Reining in equine metabolic syndrome : a gluttony of challenges

We humans are complicated creatures. Despite remarkable intellect, a fearsome ability to push boundaries and superior survival mechanisms, we are at times our own worst enemy. Metabolic syndrome continues to be a premier health problem in developed, and now increasingly in undeveloped, nations. It is spreading across the planet like an infectious disease and is costing us millions. Metabolic disease remains an important focus both for medical research and for governments desperate to ease the burden on already over-taxed health systems. Unlike some previous worldwide health epidemics, obesity-related diseases will require more than a single, silver bullet. A simple vaccine or treatment cannot overcome a lack of education, awareness and in some cases sheer determination; the human element of these diseases. Undeniably, these ‘human elements’ also complicate our ability, as veterinarians, to effectively manage the growing incidence of equine obesity and metabolic disease...

Moderate physical activity level as a protective factor against metabolic syndrome in middle-aged and older women

Aims and objectives To investigate whether physical activity is a protective factor against metabolic syndrome in middle-aged and older women. Background Socio-demographic and lifestyle behaviour factors contribute to metabolic syndrome. To minimise the risk of metabolic syndrome, several global guidelines recommend increasing physical activity level. However, only limited research has investigated the relationship between physical activity levels and metabolic syndrome in middle-aged and older women after adjusting for socio-demographic and lifestyle behaviour factors. Design Cross-sectional design. Methods A convenience sample of 326 middle-aged and older women was recruited. Metabolic syndrome was confirmed according to the National Cholesterol Education Program, Adult Treatment Panel III guidelines, and physical activity levels were measured by the International Physical Activity Questionnaire. Results The sample had a mean age of 60•9 years, and the prevalence of metabolic syndrome was 43•3%. Postmenopausal women and women with low socioeconomic status (low-education background, without personal income and currently unemployed) had a significantly higher risk of developing metabolic syndrome. After adjusting for significant socio-demographic and lifestyle behaviour factors, the women with moderate or high physical activity levels had a significantly lower (OR = 0•10; OR = 0•11, p < 0•001) risk of metabolic syndrome and a lower risk for each specific component of metabolic syndrome, including elevated fasting plasma glucose (OR = 0•29; OR = 0•26, p = 0•009), elevated blood pressure (OR = 0•18; OR = 0•32, p = 0•029), elevated triglycerides (OR = 0•41; OR = 0•15, p = 0•001), reduced high-density lipoprotein (OR = 0•28; OR = 0•27, p = 0•004) and central obesity (OR = 0•31; OR = 0•22, p = 0•027). Conclusions After adjusting for socio-demographic and lifestyle behaviour factors, physical activity level was a significant protective factor against metabolic syndrome in middle-aged and older women. Higher physical activity levels (moderate or high physical activity level) reduced the risk of metabolic syndrome in middle-aged and older women. Relevance to clinical practice Appropriate strategies should be developed to encourage middle-aged and older women across different socio-demographic backgrounds to engage in moderate or high levels of physical activity to reduce the risk of metabolic syndrome.

Xanthine oxidoreductase in essential hypertension and metabolic syndrome : Experimental studies on rodent models

Hypertension, obesity, dyslipidemia and dysglycemia constitute metabolic syndrome, a major public health concern, which is associated with cardiovascular mortality. High dietary salt (NaCl) is the most important dietary risk factor for elevated blood pressure. The kidney has a major role in salt-sensitive hypertension and is vulnerable to harmful effects of increased blood pressure. Elevated serum urate is a common finding in these disorders. While dysregulation of urate excretion is associated with cardiovascular diseases, present studies aimed to clarify the role of xanthine oxidoreductase (XOR), i.e. xanthine dehydrogenase (XDH) and its post-translational isoform xanthine oxidase (XO), in cardiovascular diseases. XOR yields urate from hypoxanthine and xanthine. Low oxygen levels upregulate XOR in addition to other factors. In present studies higher renal XOR activity was found in hypertension-prone rats than in the controls. Furthermore, NaCl intake increased renal XOR dose-dependently. To clarify whether XOR has any causal role in hypertension, rats were kept on NaCl diets for different periods of time, with or without a XOR inhibitor, allopurinol. While allopurinol did not alleviate hypertension, it prevented left ventricular and renal hypertrophy. Nitric oxide synthases (NOS) produce nitric oxide (NO), which mediates vasodilatation. A paucity of NO, produced by NOS inhibition, aggravated hypertension and induced renal XOR, whereas NO generating drug, alleviated salt-induced hypertension without changes in renal XOR. Zucker fa/fa rat is an animal model of metabolic syndrome. These rats developed substantial obesity and modest hypertension and showed increased hepatic and renal XOR activities. XOR was modified by diet and antihypertensive treatment. Cyclosporine (CsA) is a fungal peptide and one of the first-line immunosuppressive drugs used in the management of organ transplantation. Nephrotoxicity ensue high doses resulting in hypertension and limit CsA use. CsA increased renal XO substantially in salt-sensitive rats on a high NaCl diet, indicating a possible role for this reactive oxygen species generating isoform in CsA nephrotoxicity. Renal hypoxia, common to these rodent models of hypertension and obesity, is one of the plausible XOR inducing factors. Although XOR inhibition did not prevent hypertension, present experimental data indicate that XOR plays a role in the pathology of salt-induced cardiac and renal hypertrophy.

Cyanidin 3-glucoside improves diet-induced metabolic syndrome in rats

Increased consumption of dark-coloured fruits and vegetables may mitigate metabolic syndrome. This study has determined the changes in metabolic parameters, and in cardiovascular and liver structure and function, following chronic administration of either cyanidin 3-glucoside (CG) or Queen Garnet plum juice (QG) containing cyanidin glycosides to rats fed either a corn starch (C) or a high-carbohydrate, high-fat (H) diet. Eight to nine-week-old male Wistar rats were randomly divided into six groups for 16-week feeding with C, C with CG or QG, H or H with CG or QG. C or H were supplemented with CG or QG at a dose of ∼8 mg/kg/day cyanidin glycosides from week 8 to 16. H rats developed signs of metabolic syndrome including visceral adiposity, impaired glucose tolerance, hypertension, cardiovascular remodelling, increased collagen depots in left ventricle, non-alcoholic fatty liver disease, increased plasma liver enzymes and increased inflammatory cell infiltration in the heart and liver. Both CG and QG reversed these cardiovascular, liver and metabolic signs. However, no intact anthocyanins or common methylated/conjugated metabolites could be detected in the plasma samples and plasma hippuric acid concentrations were unchanged. Our results suggest CG is the most likely mediator of the responses to QG but that further investigation of the pharmacokinetics of oral CG in rats is required.

Liver fat in the metabolic syndrome and type 2 diabetes

Introduction: The epidemic of obesity has been accompanied by an increase in the prevalence of the metabolic syndrome, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). However, not all obese subjects develop these metabolic abnormalities. Hepatic fat accumulation is related to hepatic insulin resistance, which in turn leads to hyperglycemia, hypertriglyceridemia, and a low HDL cholesterol con-centration. The present studies aimed to investigate 1) how intrahepatic as compared to intramyocellular fat is related to insulin resistance in these tissues and to the metabolic syndrome (Study I); 2) the amount of liver fat in subjects with and without the metabolic syndrome, and which clinically available markers best reflect liver fat content (Study II); 3) the effect of liver fat on insulin clearance (Study III); 4) whether type 2 diabetic patients have more liver fat than age-, gender-, and BMI-matched non-diabetic subjects (Study IV); 5) how type 2 diabetic patients using exceptionally high doses of insulin respond to addition of a PPARγ agonist (Study V). Subjects and methods: The study groups consisted of 45 (Study I), 271 (Study II), and 80 (Study III) non-diabetic subjects, and of 70 type 2 diabetic patients and 70 matched control subjects (Study IV). In Study V, a total of 14 poorly controlled type 2 diabetic patients treated with high doses of insulin were studied before and after rosiglitazone treatment (8 mg/day) for 8 months. In all studies, liver fat content was measured by proton magnetic resonance spectroscopy, and sub-cutaneous and intra-abdominal fat content by MRI. In addition, circulating markers of insulin resistance and serum liver enzyme concentrations were determined. Hepatic (i.v. insulin infusion rate 0.3 mU/kg∙min combined with [3-3H]glucose, Studies I, III, and V) and muscle (1.0 mU/kg min, Study I) insulin sensitivities were measured by the euglycemic hyperinsulinemic clamp technique. Results: Fat accumulation in the liver rather than in skeletal muscle was associated with features of insulin resistance, i.e. increased fasting serum (fS) triglycerides and decreased fS-HDL cholesterol, and with hyperinsulinemia and low adiponectin concentrations (Study I). Liver fat content was 4-fold higher in subjects with as compared to those without the metabolic syndrome, independent of age, gender, and BMI. FS-C-peptide was the best correlate of liver fat (Study II). Increased liver fat was associated with both impaired insulin clearance and hepatic insulin resistance independent of age, gender, and BMI (Study III). Type 2 diabetic patients had 80% more liver fat than age-, weight-, and gender-matched non-diabetic subjects. At any given liver fat content, S-ALT underestimated liver fat in the type 2 diabetic patients as compared to the non-diabetic subjects (Study IV). In Study V, hepatic insulin sensitivity increased and glycemic control improved significantly during rosiglitazone treatment. This was associated with lowering of liver fat (on the average by 46%) and insulin requirements (40%). Conclusions: Liver fat is increased both in the metabolic syndrome and type 2 diabetes independent of age, gender, and BMI. A fatty liver is associated with both hepatic insulin resistance and impaired insulin clearance. Rosi-glitazone may be particularly effective in type 2 diabetic patients who are poorly controlled despite using high insulin doses.

Clinical application of biomarkers in prostate cancer in men with metabolic syndrome project: Prostate Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) in diagnosing localised prostate cancer

Localised prostate cancer is a heterogenous disease and a multi-modal approach is required to accurately diagnose and stage the disease. Whilst the use of magnetic resonance imaging (MRI) has become more common, small volume and multi-focal disease are oft en diffi cult to characterise. Prostate specifi c membrane antigen is a cell surface protein, which is expressed in nearly all prostate cancer cells. Its expression is signifi cantly higher in high grade prostate cancer cells. In this study, we compare multi-parametric magnetic resonance imaging and 68-Gallinium-PSMA PET with whole-mount pathology of the prostate to evaluate the applicability of multiparameteric (MP) MRI and 68Ga-PSMA PET in detecting and locating tumour foci in patients with localised prostate cancer.

The impact of the metabolic syndrome and parental risk factors in patients with type 1 diabetes

Background: One-third of patients with type 1 diabetes develop diabetic complications, such as diabetic nephropathy. The diabetic complications are related to a high mortality from cardiovascular disease, impose a great burden on the health care system, and reduce the health-related quality of life of patients. Aims: This thesis assessed, whether parental risk factors identify subjects at a greater risk of developing diabetic complications. Another aim was to evaluate the impact of a parental history of type 2 diabetes on patients with type 1 diabetes. A third aim was to assess the role of the metabolic syndrome in patients with type 1 diabetes, both its presence and its predictive value with respect to complications. Subjects and methods: This study is part of the ongoing nationwide Finnish Diabetic Nephropathy (FinnDiane) Study. The study was initiated in 1997, and, thus far, 4,800 adult patients with type 1 diabetes have been recruited. Since 2004, follow-up data have also been collected in parallel to the recruitment of new patients. Studies I to III have a cross-sectional design, whereas Study IV has a prospective design. Information on parents was obtained from the patients with type 1 diabetes by a questionnaire. Results: Clustering of parental hypertension, cardiovascular disease, and diabetes (type 1 and type 2) was associated with diabetic nephropathy in patients with type 1 diabetes, as was paternal mortality. A parental history of type 2 diabetes was associated with a later onset of type 1 diabetes, a higher prevalence of the metabolic syndrome, and a metabolic profile related to insulin resistance, despite no difference in the distribution of human leukocyte antigen genotypes or the presence of diabetic complications. A maternal history of type 2 diabetes, seemed to contribute to a worse metabolic profile in the patients with type 1 diabetes than a paternal history. The metabolic syndrome was a frequent finding in patients with type 1 diabetes, observed in 38% of males and 40% of females. The prevalence increased with worsening of the glycemic control and more severe renal disease. The metabolic syndrome was associated with a 3.75-fold odds ratio for diabetic nephropathy, and all of the components of the syndrome were independently associated with diabetic nephropathy. The metabolic syndrome, independent of diabetic nephropathy, increased the risk of cardiovascular events and cardiovascular and diabetes-related mortality over a 5.5-year follow-up. With respect to progression of diabetic nephropathy, the role of the metabolic syndrome was less clear, playing a strong role only in the progression from macroalbuminuria to end-stage renal disease. Conclusions: Familial factors and the metabolic syndrome play an important role in patients with type 1 diabetes. Assessment of these factors is an easily applicable tool in clinical practice to identify patients at a greater risk of developing diabetic complications.

HDL subspecies : association with low HDL-C, obesity, and metabolic syndrome

AIMS An independent, powerful coronary heart disease (CHD) predictor is a low level of high-density lipoprotein cholesterol (HDL-C). Discoidal preβ-HDL particles and large HDL2 particles are the primary cholesterol acceptors in reverse cholesterol transport, a key anti-atherogenic HDL mechanism. The quality of HDL subspecies may provide better markers of HDL functionality than does HDL-C alone. We aimed I) to study whether alterations in the HDL subspecies profile exist in low-HDL-C subjects II) to explore the relationship of any changes in HDL subspecies profile in relation to atherosclerosis and metabolic syndrome; III) to elucidate the impact of genetics and acquired obesity on HDL subspecies distribution. SUBJECTS The study consisted of 3 cohorts: A) Finnish families with low HDL-C and premature CHD (Study I: 67 subjects with familial low HDL-C and 64 controls; Study II: 83 subjects with familial low HDL-C, 65 family members with normal HDL-C, and 133 controls); B) a cohort of 113 low- and 133 high-HDL-C subjects from the Health 2000 Health Examination Survey carried out in Finland (Study III); and C) a Finnish cohort of healthy young adult twins (52 monozygotic and 89 dizygotic pairs) (Study IV). RESULTS AND CONCLUSIONS The subjects with familial low HDL-C had a lower preβ-HDL concentration than did controls, and the low-HDL-C subjects displayed a dramatic reduction (50-70%) in the proportion of large HDL2b particles. The subjects with familial low HDL-C had increased carotid atherosclerosis measured as intima-media-thickness (IMT), and HDL2b particles correlated negatively with IMT. The reduction in both key cholesterol acceptors, preβ-HDL and HDL2 particles, supports the concept of impaired reverse cholesterol transport contributing to the higher CHD risk in low-HDL-C subjects. The family members with normal HDL-C and the young adult twins with acquired obesity showed a reduction in large HDL2 particles and an increase in small HDL3 particles, which may be the first changes leading to the lowering of HDL-C. The low-HDL-C subjects had a higher serum apolipoprotein E (apoE) concentration, which correlated positively with the metabolic syndrome components (waist circumference, TG, and glucose), highlighting the need for a better understanding of apoE metabolism in human atherosclerosis. In the twin study, the increase in small HDL3b particles was associated with obesity independent of genetic effects. The heritability estimate, of 73% for HDL-C and 46 to 63% for HDL subspecies, however, demonstrated a strong genetic influence. These results suggest that the relationship between obesity and lipoproteins depends on different elements in each subject. Finally, instead of merely elevating HDL-C, large HDL2 particles and discoidal preβ-HDL particles may provide beneficial targets for HDL-targeted therapy.

Early Growth and Later Health, Focus on Metabolic Syndrome, Obesity and Physical Activity

The Developmental Origins of Health and Disease Hypothesis proposes that adverse health outcomes in adult life are in part programmed during fetal life and infancy. This means that e.g. restricted nutrition during pregnancy programmes the offspring to store fat more effectively, to develop faster and to reach puberty earlier. These adaptations are beneficial in terms of short term survival. However, in developed countries these adaptations often lead to an increased risk of obesity and metabolic disturbances in later life, due to a mismatch between the prenatal and postnatal environment. This thesis aimed to study the role of early growth in people who are obese as adults, but metabolically healthy as well as in those who are normal in weight but metabolically obese. Other study aims were to assess whether physical activity and cardiorespiratory fitness are programmed early in life. The role of socioeconomic status in the development of obesity from a life course setting was also studied. These studies included 2003 men and women born in Helsinki between 1934 and 1944 with detailed information of their prenatal and childhood growth as well as living conditions. They participated in the detailed clinical examination during the years 2001-2004. A sub-group of the subjects participated in the UKK Institute 2-kilometre walk test. Metabolic syndrome was defined according to the 2005 criteria of the International Diabetes Federation. Among the obese men and women 20 % were metabolically healthy. Those with metabolic syndrome did not differ in birth size compared to the healthy ones, but by two years of age, they were lighter and thinner, and remained so up to 11 years. The period when changes in BMIs were predictive of the metabolic syndrome was from birth to 7 years. Of the normal weight individuals 17 % were metabolically obese. Again, there were no differences in birth size. However, by the age 7 years, those men who later developed metabolic syndrome were thinner. Gains in BMI during the first two years of life were protective of the syndrome. Children who were heavier, and especially taller, were more physically active, exercised with higher intensity and had higher cardiorespiratory fitness in their adult life than those who were shorter and thinner as children. Lower educational attainment and lower adult social class were associated with obesity in both men and women. Childhood social class was inversely associated with body mass index only in men while lower household income was associated with higher BMI in women. These results support the role of early life factors in the development of metabolic syndrome and adult life style. Early detection of risk factors predisposing to these conditions is highly relevant from a public health point of view.

Stability of the factorial structure of metabolic syndrome from childhood to adolescence : a 6-year follow-up study

Background: Metabolic syndrome (MS) is a clustering of cardiometabolic risk factors that is considered a predictor of cardiovascular disease, type 2 diabetes and mortality. There is no consistent evidence on whether the MS construct works in the same way in different populations and at different stages in life. Methods: We used confirmatory factor analysis to examine if a single-factor-model including waist circumference, triglycerides/HDL-c, insulin and mean arterial pressure underlies metabolic syndrome from the childhood to adolescence in a 6-years follow-up study in 174 Swedish and 460 Estonian children aged 9 years at baseline. Indeed, we analyze the tracking of a previously validated MS index over this 6-years period. Results: The estimates of goodness-of-fit for the single-factor-model underlying MS were acceptable both in children and adolescents. The construct stability of a new model including the differences from baseline to the end of the follow-up in the components of the proposed model displayed good fit indexes for the change, supporting the hypothesis of a single factor underlying MS component trends. Conclusions: A single-factor-model underlying MS is stable across the puberty in both Estonian and Swedish young people. The MS index tracks acceptably from childhood to adolescence.