type 2 diabetes (T2D). Obesity and the type of body fat distribution are still the core aspects of insulin resistance and seem to be the physiopathologic links common to metabolic syndrome, cardiovascular disease and T2D. The earlier the appearance of the clustering of risk factors and the higher the time of exposure, the greater will be the chance of developing coronary disease with a more severe endpoint. The age when the event may occur seems to be related to the presence and aggregation of risk factors throughout life.The treatment in this age-group is non pharmacological and aims at promoting changes in lifestyle. However, pharmacological treatments are indicated in special situations.The major goals in dietary treatments are not only limited to weight loss, but also to an improvement in the quality of life. Modification of risk factors associated to comorbidities, personal satisfaction of the child or adolescent and trying to establish healthy life habits from an early age are also important. There is a continuous debate on the best possible exercise to do, for children or adolescents, in order to lose weight. The prescription of physical activity to children and adolescents requires extensive integrated work among multidisciplinary teams, patients and their families, in order to reach therapeutic success.The most important conclusion drawn from this symposium was that if the growing prevalence of overweight and obesity continues at this pace, the result will be a population of children and adolescents with metabolic syndrome. This would lead to high mortality rates in young adults, changing the current increasing trend of worldwide longevity. Government actions and a better understanding of the causes of this problem must be implemented worldwide, by aiming at the prevention of obesity in children and adolescents.
Diabetol Metab Syndr 2010 Aug 18
PMID:Metabolic syndrome, dyslipidemia, hypertension and type 2 diabetes in youth: from diagnosis to treatment. 2071 58

The debates continue over the validity of the metabolic syndrome concept. The continuous increment of the obesity pandemic is almost worldwide paralleled by rising rates of metabolic syndrome prevalence. Then, it seems obvious that these debates drove the need for further investigations as well as a deeper cooperation between relevant national and international organizations regarding the issue. Instead, part of the scientific community elected to totally "dismiss" the concept of the metabolic syndrome. Meanwhile, the best available evidence from three consecutive large meta-analyses has systematically shown that people with metabolic syndrome are at increased risk of cardiovascular events. The most recent and largest of them included near one million patients (total n = 951,083). The investigators concluded that the metabolic syndrome is associated with a 2-fold increase in cardiovascular outcomes and a 1.5-fold increase in all-cause mortality rates. One of the ways to hit the metabolic syndrome is an utterly simplistic view on this concept as a predictive tool only. Of course, the presence of the metabolic syndrome possesses a definite predictive value, but first of all it is a widely accepted concept regarding a biological condition based on the complex and interrelated pathophysiological mechanisms starting from excess central adiposity and insulin resistance. Therefore, it is completely unfair to compare it with statistically constructed predictive tools, including stronger prognostic variables even unrelated to each other from the biological point of view. For example, in the criteria for metabolic syndrome (in contrast to Framingham score) age and cholesterol--presumably low density lipoprotein-cholesterol (LDL-C)--levels are not included, as well as a variety of strong predictors used in other risk-stratification scores: previous myocardial infarction, heart failure, smoking, family history, etc. However, the metabolic syndrome identifies additional important residual vascular risk mainly associated with insulin resistance and atherogenic dyslipidemia (low high density lipoprotein-cholesterol (HDL-C), high triglycerides, small, dense LDL-C). Therefore, the metabolic syndrome could be a useful additional contributor in estimation of global cardiovascular risk beyond age, high LDL-C or other standard risk factors. The components of the metabolic syndrome have partially overlapping mechanisms of pathogenic actions mediated through common metabolic pathways. Therefore their total combined effect could be less than the summed of the individual effects. The concept that the metabolic syndrome is a consequence of obesity and insulin resistance, provides a useful "life-style changes" approach for prevention and treatment: caloric restriction, weight-loss and increased physical activity. The next step could theoretically be pharmacological interventions such as metformin, acarbose, fibrates, weight-loss drugs (currently only orlistat is practically available) and perhaps glucagon-like peptide-1 agonists. A third step should probably be kept for bariatric surgery.
Cardiovasc Diabetol 2011 Jan 27
PMID:"The metabolic syndrome... is dead": these reports are an exaggeration. 2126 24

Cardiovascular disease (CVD) risk in type 2 diabetes (T2DM) is only partially reduced by intensive glycemic control. Diabetic dyslipidemia is suggested to be an additional important contributor to CVD risk in T2DM. Multiple lipid lowering medications effectively reduce fasting LDL cholesterol and triglycerides concentrations and several of them routinely reduce CVD risk. However, in contemporary Western societies the vasculature is commonly exposed to prolonged postprandial hyperlipidemia. Metabolism of these postprandial carbohydrates and lipids yields multiple proatherogenic products. Even a transient increase in these factors may worsen vascular function and induces impaired endothelial dependent vasodilatation, a predictor of atherosclerosis and future cardiovascular events. There is a recent increased appreciation for the role of gut-derived incretin hormones in controlling the postprandial metabolic milieu. Incretin-based medications have been developed and are now used to control postprandial hyperglycemia in T2DM. Recent data indicate that these medications may also have profound effects on postprandial lipid metabolism and may favorably influence several cardiovascular functions. This review discusses (1) the postprandial state with special emphasis on postprandial lipid metabolism and its role in endothelial dysfunction and cardiovascular risk, (2) the ability of incretins to modulate postprandial hyperlipidemia and (3) the potential of incretin-based therapeutic strategies to improve vascular function and reduce CVD risk.
Cardiovasc Diabetol 2011 Jul 07
PMID:Postprandial hyperlipidemia, endothelial dysfunction and cardiovascular risk: focus on incretins. 2173 46


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