Vitamin D3 mediated effects on postprandial leukocyte activation and arterial stiffness in men and women.

Postprandial inflammation is considered to be pro-atherogenic. Vitamin D can reduce inflammation and arterial stiffness. We hypothesized that vitamin D3 improves postprandial arterial elasticity by the modulation of leukocyte activation. Healthy volunteers underwent two oral fat-loading tests (OFLTs). The augmentation index (AIx) and flow cytometric quantification of leukocyte activation markers were measured. After the first OFLT, 100 000 IU of vitamin D3 was administered and a second OFLT was carried out 7 days later. Six men and six women were included. A favorable reduction in AIx was found after vitamin D3 supplementation (P=0.042) in both genders. After vitamin D3, exclusively in women a reduction in the area under the postprandial curve for monocytes CD11b and CD35 by 10.5% (P=0.016) and 12.5% (P=0.04) and neutrophil CD11b by 17.0% (P=0.014) was observed. In conclusion, vitamin D3 probably increased postprandial arterial elasticity in men and women, but reduced postprandial leukocyte activation exclusively in women.

Leukocyte cell population data (volume conductivity scatter) in postprandial leukocyte activation.

INTRODUCTION: Changes in leukocyte cell population data have been reported in various infectious diseases, but little is known in other inflammatory conditions such as the postprandial state. We investigated whether leukocyte cell population data change during postprandial leukocyte activation. METHODS: Healthy volunteers underwent a standardized oral fat loading test (OFLT). Flowcytometric quantitation of leukocyte activation markers CD11b, CD66b, CD35, and CD36, together with leukocyte cell population data from LH750 hematology analyzers were measured fasting and at 4 and 8 h postprandially. RESULTS: Twelve volunteers were included. Postprandial leukocyte activation was confirmed by increased expression of CD11b by monocytes (+11.7%) and neutrophils (+15.0%) and by increased expression of CD66b (+14.7%) and CD35 (+16.6%) by neutrophils at T = 4 h. The mean scatter from neutrophils, reflecting granularity, significantly decreased at T = 4 h (P < 0.05) and returned to baseline at T = 8 h (P-anova 0.048). The mean volume of monocytes increased significantly at T = 4 h (P < 0.001) and returned to baseline at T = 8 h (P-anova 0.0008). At T = 4 h, CD11b expression on neutrophils was associated with a reduction in mean scatter of neutrophils (Pearson's r: -0.677, P = 0.016). CONCLUSION: Postprandial leukocyte activation is accompanied by temporary changes in leukocyte cell population data, similar to changes observed during various infections, but to a lesser extent.

AT1 Receptor Gene Polymorphisms in relation to Postprandial Lipemia.

Background. Recent data suggest that the renin-angiotensin system may be involved in triglyceride (TG) metabolism. We explored the effect of the common A1166C and C573T polymorphisms of the angiotensin II type 1 receptor (AT1R) gene on postprandial lipemia. Methods. Eighty-two subjects measured daytime capillary TG, and postprandial lipemia was estimated as incremental area under the TG curve. The C573T and A1166C polymorphisms of the AT1R gene were determined. Results. Postprandial lipemia was significantly higher in homozygous carriers of the 1166-C allele (9.39 ± 8.36 mM*h/L) compared to homozygous carriers of the 1166-A allele (2.02 ± 6.20 mM*h/L) (P < 0.05). Postprandial lipemia was similar for the different C573T polymorphisms. Conclusion. The 1166-C allele of the AT1R gene seems to be associated with increased postprandial lipemia. These data confirm the earlier described relationships between the renin-angiotensin axis and triglyceride metabolism.

Cell-mediated lipoprotein transport: a novel anti-atherogenic concept.

Lipoprotein transport is thought to occur in the plasma compartment of the blood, where lipoproteins are modulated by various enzymatic reactions. Subsequently, lipoproteins can migrate through the endothelial barrier to the subendothelial space or are taken up by the liver. The interaction between pro-atherogenic (apoB-containing) lipoproteins and blood cells (especially monocytes and macrophages) in the subendothelial space is well known. This lipoprotein-inflammatory cell interplay is central in the development of the atherosclerotic plaque. In this review, a novel interaction is described between lipoproteins and both leukocytes and erythrocytes in the blood compartment. This lipoprotein-blood cell interaction may also be related to the process of atherosclerosis by inducing inflammatory changes in the case of leukocytes (pro-atherogenic) and as an anti-atherogenic transport-system by adherence to erythrocytes. Triglyceride rich lipoprotein (TRL)-mediated leukocyte activation can lead to an inflammatory situation with generation of oxidative stress and the production of cytokines, ultimately resulting in acute endothelial dysfunction. Binding of apoB containing lipoproteins to erythrocytes may be a potential anti-atherogenic mechanism protecting the vessel wall from the pro-inflammatory effects of these lipoproteins and also playing a role in the removal of these particles from the circulation. One of the proposed mechanisms of this interaction implies complement activation on the lipoprotein surface and binding to the Complement Receptor 1 (CR1) on erythrocytes and leukocytes, followed by clearance by the liver.

Four patients with hypothyroid Graves' disease.

In autoimmune hypothyroidism (Hashimoto's disease), TPO (thyroid peroxidase) antibodies may be detected, while in autoimmune hyperthyroidism (Graves' disease) thyroid-stimulating hormone (TSH ) receptor antibodies (TSH -R-AB s) are frequently present. Less well known is the fact that autoimmune hypothyroidism can present with TSH-R-ABs and ophthalmic Graves' disease (OGD). This condition is also known as hypothyroid Graves' disease. In this report we describe four patients with this uncommon phenomenon. These four cases demonstrate that differences between Hashimoto and Graves' disease are less clear than expected. Hypothetically the thyroid cell might be 'attacked' by blocking and stimulating antibodies. Dependent on the relative concentrations, hypothyroidism or hyperthyroidism may occur. So the differences between Hashimoto's disease and Graves' disease, at least in these cases, may be gradual and small.

Food-dependent Cushing's syndrome.

It has recently been proposed that other hormones than ACTH can control cortisol production in Cushing's syndrome with bilateral adrenal hyperplasia. We present a case of food-dependent Cushing's syndrome. After a positive response of cortisol production during mixed meals, several tests identified glucose-dependent insulinotropic polypeptide (GIP) as the driving hormone responsible for the cortisol overproduction. Identification of aberrant hormone receptor expression is of importance because it may create a possibility for pharmacological treatment.

Novel aspects of postprandial lipemia in relation to atherosclerosis.

Postprandial hyperlipidemia is considered to be a substantial risk factor for atherosclerosis. Interestingly, this concept has never been supported by randomized clinical trials. The difficulty lies in the fact that most interventions aimed to reduce postprandial lipemia, will also affect LDL-C levels. The atherogenic mechanisms of postprandial lipids and lipoproteins can be divided into direct lipoprotein-mediated and indirect effects; the latter, in part, by inducing an inflammatory state. Elevations in postprandial triglycerides (TG) have been related to the increased expression of postprandial leukocyte activation markers, up-regulation of pro-inflammatory genes in endothelial cells and involvement of the complement system. This set of events is part of the postprandial inflammatory response, which is one of the recently identified potential pro-atherogenic mechanisms of postprandial lipemia. Especially, complement component 3 levels show a close correlation with postprandial lipemia and are also important determinants of the metabolic syndrome. In clinical practice, fasting TG are frequently used as reflections of postprandial lipemia due to the close correlation between the two. The use of serial capillary measurements in an out-of-hospital situation is an alternative for oral fat loading tests. Daylong TG profiles reflect postprandial lipemia and are increased in conditions like the metabolic syndrome, type 2 diabetes and atherosclerosis. Studies are needed to elucidate the role of postprandial inflammation in atherogenesis and to find new methods in order to reduce selectively the postprandial inflammatory response. Future studies are needed to find new methods in order to reduce selectively the postprandial inflammatory response.

Proposal for a multidisciplinary approach to the patient with morbid obesity: the St. Franciscus Hospital morbid obesity program.

Morbid obesity is a serious disease as it is accompanied by substantial co-morbidity and mortality. The prevalence is increasing to an alarming extent, in Europe as well as in the United States. In the past few decades, bariatric surgery has developed and gained importance. It currently represents the only long-lasting therapy for this group of patients, resulting in an efficient reduction in body weight and obesity-related medical conditions, mostly cardiovascular in nature. The importance of a standardized protocol, the use of selection criteria, and a multidisciplinary approach have been stressed but not yet described in detail. Therefore, in this article, the multidisciplinary approach and the treatment protocol that have been applied in our hospital for more than 20 years are set out in a detailed manner. The application of a strict protocol may help to select and follow-up motivated patients and to organize multidisciplinary research activities.

A 'smart' type of Cushing's syndrome.

Cushing's syndrome results from lengthy and inappropriate exposure to excessive concentrations of either endogenous or exogenous glucocorticoids. This case report describes a patient with a novel type of Cushing's syndrome due to the use of party drugs. A 35-year-old woman had gained 8 kg body weight in 5 months and complained of anxiety. She showed a Cushing-like appearance and mild hypertension (blood pressure, BP 150/95 mmHg). She reported daily use of increasing doses of gamma-hydroxybutyric acid (GHB), a popular party drug. ACTH plasma levels were in the upper normal range (41 ng/l), with normal plasma cortisol (0.36 micromol/l). She showed an abnormal overnight 1 mg dexamethasone suppression test (cortisol 0.38 micromol/l). The urinary excretion of free cortisol in 24 h was also increased (0.47 micromol/24 h). CT scanning of the abdomen showed normal adrenals. After stopping GHB intake she lost 7 kg body weight and her BP normalized (BP 135/80 mmHg). GHB is a popular party drug in the Netherlands, but it is also used as a narcotic and for the treatment of narcolepsy. We hypothesize that GHB may bind to the pituitary gland gamma-aminobutyric acid-B receptors leading to ACTH overproduction.

Postprandial inflammation and endothelial dysfuction.

Postprandial hyperlipidaemia is a common metabolic disturbance in atherosclerosis. During the postprandial phase, chylomicrons and their remnants can penetrate the intact endothelium and cause foam cell formation. These particles are highly atherogenic after modification. People in the Western world are non-fasting for most of the day, which consequently leads to a continuous challenge of the endothelium by atherogenic lipoproteins and their remnants. Furthermore, atherosclerosis is considered a low-grade chronic inflammatory disease. Many studies have shown that the process of atherogenesis in part starts with the interaction between the activated leucocytes and activated endothelium. Postprandial lipoproteins can activate leucocytes in the blood and up-regulate the expression of leucocyte adhesion molecules on the endothelium, facilitating adhesion and migration of inflammatory cells into the subendothelial space. Another inflammatory process associated with postprandial lipaemia is the activation of the complement system. Its central component C3 has been associated with obesity, coronary sclerosis, the metabolic syndrome and fasting and postprandial TAGs (triacylglycerols). Moreover, chylomicrons are the strongest stimulators of adipocyte C3 production via activation of the alternative complement cascade. A postprandial C3 increment has been shown in healthy subjects and in patients with CAD (coronary artery disease) and with FCHL (familial combined hyperlipidaemia). Postprandial lipaemia has been related to TAG and free fatty acid metabolism. All of these mechanisms provide an alternative explanation for the atherogenicity of the postprandial period.

Thiazolidinediones for the treatment of type 2 diabetes.

Thiazolidinediones (TZD), or glitazones, represent a new generation of antidiabetic drugs that have recently been introduced in Europe. They improve insulin resistance, one of the key anomalies involved in the pathogenesis of type 2 diabetes mellitus, by activating the nuclear peroxoxisome proliferator activated receptor-gamma (PPAR-gamma), leading to crucial metabolic alterations in adipose tissue. Rosiglitazone and pioglitazone have been shown to be active as monotherapy, in combination therapy with metformin or sulfonylureas, and even in triple therapy. They are generally well tolerated but can induce fluid retention. Cardiac failure is a contraindication for the use of TZDs, as is the concomitant administration of insulin. Aside from their effect on glycemic control, TZDs act on several cardiovascular risk factors and may protect pancreatic beta cells from apoptosis. The cardiovascular protective effect of TZDs has recently been demonstrated with the results of the PROactive study, and long-term preservation of beta-cell function is currently under further investigation.

Insulin detemir used in basal-bolus therapy in people with type 1 diabetes is associated with a lower risk of nocturnal hypoglycaemia and less weight gain over 12 months in comparison to NPH insulin.

AIM: The aim of this study was to compare the long-term safety and efficacy of twice-daily insulin detemir or NPH insulin as the basal component of basal-bolus therapy in people with type 1 diabetes. METHODS: A multicentre, open-label, parallel-group study was conducted over 12 months and completed by 308 people (from an original randomized cohort of 428). Patients were randomized in a 2:1 ratio to receive insulin detemir or NPH insulin before breakfast and dinner, with insulin aspart at mealtimes. RESULTS: Glycaemic control improved in both groups with HbA(1c) decreasing by 0.64 and 0.56% point in the insulin detemir and NPH insulin groups, reaching baseline-adjusted final values of 7.53 +/- 0.10% and 7.59 +/- 0.13%, respectively. No significant difference was apparent between treatments in terms of HbA(1c), fasting plasma glucose or 9-point blood glucose profiles. Fewer hypoglycaemic events (major and minor) occurred in association with insulin detemir compared with NPH insulin, but the overall hypoglycaemic risk did not differ statistically significantly (RR for detemir, 0.78 [0.56-1.08]). However, the risk of nocturnal hypoglycaemia during the maintenance phase (month 2-12) was 32% lower in the detemir group (p = 0.02) and lower in every month. This risk reduction remained statistically significant after correction for HbA(1c). After 12 months, baseline-adjusted mean body weight was significantly lower in the insulin detemir group than in the NPH insulin group (p < 0.001). CONCLUSIONS: In long-term basal-bolus therapy, insulin detemir with insulin aspart as mealtime insulin is well tolerated and reduces the risks of nocturnal hypoglycaemia and weight gain compared to NPH insulin.

Autonomic nervous function, arterial stiffness and blood pressure in patients with Type I diabetes mellitus and normal urinary albumin excretion.

Type I diabetic patients (DM-1) with an elevated urinary albumin excretion (UAE>30 mg/24 h) have a high cardiovascular risk. However, DM-1 patients with normal UAE have incipient abnormalities of the cardiovascular and nervous systems, such as elevations of blood pressures, increases in arterial stiffness and deterioration of autonomic nervous function. We studied the interrelationships of these abnormalities in normoalbuminuric DM-1 patients. In 76 patients, we performed two cardiovascular reflex tests (deep in- and expiration test (IE test) and lying-to-standing test (LS test)), and determined aortic pulse wave velocity (PWV), local arterial compliances of the common carotid, femoral and brachial arteries, and 24-h blood pressures. The DeltaRRmax value of the LS test was associated with aortic PWV (negatively) and the compliance coefficients of the carotid, femoral and brachial arteries. Per 100-ms increase in DeltaRRmax, pulse wave velocity decreased by 0.39 m/s, compliance coefficients of the carotid, femoral and brachial arteries increased by 0.06, 0.08 and 0.05 mm2/kPa, respectively. These associations were independent of age, 24-h mean arterial pressure and 24-h heart rate. Increases in arterial stiffness were associated with increases in 24-h systolic and pulse pressure (per 1 m/s increase in PWV, systolic and pulse pressure increased by 2.1 and 1.7 mmHg, respectively). In normoalbuminuric DM-1 patients, deterioration of autonomic nervous function is associated with an increase in arterial stiffness, which, in turn, was associated with, and may cause, increased systolic and pulse pressure. These findings suggest that preventive strategies targeting autonomic dysfunction may reduce cardiovascular morbidity in diabetes.