HDL functionality in South Asians as compared to white Caucasians.

BACKGROUND AND AIMS: South Asians have an exceptionally high risk of developing cardiovascular disease compared to white Caucasians. A contributing factor might be dysfunction of high density lipoprotein (HDL). We aimed to compare HDL function in different age groups of both ethnicities. METHODS AND RESULTS: HDL functionality with respect to cholesterol efflux, anti-oxidation and anti-inflammation was determined using fasting, apoB-depleted, plasma samples from South Asian and white Caucasian neonates (n = 14 each), adolescent healthy men (n = 12 each, 18-25 y), and adult overweight men (n = 12 each, 40-50 y). Adolescents were subjected to a 5-day high fat high calorie diet (HCD) and adults to an 8-day very low calorie diet (LCD). Additionally, HDL composition was measured in adolescents and adults using (1)H-NMR spectroscopy. Anti-oxidative capacity was lower in South Asian adults before LCD (19.4 ± 2.1 vs. 25.8 ± 1.2%, p = 0.045, 95%-CI = [0.1; 12.7]) and after LCD (16.4 ± 2.4 vs. 27.6 ± 2.7%, p = 0.001, 95%-CI = [4.9; 17.5]). Anti-inflammatory capacity was reduced in South Asian neonates (23.8 ± 1.2 vs. 34.9 ± 1.3%, p = 0.000001, 95%-CI = [-14.6; -7.5]), and was negatively affected by an 8-day LCD only in South Asian adults (-12.2 ± 4.3%, p = 0.005, 95%-CI = [-5.9; -1.2]). Cholesterol efflux capacity was increased in response to HCD in adolescents (South Asians: +6.3 ± 2.9%, p = 0.073, 95%-CI = [-0.02; 0.46], Caucasians: +11.8 ± 3.4%, p = 0.002, 95%-CI = [0.17;0.65]) and decreased after LCD in adults (South Asians: -10.3 ± 2.4%, p < 0.001, 95%-CI = [-0.57; -0.20], Caucasians: -13.7 ± 1.9%, p < 0.00001, 95%-CI = [-0.67; -0.33]). Although subclass analyses of HDL showed no differences between ethnicities, cholesterol efflux correlated best with cholesterol and phospholipid within small HDL compared to other HDL subclasses and constituents. CONCLUSION: Impaired HDL functionality in South Asians may be a contributing factor to their high CVD risk. CLINICAL TRIAL REGISTRATION: NTR 2473 (URL: http://www.trialregister.nl/).

Cardiovascular flexibility in middle-aged overweight South Asians vs. white Caucasians: response to short-term caloric restriction.

BACKGROUND AND AIMS: South Asians have a higher risk of developing cardiovascular disease than white Caucasians. The underlying cause is unknown, but might be related to higher cardiac susceptibility to metabolic disorders. Short-term caloric restriction (CR) can be used as a metabolic stress test to study cardiac flexibility. We assessed whether metabolic and functional cardiovascular flexibility to CR differs between South Asians and white Caucasians. METHODS AND RESULTS: Cardiovascular function and myocardial triglycerides were assessed using a 1.5T-MRI/S-scanner in 12 middle-aged overweight male South Asians and 12 matched white Caucasians before and after an 8-day very low calorie diet (VLCD). At baseline South Asians were more insulin resistant than Caucasians. Cardiac dimensions were smaller, despite correction for body surface area, and pulse wave velocity (PWV) in the distal aorta was higher in South Asians. Systolic and diastolic function, myocardial triglycerides and pericardial fat did not differ significantly between groups. After the VLCD body weight reduced on average by 4.0 ± 0.2 kg. Myocardial triglycerides increased in both ethnicities by 69 ± 18%, and diastolic function decreased although this was not significant in South Asians. However, pericardial fat and PWV in the proximal and total aorta were reduced in Caucasians only. CONCLUSION: Myocardial triglyceride stores in middle-aged overweight and insulin resistant South Asians are as flexible and amenable to therapeutic intervention by CR as age-, sex- and BMI-matched but less insulin resistant white Caucasians. However, paracardial fat volume and PWV showed a differential effect in response to an 8-day VLCD in favor of Caucasians. CLINICAL TRIAL REGISTRATION: NTR 2473 (URL: http://www.trialregister.nl/trialreg/admin/rctsearch.asp?Term=2473).

Ectopic fat and insulin resistance: pathophysiology and effect of diet and lifestyle interventions.

The storage of triglyceride (TG) droplets in nonadipose tissues is called ectopic fat storage. Ectopic fat is associated with insulin resistance and type 2 diabetes mellitus (T2DM). Not the triglycerides per se but the accumulation of intermediates of lipid metabolism in organs, such as the liver, skeletal muscle, and heart seem to disrupt metabolic processes and impair organ function. We describe the mechanisms of ectopic fat depositions in the liver, skeletal muscle, and in and around the heart and the consequences for each organs function. In addition, we systematically reviewed the literature for the effects of diet-induced weight loss and exercise on ectopic fat depositions.

Immediate and long-term effects of addition of exercise to a 16-week very low calorie diet on low-grade inflammation in obese, insulin-dependent type 2 diabetic patients.

OBJECTIVE: To assess the short- and long-term effects of addition of exercise to a very low calorie diet (VLCD) on low-grade inflammation in obese patients with type 2 diabetes mellitus (T2DM). METHODS: Twenty seven obese, insulin-dependent T2DM patients followed a 4-month VLCD with (n=13) or without (n=14) exercise and were followed up to 18 months. Anthropometric measurements, metabolic and inflammatory parameters were assessed before, directly after the intervention and at 6 and 18 months follow-up. The same measurements were performed only once in 56 healthy lean and 56 healthy obese controls. RESULTS: At baseline hsCRP, IL10 and IL8 were significantly elevated in obese T2DM compared to lean healthy controls. After 4 months, despite substantial weight loss (-25.4 ± 1.3 kg), neither the VLCD nor VLCD+exercise had an effect on plasma cytokines. At 6 months, in the weight-stabilizing period, measures of low-grade inflammation had decreased substantially and equally in both intervention groups. Despite subsequent weight regain, beneficial effect was sustained up to 18 months in both groups, except for IL1 and hsCRP which had returned to baseline in the VLCD-only group. CONCLUSION: Our findings suggest that severe caloric restriction increases cytokine production by adipose tissue macrophages and that the beneficial effects of weight loss become apparent only in the eucaloric state.

Physiologic hyperleptinemia in obesity does not affect vasopressin secretion in acute hypo- or hyperosmolality.

PURPOSE: Abnormal water excretion after ingestion of a water load has been described in obesity. We hypothesized that AVP secretion is abnormal in obese subjects in acute hypo- and hyperosmolality and that the hormone leptin is partly responsible for this. METHODS: We studied the relation between leptin, AVP and serum osmolality in two separate tests: (1) after ingestion of a water load (20 ml/kg lean body mass plus 5 ml /kg of adipose tissue) and (2) after iv hypertonic saline (5% NaCl) at a rate of 0.1 ml/kg lean body mass/minute for 120 min in ten subjects of normal weight (BMI > 20 and < 25 kg/m2; controls) and ten obese females (BMI > 30 kg/m2). Obese subjects were tested before (98.6 +/- 9.3 kg) and after weight loss (90.2 +/- 8.5 kg). RESULTS: In the water load experiment, obese subjects excreted a smaller percentage of the water load than controls. Weight loss restored the ability to excrete the water load in the obese. In the water load and hypertonic saline infusion experiment, plasma AVP concentrations and the area under the curve (AUC) for AVP concentration were not different in obese from normal weight women. Baseline leptin concentration was not correlated with baseline AVP or the change in AVP during the experiment in any of the groups. Weight loss did not change AVP responses in obese subjects. CONCLUSION: AVP secretion in response to acute hypo- and hyperosmolality is not different in normal weight and obese subjects. There is no correlation between leptin and AVP in normal weight or obese subjects.

[Walking in the International Four Days Marches Nijmegen: an estimation of the risks]. / Het lopen van de Nijmeegse Vierdaagse: schatting van de risico's.

In 2006, the annual Four Days Marches in Nijmegen, the Netherlands, were cancelled after the first day because two participants had died, and many had become unwell while walking in unusually high ambient temperatures. During the 2007 edition, an observational study of the physiological impact and health risks for walkers was carried out. This time, the ambient conditions were mild. Most participants (90.7%) finished the march without serious complaints or clinical complications, despite significant disturbances in fluid balance and electrolytes. The training level of the participants varied considerably. If we compare the results of this physiological study with studies during marathons, similarities in physiological adaptions are found, most probably due to the same biological mechanisms. However, the participants of the Four Days Marches are incomparable with long-distance runners. There is as yet no well-founded advice concerning the fluid intake of Four Days Marches participants. Increase or decrease in body weight may be an interesting diagnostic tool to measure the risk of dehydration or overhydration.

[Measures to prevent or delay type 2 diabetes mellitus]. / Maatregelen voor preventie of uitstel van diabetes mellitus type 2.

--The incidence of type 2 diabetes mellitus is increasing, as is the rate of related long-term complications. --Increased body weight and lack of exercise are the major non-genetic factors that are responsible for the increased incidence of type 2 diabetes mellitus. --People predisposed to developing type 2 diabetes mellitus can be identified easily by taking a patient history (e.g. genetic predisposition, gestational diabetes, medication), performing a physical examination (e.g. body-mass index, fat distribution) and laboratory tests (e.g. impaired fasting and post-load blood glucose levels). --Intensive lifestyle modifications reduce the risk of type 2 diabetes mellitus by 42-58%. --Drug therapy is less effective than lifestyle modifications in the prevention of type 2 diabetes mellitus. Moreover, the disease course after treatment is discontinued is unknown. --Successful intervention resulting in a sustained effect is expected to have a preventive effect on the long-term complications of type 2 diabetes mellitus.

Loss of 50% of excess weight using a very low energy diet improves insulin-stimulated glucose disposal and skeletal muscle insulin signalling in obese insulin-treated type 2 diabetic patients.

AIMS/HYPOTHESIS: Both energy restriction (ER) per se and weight loss improve glucose metabolism in obese insulin-treated type 2 diabetic patients. Short-term ER decreases basal endogenous glucose production (EGP) but not glucose disposal. In contrast the blood glucose-lowering mechanism of long-term ER with substantial weight loss has not been fully elucidated. The aim of this study was to investigate the effect of loss of 50% of excess weight [50% excess weight reduction (EWR)] on EGP, whole-body insulin sensitivity and the disturbed myocellular insulin-signalling pathway in ten obese insulin-treated type 2 diabetic patients. METHODS: A euglycaemic-hyperinsulinaemic clamp with stable isotopes ([6,6-(2)H2]glucose and [2H5]glycerol) combined with skeletal muscle biopsies was performed during a very low energy diet (VLED; 1,883 kJ/day) on day 2 and again after 50% EWR. Oral blood glucose-lowering agents and insulin were discontinued 3 weeks prior to the VLED and at the start of the VLED, respectively. RESULTS: Loss of 50% EWR (20.3+/-2.2 kg from day 2 to day of 50% EWR) normalised basal EGP and improved insulin sensitivity, especially insulin-stimulated glucose disposal (18.8+/-2.0 to 39.1+/-2.8 micromol kg fat-free mass(-1) min(-1), p=0.001). The latter was accompanied by improved insulin signalling at the level of the recently discovered protein kinase B/Akt substrates AS160 and PRAS40 along with a decrease in intramyocellular lipid (IMCL) content. CONCLUSIONS/INTERPRETATION: Considerable weight loss in obese, insulin-treated type 2 diabetic patients normalises basal EGP and improves insulin sensitivity resulting from an improvement in insulin signal transduction in skeletal muscle. The decrease in IMCL might contribute to this effect.

[Hyponatraenmia during a long-distance run: due to excessive fluid intake]. / Hyponatriëmie tijdens een duurloop: door overmatige vochtinname.

Hyponatraemia during a long-distance run, such as a marathon, is usually mild and asymptomatic. However, in runners who present with symptoms at a healthcare station, the diagnosis of hyponatraemia can have significant consequences. The complaints are usually aspecific, but in more severe hyponatraemia, signs of cerebral dysfunction due to incipient to severe cerebral oedema predominate. The most important aetiological factor is an excessive electrolyte-free fluid intake. The most important risk factors for the development of hyponatraemia are: a long duration of the run, female gender, recent use of NSAIDs, lower body weight and environmental factors like high temperature and high humidity. In the presence of symptoms, rapid correction must be started by administration ofhypertonic saline, sometimes in combination with a loop diuretic in cases of eu- and hypervolaemia. Isotonic saline must be added in case of dehydration. Prevention consists primarily of advice to moderate the fluid intake.

Plasma arginine vasopressin and atrial natriuretic peptide concentration in patients with hyponatremia at diagnosis and following treatment.

BACKGROUND: Much evidence for arginine vasopressin (AVP) and atrial natriuretic peptide (ANP) in the pathogenesis of hyponatremia in humans is based on single measurements. To study the roles of AVP and ANP in the pathogenesis and recovery of hyponatremia, sequential measurements of ANP and AVP were taken during treatment in a group of hyponatremic patients with different etiologies. METHODS: Consecutive adult patients with hyponatremia (serum Na <130 mmol/l) and healthy controls were studied. Volume status was determined by clinical and laboratory criteria. Plasma AVP and ANP, fractional sodium excretion, and urine osmolality were determined daily until serum Na was above 135 mmol/l or for at most 7 days. RESULTS: A total of 16 controls and 40 hyponatremic patients (12 normovolemic, 9 hypervolemic, and 19 hypovolemic) were studied. Patients' plasma AVP on the first day [1.0 (0.3-2.3) ng/l] and on the last day [1.1 (0.3-2.5) ng/l] of the study did not differ from that of controls [0.7 (0.5-1.0) ng/l]. Serum sodium concentration increased significantly in patients between the first and the last day. Patients had significantly lower ANP concentrations, both on the first day [25 (15-46) ng/l] and on the last day [29 (17-46) ng/l], than controls [41 (28-51) ng/l]. Plasma AVP was elevated relative to serum osmolality on the first day and to a lesser extent on the last day of the study. CONCLUSIONS: AVP is inappropriately high in a majority of hyponatremic patients. Plasma AVP and ANP concentrations do not change during treatment in hyponatremic patients despite a significant increase in serum osmolality. A low ANP concentration in clinically normovolemic and hypovolemic patients indicates volume depletion, which may lead to baroreceptor-stimulated AVP secretion.

Cardiovascular risk factors after bariatric surgery: Do patients gain more than expected from their substantial weight loss?

BACKGROUND: While it has been established that even limited weight loss (5-10%) improves obesity-associated cardiovascular risk factors, it is not known if considerable weight loss following laparoscopic adjustable silicone gastric banding (LASGB) results in a cardiovascular risk profile that is comparable, worse, or even better than that of matched control subjects. METHODS: Cardiovascular risk factors were compared in three groups of 24 women each: an index group that had lost considerable weight following LASGB for morbid obesity (BMI>40 kg/m(2)), a control group with the same BMI that the index group achieved after weight loss, and a pre-weight loss group of women with a BMI above 40 kg/m(2). Anthropometric measures, fasting serum glucose, insulin, lipids, C-reactive protein, and homocysteine levels were determined and insulin sensitivity was estimated using a homeostasis model assessment index (HOMA-IR). RESULTS: After bariatric surgery, the index group had a BMI of 32.0+/-0.8 kg/m(2). This resulted in a significantly better cardiovascular risk profile than that of the pre-weight loss group (BMI 42.8+/-0.6 kg/m(2)). Unexpectedly, after weight loss, the index group had significantly lower systolic blood pressure, fasting serum insulin, and HOMA-IR than the BMI-matched (32.8+/-0.9 kg/m(2)) control group. Although not significant, diastolic blood pressure, LDL-cholesterol, and CRP levels were also lower. CONCLUSION: Considerable weight loss following bariatric surgery leads to a greater improvement in cardiovascular risk factors than might be expected from the weight loss.

[Thyroid function, activities of daily living and survival in extreme old age: the 'Leiden 85-plus Study']. / Schildklierfunctie, dagelijks functioneren en overleving van de oudste ouderen; de 'Leiden 85-plus Studie'.

OBJECTIVE: To determine the relationship between differences in thyroid function, changes in the activities of daily living and survival in the extremely-old segment of the general population in order to see whether screening for and treatment of subclinical thyroid-function disorders in the elderly will have a positive effect. DESIGN: Prospective observational population study among 85-year-olds. METHOD: As part of the 'Leiden 85-plus Study', all persons were followed who had their 85th birthday during the period from 1 September 1997 to 31 August 1999 (average length of time followed: 3.7 years; SD: 1.4). There were 558 participants. The thyroid function of these subjects was determined and the limitations in the activities of daily living, depressive symptoms, cognitive function and mortality were recorded annually. RESULTS: At the age of 85, there was no relation between the serum levels of thyroid-stimulating hormone (TSH) or free thyroxine (FT4) and limitations in the activities of daily living, the occurrence of depressive symptoms and cognitive deterioration. Neither was any relationship found during the period of follow-up. A higher TSH-level was associated with a lower mortality, even after correction for the differences in performance and health during the base measurement (mortality risk: 0.77 per SD-increase in TSH; 95% CI: 0.63-0.94). The mortality risk per SD-increase in FT4 was 1.16 (95% CI: 1.04-1.30). CONCLUSION: From the age of 85, there was no relationship between thyroid function and limitations in the activities of daily living, the occurrence of depressive symptoms or a deterioration in cognitive functions. Moreover, elderly persons with a less active thyroid gland lived longer. This raises the question whether the screening for and treatment of subclinical thyroid-function disorders in persons of extreme old age, as recommended, will have any positive effects.

The metabolic syndrome: a vascular perspective.

The metabolic syndrome (MS) is a clustering of cardiovascular risk factors. Current definitions of MS use hypertension, waist circumference, fasting glucose, triglyceride and HDL-cholesterol levels as defining variables. The prevalence of MS is increasing in our society due to lifestyle changes that result in decreased physical activity and increased body weight. Patients with MS have a three times greater risk of coronary heart disease and stroke, and a two to four times greater risk of dying from atherosclerotic coronary heart disease than those without MS. Imaging studies have shown an increased burden and progression of atherosclerosis. Also, MS patients seem to be more vulnerable to events at comparable levels of atherosclerosis. First-line treatment for MS is therapeutic lifestyle intervention, including exercise and weight reduction. Medical intervention strategies using blood pressure-lowering medication, statins, fibrates and metformin seem the most appropriate to date. The effects of thiazolidinediones on cardiovascular endpoints have not been studied to a large extent in the setting of MS. Evidence regarding risk assessment and optimal medical strategies will be an important aspect of vascular research in the coming years.

A nasal squamous cell carcinoma complicated by a paraneoplastic syndrome consisting of a myositis and anti-Jo-1 autoantibodies.

We report a female patient with the clinical features of a Jo-1-syndrome as a paraneoplastic phenomenon secondary to a nasal squamous cell carcinoma.

Vasopressin: physiology and clinical use in patients with vasodilatory shock: a review.

Vasopressin is a nonapeptide synthesised in the hypothalamus and released upon stimulations such as hyperosmolality, hypotension and hypovolaemia. In acute shock states serum vasopressin levels increase rapidly and decrease in prolonged septic shock. The administration of vasopressin in healthy subjects has little effect, whereas in vasodilatory shock it increases the mean arterial pressure through V1 receptors and decreases the cardiac output. Vasopressin stimulates the V2 receptors in the kidney leading to reabsorption of water through aquaporin 2. However, in vasodilatory shock the antidiuretic effects are overcome by the effect vasopressin has on the kidneys: improvement of renal blood flow leading to water excretion. Twenty-four studies on the use of vasopressin in patients with vasodilatory shock are reviewed. They show that vasopressin potentiates norepinephrine effects, increases blood pressure significantly in patients with vasodilatory shock and may improve renal function. Side effects ranging from ischaemic skin lesions to possible intestinal ischaemia should not be underestimated. Above a dose of 0.04 U/min it may lead to cardiac arrest. Effects on mortality cannot be interpreted from these studies. Broad clinical use should await controlled trials to clarify its effects on clinical outcomes such as organ failure and mortality.

Factors predicting the blood glucose lowering effect of a 30-day very low calorie diet in obese Type 2 diabetic patients.

OBJECTIVE: To identify factors which predict the blood glucose lowering effect of monotherapy with a 30-day very low calorie diet (VLCD) in obese Type 2 diabetic patients. A responder was a priori defined as a patient with a fasting plasma glucose (FPG) level < 10 mmol/l on day 30. RESEARCH DESIGN AND METHODS: In 17 obese patients (BMI 37.6 +/- 5.6 (mean +/- SD) kg/m(2)) with Type 2 diabetes, all blood glucose lowering medication (including insulin) was discontinued on day -1 followed by a 30-day VLCD. On day 2 and 30 of the VLCD an intravenous glucose tolerance test (IVGTT) was performed. RESULTS: Of the 14 patients who completed the 30-day VLCD, eight qualified as responder. Responders and non-responders could be distinguished by day 2. Responders had a shorter duration of Type 2 diabetes and higher fasting serum insulin, C-peptide and HOMA-beta-values. In addition, responders displayed a more prominent second-phase insulin response following i.v. glucose loading and higher k-values. In a stepwise discriminant analysis, the change in FPG from day 0 to day 2 (responders +0.64 +/- 2.3, non-responders +4.15 +/- 3.3 mmol/l, P = 0.035) in combination with the area under the curve of insulin (AUC) above baseline during an IVGTT on day 2 (responders 571 +/- 236, non-responders 88 +/- 65 mU*50 min, P < 0.001), distinguished responders completely from non-responders. CONCLUSION: Preservation of the capacity of beta-cells to secrete insulin predicts a favourable metabolic response to a VLCD in obese Type 2 diabetic patients.

[The value and limitations of the body mass index (BMI) in the assessment of the health risks of overweight and obesity]. / De waarde en de beperkingen van de 'body mass index' (BMI) voor het bepalen van het gezondheidsrisico van overgewicht en obesitas.

--The Body Mass Index (BMI) is used as a measure of overweight and obesity. In epidemiological studies age, sex and ethnic background all have to be taken into consideration, particularly when determining the health risk caused by the amount of body fat. --Caution should be observed when using the BMI as a measure for interpreting overweight and obesity as body composition can be highly variable yet have the same BMI. Therefore, BMI is not a reliable measurement of body composition in individuals particularly in older and younger people. --Excess body fat in the visceral depot poses a separate health risk. The BMI does not give any insight into regional body fat distribution. Waist circumference is a valid index of visceral fat accumulation and can therefore be used as an indicator of health risks associated with visceral obesity.