Interfaces between cardiovascular and kidney disease among Aboriginal Australians

Rates of kidney disease among several indigenous groups have been shown to be substantially higher than corresponding non-indigenous groups. This excess has been clearly shown among Aboriginal Australians with respect to both end-stage kidney disease and early kidney disease. Rates of cardiovascular disease among Aboriginal Australians are also very high, as are rates of diabetes, smoking, and possibly overweight and obesity. These factors have been traditionally linked with cardiovascular and renal disease as part of a broader metabolic syndrome. However, the links and interfaces between cardiovascular and kidney disease in this environment extend beyond these traditional factors. The factors associated with atherosclerosis have expanded in recent years to include markers of inflammation, some infection, antioxidants, and other non-traditional risk factors. Given the high rates of acute infection and poor living conditions endured by many indigenous people, one might expect these non-traditional risk factors to be highly prevalent. In this review, we explore the relationships between markers of inflammation, some serological markers of infection, and other selected markers and both cardiovascular and renal disease. In doing so, we demonstrate links between kidney and cardiovascular disease at a number of levels, beyond the traditional cardiovascular/renal risk factors. Many of these factors are beyond the control of the individual or even community; addressing these issues a broader focus and biopsychosocial model. (C) 2005 by the National Kidney Foundation, Inc.

Adiponectin multimerization is dependent on conserved lysines in the collagenous domain: Evidence for regulation of multimerization by alterations in posttranslational modifications

Adiponectin is a secreted, multimeric protein with insulin-sensitizing, antiatherogenic, and antiinflammatory properties. Serum adiponectin consists of trimer, hexamer, and larger high-molecular-weight (HMW) multimers, and these HMW multimers appear to be the more bioactive forms. Multimer composition of adiponectin appears to be regulated; however, the molecular mechanisms involved are unknown. We hypothesize that regulation of adiponectin multimerization and secretion occurs via changes in posttranslational modifications (PTMs). Although a structural role for intertrimer disulfide bonds in the formation of hexamers and HMW multimers is established, the role of other PTMs is unknown. PTMs identified in murine and bovine adiponectin include hydroxylation of multiple conserved proline and lysine residues and glycosylation of hydroxylysines. By mass spectrometry, we confirmed the presence of these PTMs in human adiponectin and identified three additional hydroxylations on Pro71, Pro76, and Pro95. We also investigated the role of the five modified lysines in multimer formation and secretion of recombinant human adiponectin expressed in mammalian cell lines. Mutation of modified lysines in the collagenous domain prevented formation of HMW multimers, whereas a pharmacological inhibitor of prolyl- and lysyl-hydroxylases, 2,2'-dipyridyl, inhibited formation of hexamers and HMW multimers. Bacterially expressed human adiponectin displayed a complete lack of differentially modified isoforms and failed to form bona fide trimers and larger multimers. Finally, glucose-induced increases in HMW multimer production from human adipose explants correlated with changes in the two-dimensional electrophoresis profile of adiponectin isoforms. Collectively, these data suggest that adiponectin multimer composition is affected by changes in PTM in response to physiological factors.

Can physical activity prevent diabetes?

Most physical activity researchers are familiar with the epidemiological evidence that suggests that physical activity has an important role in the primary prevention of Type 2 diabetes. There is compelling evidence from large well-conducted prospective cohort trials to show that the risk of diabetes is reduced by up to 50% in people who are habitually active. There is also evidence from large randomised controlled trails to support the view that physical activity, as part of a lifestyle change program, can prevent Type 2 diabetes and the onset and progression of metabolic syndrome. This is the strongest evidence in support of a beneficial role for physical activity in the primary prevention of any health problem; much stronger than that for the links between smoking and lung cancer. This presentation will critically evaluate this evidence, and explore the notion that, while physical activity may postpone the development of Type 2 diabetes, it may not actually prevent the onset of problem at the population level. As the (self-reported) prevalence of Type 2 diabetes has more than doubled in the last 20 years, it is critical that we explore effective strategies for ensuring that we can ‘activate’ Australians sufficiently to prevent, rather than simply postpone, the development of this significant health problem.

Treatment with metformin

Metformin is an anti-hyperglycaemic agent widely used in the treatment of type 2 diabetes. It counters insulin resistance through insulin-dependent and -independent effects on cellular nutrient and energy metabolism, improving glycaemic control without weight gain and without increasing the risk of hypoglycaemia. Metformin can also benefit several risk factors for vascular disease independently of glycaemic control. In subjects with metabolic syndrome, metformin improves prognosis. It decreases progression of impaired glucose tolerance to type 2 diabetes, assists weight reduction especially in conjunction with lifestyle management and exerts other potentially favourable cardiovascular effects. For example, metformin can modestly improve the lipid profile in some dyslipidaemic individuals, reduce pro-inflammatory cytokines and monocyte adhesion molecules and decrease advanced glycation end products. Metformin can also improve parameters of endothelial function in the macro- and micro-vasculature, indicating lower athero-thrombotic risk, but it does not appear to reduce blood pressure. In normoglycaemic individuals with risk factors for diabetes and in women with polycystic ovary syndrome there is evidence that metformin can defer or prevent the development of diabetes. Thus, metformin offers beneficial effects to delay the onset and reverse or reduce the progression of many of the metabolic features and cardiovascular risk factors associated with metabolic syndrome.

Defective peroxisomal proliferators activated receptor gamma activity due to dominant-negative mutation synergizes with hypertension to accelerate cardiac fibrosis in mice

Aims: Humans with inactivating mutations in peroxisomal proliferators activated receptor gamma (PPAR?) typically develop a complex metabolic syndrome characterized by insulin resistance, diabetes, lipodystrophy, hypertension, and dyslipidaemia which is likely to increase their cardiovascular risk. Despite evidence that the activation of PPAR? may prevent cardiac fibrosis and hypertrophy, recent evidence has suggested that pharmacological activation of PPAR? causes increased cardiovascular mortality. In this study, we investigated the effects of defective PPAR? function on the development of cardiac fibrosis and hypertrophy in a murine model carrying a human dominant-negative mutation in PPAR?. Methods and results: Mice with a dominant-negative point mutation in PPAR? (P465L) and their wild-type (WT) littermates were treated with either subcutaneous angiotensin II (AngII) infusion or saline for 2 weeks. Heterozygous P465L and WT mice developed a similar increase in systolic blood pressure, but the mutant mice developed significantly more severe cardiac fibrosis to AngII that correlated with increased expression of profibrotic genes. Both groups similarly increased the heart weight to body weight ratio compared with saline-treated controls. There were no differences in fibrosis between saline-treated WT and P465L mice. Conclusion: These results show synergistic pathogenic effects between the presence of defective PPAR? and AngII-induced hypertension and suggest that patients with PPAR? mutation and hypertension may need more aggressive therapeutic measures to reduce the risk of accelerated cardiac fibrosis. © The Author 2009.

Metformin - The gold standard:a scientific handbook

Metformin may play in important role in the future in helping to prevent the development of diabetes: it is a strong candidate therapy for delaying the onset of the disease and potentially as part of a treatment programme to correct features of the metabolic syndrome. This book celebrates 50 years of research into metformin and its use in the treatment of diabetes. Metformin is still the drug of choice for managing patients with type 2 diabetes and all new drugs are tested in comparison with this, the gold standard. Comprising seven sections, addressing different aspects of research on metformin and its applications, this book is edited by a world class team of expert diabetologists and beautifully presented in two colour throughout. It also includes a bibliography of all papers published on metformin and a complete list of all authors on those papers.

New drugs for type 2 diabetes mellitus:what is their place in therapy?

Oral therapy for type 2 diabetes mellitus, when used appropriately, can safely assist patients to achieve glycaemic targets in the short to medium term. However, the progressive nature of type 2 diabetes usually requires a combination of two or more oral agents in the longer term, often as a prelude to insulin therapy. Issues of safety and tolerability, notably weight gain, often limit the optimal application of anti-diabetic drugs such as sulforylureas and thiazolidinediones. Moreover, the impact of different drugs, even within a single class, on the risk of long-term vascular complications has come under scrutiny. For example, recent publication of evidence suggesting potential detrimental effects of rosiglitazone on myocardial events generated a heated debate and led to a reduction in use of this drug. In contrast, current evidence supports the view that pioglitazone has vasculoprotective properties. Both drugs are contraindicated in patients who are at risk of heart failure. An additional recently identified safety concern is an increased risk of fractures, especially in postmenopausal women. Several new drugs with glucose-lowering efficacy that may offer certain advantages have recently become available. These include (i) injectable glucagonlike peptide-1 (GLP-1) receptor agonists and oral dipeptidyl peptidase-4 (DPP-4) inhibitors; (ii) the amylin analogue pramlintide; and (iii) selective cannabinoid receptor-1 (CB1) antagonists. GLP-1 receptor agonists, such as exenatide, stimulate nutrient-induced insulin secretion and reduce inappropriate glucagon secretion while delaying gastric emptying and reducing appetite. These agents offer a low risk of hypoglycaemia combined with sustained weight loss. The DPP-4 inhibitors sitagliptin and vildagliptin are generally weight neutral, with less marked gastrointestinal adverse effects than the GLP-1 receptor agonists. Potential benefits of GLP-1 receptor stimulation on P cell neogenesis are under investigation. Pancreatitis has been reported in exenatide-treated patients. Pramlintide, an injected peptide used in combination with insulin, can reduce insulin dose and bodyweight. The CB1 receptor antagonist rimonabant promotes weight loss and has favourable effects on aspects of the metabolic syndrome, including the hyperglycaemia of type 2 diabetes. However, in 2007 the US FDA declined approval of rimonabant, requiring more data on adverse effects, notably depression. The future of dual peroxisome proliferator-activated receptor-alpha/gamma agonists, or glitazars, is presently uncertain following concerns about their safety. In conclusion, several new classes of drugs have recently become available in some countries that offer new options for treating type 2 diabetes. Beneficial or neutral effects on bodyweight are an attractive feature of the new drugs. However, the higher cost of these agents, coupled with an absence of long-term safety and clinical outcome data, need to be taken into consideration by clinicians and healthcare organizations.

Risk factors of type 2 diabetes and cardiovascular diseases among Jamaican adolescents

Purpose. The purpose of the study was to examine Jamaican adolescents in a school setting, for risk factors of type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVDs). Methods. A descriptive epidemiological cross-sectional study of 276 Jamaican adolescents (112 males and 164 females) ages 14-19 years (15.6±1.2), randomly selected from grades 9-12 from ten high schools on the island. Thirteen risk factors were examined. Risk factors were compared with BMI levels and demographics. A sub-study validated finger prick testing of fasting blood glucose, total cholesterol, and HbA1c versus venous testing in 59 subjects. Results. Prevalence of overweight was 33.0% (n=91) with mean BMI of 23.74±7.74. Approximately 66.7% of subjects reported ≥ 3 risk factors. The number of T2DM and CVDs risk factors increased for subjects with BMI above 25. One third of the overweight subjects were classified with the metabolic syndrome. High BMI was associated with high waist circumference (r = .767, p < .01), high waist-to-hip ratio (r = .180, p < .01), presence of Acanthosis Nigricans (r = .657, p < .01), high total cholesterol (r = .158, p < .01), family history of T2DM (r = .157, p < .01), and hypertension (r = .422, p < .01). Regression analyses significantly predicted gender and physical activity (p < .001), and total number of risk factors for T2DM and CVDs (p < .001). Paired samples t-tests revealed no significant differences between methods of testing for TC and HbA1c (p < .01) but not for FBG (p > .05). Percentage bias for the methods of blood testing met the reference standards for fasting blood glucose but not for total cholesterol and HbA1c. Bland Altman tests of agreement between the two methods indicated good agreement for all three tests. Conclusion. Jamaican adolescents are at high risk for T2DM and CVDs as seen in other study populations. Effective programs to prevent T2DM and CVDs are needed. Family history of diseases, anthropometric measures, and gender identified more subjects at risk than did the biochemical measures. Comparison between finger prick and venous blood methods suggested that finger prick is an adequate method to screen for risk factors in children and adolescents.

Beyond BMI: The “Metabolically healthy obese” phenotype & its association with clinical/subclinical cardiovascular disease and all-cause mortality -- a systematic review

Background A subgroup has emerged within the obese that do not display the typical metabolic disorders associated with obesity and are hypothesized to have lower risk of complications. The purpose of this review was to analyze the literature which has examined the burden of cardiovascular disease (CVD) and all-cause mortality in the metabolically healthy obese (MHO) population. Methods Pubmed, Cochrane Library, and Web of Science were searched from their inception until December 2012. Studies were included which clearly defined the MHO group (using either insulin sensitivity and/or components of metabolic syndrome AND obesity) and its association with either all cause mortality, CVD mortality, incident CVD, and/or subclinical CVD. Results A total of 20 studies were identified; 15 cohort and 5 cross-sectional. Eight studies used the NCEP Adult Treatment Panel III definition of metabolic syndrome to define “metabolically healthy”, while another nine used insulin resistance. Seven studies assessed all-cause mortality, seven assessed CVD mortality, and nine assessed incident CVD. MHO was found to be significantly associated with all-cause mortality in two studies (30%), CVD mortality in one study (14%), and incident CVD in three studies (33%). Of the six studies which examined subclinical disease, four (67%) showed significantly higher mean common carotid artery intima media thickness (CCA-IMT), coronary artery calcium (CAC), or other subclinical CVD markers in the MHO as compared to their MHNW counterparts. Conclusions MHO is an important, emerging phenotype with a CVD risk between healthy, normal weight and unhealthy, obese individuals. Successful work towards a universally accepted definition of MHO would improve (and simplify) future studies and aid inter-study comparisons. Usefulness of a definition inclusive of insulin sensitivity and stricter criteria for metabolic syndrome components as well as the potential addition of markers of fatty liver and inflammation should be explored. Clinicians should be hesitant to reassure patients that the metabolically benign phenotype is safe, as increased risk cardiovascular disease and death have been shown.

Risk factors of type 2 diabetes and cardiovascular diseases among Jamaican adolescents

Purpose: The purpose of the study was to examine Jamaican adolescents in a school setting, for risk factors of type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVDs). Methods: A descriptive epidemiological cross-sectional study of 276 Jamaican adolescents (112 males and 164 females) ages 14-19 years (15.6±1.2), randomly selected from grades 9-12 from ten high schools on the island. Thirteen risk factors were examined. Risk factors were compared with BMI levels and demographics. A sub-study validated finger prick testing of fasting blood glucose, total cholesterol, and HbAlc versus venous testing in 59 subjects. Results: Prevalence of overweight was 33.0% (n=91) with mean BMI of 23.74±7.74. Approximately 66.7% of subjects reported > 3 risk factors. The number of T2DM and CVDs risk factors increased for subjects with BMI above 25. One third of the overweight subjects were classified with the metabolic syndrome. High BMI was associated with high waist circumference (r =.767, p (r = .180, p.05). Percentage bias for the methods of blood testing met the reference standards for fasting blood glucose but not for total cholesterol and HbAlc. Bland Altman tests of agreement between the two methods indicated good agreement for all three tests. Conclusion: Jamaican adolescents are at high risk for T2DM and CVDs as seen in other study populations. Effective programs to prevent T2DM and CVDs are needed. Family history of diseases, anthropometric measures, and gender identified more subjects at risk than did the biochemical measures. Comparison between finger prick and venous blood methods suggested that finger prick is an adequate method to screen for risk factors in children and adolescents.

Prevalência da síndrome metabólica e seus componentes nos estágios pubertários de escolares do sexo feminino norte-rio-grandenses

The diagnosis of nutritional status is extremely re levant in clinical practice and population assessment, due to the association betwe en body fat and metabolic alterations. The aim of this study is to analyze th e prevalence of metabolic syndrome (MS) and its components in the pubertal stages of f emale students in Rio Grande do Norte state, Brazil, in accordance with Internation al Diabetes Federation criteria. This is a cross-sectional study with 449 students aged betw een 8 and 19 years, stratified into pubertal stages systematized by Marshal and Tanner (1969), as follows: 27.6% prepubertal, 44.3% pubertal and 28.1% postpubertal, with mean ages of 9.4±1.27, 12.4±2.23 and 15.1±1.88 years, respectively. Preval ences were analyzed using distribution of frequencies and their respective 95 % confidence intervals, while the chi- square test and odds ratio were applied to analyze the associations between variables. The general prevalence of MS was 3.3% (CI: 2% - 5%) , without occurrences in the prepubertal stage, observing that it emerges from t he pubertal stage onwards with a prevalence of 2.5% (CI 95% 0.1% - 5%), 1% (CI 95% 0.4% - 2.3%) of cases with overweight and 1.5% (CI 95% -0.1% - 3.2%) with obes e individuals, while in the postpubertal stage the prevalence is 7.9% (CI 95% 3 .2% - 12.6%), 0.8% (CI 95% -0.8% - 2.3%) normal weight cases, 4% (CI 95% 0.6% - 7.4% ) overweight and 3.1% (CI 0.1% - 6.2%) obese individuals. There was an association (p<0.02) between pubertal stages and MS ( x 2 =5.2), with an OR of 3.3 (CI: 1.2 - 5), showing tha t postpubertal adolescents are more prone to SM than pubertals, while the OR i n obese individuals was 2.1 (CI: 2– 2.2) compared to the overweight. Body mass index (B MI) ( x 2 = 29.4; p<0.001) and age range ( x 2 = 13.1; p<0.001) showed a significant linear assoc iation with MS. Of the adolescents with MS, those aged ten years or younge r exhibited higher %G. The most prevalent components in all the stages were altered waist circumference (27.2% [CI 23% - 31%]) and low HDL cholesterol (39.6% [CI 35% – 44%]), which, coupled with hypertension, displayed significant differences in the postpubertal stage in relation to the other stages. The results show that MS emerges from the pubertal stage onwards in proportion to excess childhood body fat, a fact tha t calls for prevention strategies using an educational approach, reducing the large demand on the National Health System. Keywords: Metabolic syndrome, pubertal stages, risk factors.

Parâmetros bioquímicos e níveis de IgE total e específicas para aeroalérgenos em mulheres obesas com síndrome dos ovários policísticos

Introduction: Polycystic ovary syndrome (PCOS) whose classic features (menstrual irregularity of oligo/ amenorrhea type, chronic anovulation, infertility and hyperandrogenism clinical and/ or biochemical), is associated with aspects of metabolic syndrome (MS), as obesity and insulin resistance. The level of obesity determines different levels of inflammation, increasing cytokines participants of metabolic and endocrine functions, beyond modulate the immune response. Metabolic changes, added to the imbalance of sex hormones underlying irregular menstruation observed in (PCOS) can trigger allergic processes and elevation of total and specific IgE antibodies indicate that a sensitization process was started. Objective: To evaluate the influence of PCOS on biochemical parameters and levels of total and specific IgE to aeroallergens in obese women. Methods: After approval by the Committee of Ethics in Research, were recruited 80 volunteers with BMI ≥ 30 kg/m2 and age between 18 and 45 years. Among these, 40 with PCOS according to the Rotterdam criteria and 40 women without PCOS (control group). All participants were analysed with regard to anthropometric, clinical, gynecological parameters, interviewed using a questionnaire, and underwent blood sampling for realization of laboratory tests of clinical biochemistry: Total cholesterol, LDL-cholesterol, HDL- cholesterol, Triglycerides, Fasting glucose, Urea, Creatinine, Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) and immunological: total and specific IgE to Dermatophagoides pteronyssinus, Blomia tropicalis, Dermatophagoides farinae and Dermatophagoides microceras.Statistical analysis was performed using SPSS 15.0 software through the chi-square tests, Fisher, Student t test and binary logistic regression, with significance level (p <0.05). Results: It was observed in the group of obese women with PCOS that 29 (72.5%) had menstrual cycle variable and 27 (67.5%) had difficulty getting pregnant. According to waist-hip ratio, higher average was also observed in obese PCOS (0.87). Blood level of HDL (36.9 mg/dL) and ALT (29.3 U/L) were above normal levels in obese women with PCOS, with statistically significant relationship. In the analysis of total and specific IgE to D. pteronyssinus high results were also prevalent in obese PCOS, with blood level (365,22 IU/mL) and (6.83 kU/L), respectively, also statistically significant. Conclusions: Observed predominance of cases with high levels of total IgE in the group of obese women with PCOS, 28 (70%) of the participants, whose mean blood concentration of the group was 365.22 IU/mL. In the analysis of Specific IgE between the groups, the allergen Dermatophagoides pteronyssinus showed greater dispersion and average the results of sensitization in the group of obese PCOS, whose mean blood concentration was 6.83 kU/l. Keywords: Obesity, Allergens and Polycystic Ovary Syndrome

Maternal gestational weight gain and offspring's risk of cardiovascular disease and mortality

Funding: This research was supported by Chest Heart and Stroke Scotland (R10/A128)

Maternal gestational weight gain and offspring's risk of cardiovascular disease and mortality

Funding: This research was supported by Chest Heart and Stroke Scotland (R10/A128)