Accumulation of advanced glycation end products is associated with macrovascular events and glycaemic control with microvascular complications in Type 2 diabetes mellitus.

AIM: The United Kingdom Prospective Diabetes Study (UKPDS) study showed that glycaemic control (HbA1c ) can predict vascular complications in Type 2 diabetes mellitus. The Diabetes Control and Complications Trial (DCCT) study showed that accumulation of advanced glycation end products (AGEs) from skin biopsies predicts vascular complications in Type 1 diabetes. Previously, we showed that tissue AGEs can be measured non-invasively using skin autofluorescence (SAF). The aim of this study was to compare the predictive value of HbA1c and SAF for new macrovascular events and microvascular complications in people with Type 2 diabetes. METHODS: A prospective cohort study of 563 participants, median age 64 years [interquartile range (IQR) 57-72], diabetes duration of 13 years, from five Dutch hospitals was performed. RESULTS: After a median follow-up of 5.1 (IQR 4.3-5.9) years, 79 (15%) participants had died and 49 (9%) were lost to follow-up. Some 133 (26%) developed a microvascular complication and 189 (37%) a macrovascular event. Tertiles of HbA1c were significantly associated with development of microvascular complications (log rank P = 0.022), but not with macrovascular events. Tertiles of SAF were significantly associated with macrovascular events (log rank P = 0.003). Cox regression analysis showed SAF was associated with macrovascular events: crude hazard ratio (HR) 1.53 (P < 0.001) per unit increase, HR 1.28 (P = 0.03) after correction for UKPDS score. HbA1c was predictive for microvascular complications: crude HR 1.20 (P = 0.004), HR 1.20 (P = 0.004) after correction for UKPDS score. CONCLUSION: This study shows that tissue accumulation of AGEs, assessed by SAF, is associated with development of macrovascular events in people with Type 2 diabetes, whereas HbA1c is associated with the development of microvascular complications.

Association of complement receptor 1 gene polymorphisms with cognitive function.

Previous evidence suggest involvement of the complement receptor 1 (CR1) in development of Alzheimer's disease. We investigated the association of CR1 gene polymorphisms with cognitive function in older subjects. Single nucleotide polymorphisms (SNPs) within the CR1 region on chromosome 1 ( n = 73) were assessed in 5,244 participants in the PROspective Study of Pravastatin in the Elderly at Risk (51.9% female, mean age 75.3 yr). Linear regression, adjusted for age, sex, country, and use of pravastatin, was used to assess the association between the SNPs and cognitive function. All 73 SNPs within the genomic region of the CR1 gene on chromosome 1 were extracted. Eighteen were independent, according to a relatively stringent R2 threshold of >0.8 with LDlink. Twelve of the 18 investigated CR1 SNPs were significantly associated with a decline in cognitive function (all P < 0.05). These data indicate that genetic variation within the CR1 gene is associated not only with Alzheimer's disease, but also with general cognitive function during late life.

Perinatal outcomes in gestational diabetes in relation to ethnicity in the Netherlands.

BACKGROUND: The influence of ethnicity in women with gestational diabetes in relation to maternal, pregnancy and neonatal outcome is not well defined. AIM: To compare the perinatal outcome in women with gestational diabetes between different ethnic groups reflecting the multi-ethnic population in the Netherlands. METHODS: Patients with gestational diabetes (n = 388) who visited the multidisciplinary outpatient clinic for Diabetes Care and Obstetrics of the Sint Franciscus Gasthuis in Rotterdam between 2010 and 2013 were included. Ethnicity was distinguished into six groups: Moroccan (n = 100); Turkish (n = 43); Caucasian (n = 146); Suriname-Creole (n = 23); Suriname-Hindu (n = 32); and Miscellaneous (n = 44). RESULTS: Caucasians were the largest group with gestational diabetes (37.7%), followed by Moroccans (25.8%). Body mass index before pregnancy was highest in Surinamese-Creole women, followed by Turks and Moroccans (p < 0.001). Gravidity and parity were highest in Moroccans. Gravidity was lowest in Surinamese-Hindus and parity was lowest in Caucasians (p < 0.001). There was also a remarkable, significant difference in the mode of delivery between the ethnicities with the lowest number of normal deliveries in Caucasians and the highest in Moroccans (p = 0.03). Assisted delivery occurred most frequently in Caucasian women, although there was no difference in the frequency of caesarean sections. Birth weight was the only neonatal parameter showing significant differences between the ethnicities, with the highest birth weight for Moroccan children and the lowest for Surinamese children (3542 g vs. 3200; p = 0.001). CONCLUSION: This study did not show major differences in maternal or neonatal complications, however there are significant disparities in (percentile) birth weight and mode of delivery across the different ethnic groups.

Adherence to cardiovascular prevention strategies in patients with rheumatoid arthritis.

OBJECTIVES: Patients with rheumatoid arthritis (RA) have a high risk of cardiovascular disease (CVD). Recent national and international guidelines suggest strict treatment of CVD risk factors in RA. The aim of this study was to evaluate the self-reported adherence to CV prevention strategies in patients with RA. METHOD: RA patients visiting an outpatient clinic for strict CVD risk management received a validated questionnaire to evaluate adherence to CV prevention strategies. Strict treatment targets were defined and lifestyle recommendations were given following a prespecified protocol. CVD risk was assessed using the SCORE algorithm. RESULTS: In total, 111 questionnaires were returned (response rate of 82%). A high 10-year CVD risk (≥ 20%) was present in 53%, but only 3% thought they had an increased CVD risk. A total of 53% of patients reported that they 'follow the doctors' suggestions exactly' and 75% reported finding it 'easy to follow the suggestions'. Of the 69% of patients who were prescribed lipid- and/or blood pressure-lowering drugs, 90% reported taking all prescribed tablets. The advice to follow a diet was given to 42%, of whom 68% said they followed the advised diet. Physical exercise was advised to 67%, of whom 62% said they performed specific physical exercise on at least 3 days a week. The adherence to lifestyle recommendations was not significantly different across the CVD risk groups. CONCLUSIONS: RA patients tend to underestimate their CVD risk. The self-reported adherence of RA patients to CVD risk management was high concerning pharmaceutical interventions and moderate in the case of lifestyle interventions.

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.

Cardiovascular risk in rheumatoid arthritis: how to lower the risk?

Patients with rheumatoid arthritis (RA) carry an excess risk for cardiovascular disease, which is comparable to the risk in patients with type 2 diabetes mellitus. The mechanisms involved are partly related to traditional cardiovascular risk factors, disease-associated inflammation and undertreatment of traditional cardiovascular disease (CVD) risk factors. Since atherosclerosis is an inflammatory disease, the auto-immune mediated inflammation observed in RA patients contributes to increased endothelial dysfunction, oxidative stress and activation and vascular migration of leukocytes. This concept is underscored by the CVD risk reduction that is seen by anti-inflammatory disease modifying anti-rheumatic drugs such as methotrexate and TNFα inhibitors. The evidence for underdiagnosis and undertreatment of traditional CVD risk factors in RA strengthens the potential benefit of structured CVD risk management in these patients. Current cardiovascular guidelines recommend screening and treatment of CVD risk factors in RA patients, without well defined treatment targets. At present, there is a lack of scientific evidence to establish treatment targets for CVD risk factors in RA. Therefore, expanding research regarding screening and treatment of traditional CVD risk factors in RA patients is needed.

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.

Decreased excitability of the distal motor nerve of young patients with type 1 diabetes mellitus.

OBJECTIVE: The compound muscle action potential (CMAP) scan is a novel neurophysiological technique that appears more sensitive in detecting peripheral motor neuropathy than conventional methods. This study explores the value of the CMAP scan for the detection of subclinical diabetic peripheral motor neuropathy. METHODS: In this cross-sectional pilot study, CMAP scanning of the peroneal nerve was performed in (i) 13 well-controlled patients (8-25 yr old) with type 1 diabetes mellitus (T1DM) duration between 2.5 and 5 yr; (ii) 17 patients (10-25 yr old) with a duration of T1DM of at least 10 yr, poorly controlled and/or with microvascular complications and (iii) 13 adults with T1DM and established clinical diabetic peripheral neuropathy (DPN). Various CMAP scan variables, including measures of axonal excitability and axonal loss and reinnervation, were compared between patients and healthy controls. RESULTS: Axonal excitability was significantly decreased in the young patient groups as compared to their controls. The CMAP scan measures of axonal loss and reinnervation differed only between patients with clinical DPN and their controls. CONCLUSIONS: Motor nerve axonal excitability seems to be reduced early in T1DM, even in well-controlled young patients, and probably before (irreversible) axonal damage occurs. These changes can be measured by the CMAP scan, which makes this a promising tool for detecting nerve dysfunction in T1DM.

Skin autofluorescence and risk of micro- and macrovascular complications in patients with Type 2 diabetes mellitus-a multi-centre study.

AIMS: Skin autofluorescence is a non-invasive marker of advanced glycation end product accumulation. In a previous study, skin autofluorescence correlated with and predicted micro- and macrovascular complications in Type 2 diabetes in a primary care setting. The present cross-sectional study aims to confirm the association between skin autofluorescence and diabetic complications in patients with Type 2 diabetes in a multi-centre secondary care setting. METHODS: We analysed 563 subjects with Type 2 diabetes mellitus from five Dutch hospitals. RESULTS: Median age was 64 years, median duration of diabetes 13 years and median HbA(1c) 58 mmol/mol (7.5%). Sixty-one per cent of patients had microvascular complications (38% nephropathy, 36% retinopathy, 35% neuropathy) and 42% had macrovascular complications. Median UK Prospective Diabetes Study 10-year risk for coronary events was 19%. Median skin autofluorescence was elevated compared with age-matched healthy control subjects: 2.77 (interquartile range 2.39-3.28) vs. 2.46 (2.08-2.84) arbitrary units. Skin autofluorescence was particularly increased in patients with complications: no complications, median 2.56 (2.26-2.90); microvascular complications, 2.79 (2.38-3.29); macrovascular complications, 2.85 (2.41-3.41); both micro- and macrovascular complications, 2.96 (2.56-3.60) arbitrary units, P < 0.001. Logistic regression analysis showed that age, duration of diabetes, renal function, gender, atrial fibrillation and skin autofluorescence were independently associated with macrovascular complications. Multiple regression analysis identified age, smoking, renal function, macrovascular complications and the number of microvascular complications as the determinants of skin autofluorescence. CONCLUSIONS: This study confirms that skin autofluorescence is increased in patients with Type 2 diabetes in a secondary care setting. Skin autofluorescence was associated with macrovascular complications in patients with diabetes and this association was independent of classical risk factors.

A physician's guide for the management of hypertriglyceridemia: the etiology of hypertriglyceridemia determines treatment strategy.

Hypertriglyceridemia is a common lipid disorder associated to different, highly prevalent metabolic derangements like diabetes mellitus, the metabolic syndrome and obesity. The choice of treatment depends on the underlying pathogenesis and the consequences for atherosclerosis or pancreatitis. A family history, physical examination and analysis of the lipid profile including measurement of apolipoprotein B or non-HDL-C are necessary to establish the underlying primary or secondary cause. Due to physiological diurnal variations of triglycerides (TG), the time of measurement (fasting or postprandial) should be taken into account when evaluating TG values. Increased awareness arises concerning the impact of postprandial hypertriglyceridemia on the development of atherosclerosis. Hypertriglyceridemia is strongly associated to postprandial hyperlipidemia, remnant accumulation, increased small dense LDL concentrations, low HDL-C, increased oxidative stress, endothelial dysfunction, leukocyte activation and insulin resistance. All these factors are strongly linked to the development of atherosclerosis. Treatment should be aimed at reducing the secretion of triglyceride-rich lipoproteins, increasing intravascular lipolysis and reducing the number of circulating remnants. The main intervention is a change of lifestyle with decreased alcohol consumption, increased physical activity, dietary changes and, if applicable, adaptation of used medication. Fibrates, fish oil and nicotinic acid are the first choice of treatment in sporadic and familial hypertriglyceridemia to reduce the risk of pancreatitis, whereas high dose statins, sometimes in combination with fibrates, nicotinic acid, or fish oil capsules, are indicated for familial combined hyperlipidemia. Statins are necessary to reach low LDL-C concentrations in patients with type 2 diabetes mellitus and statin dosage should be increased when hypertriglyceridemia is present to reach secondary treatment targets for apolipoprotein B or non-HDL-C. Finally, family screening is mandatory to detect familial lipid disorders for early intervention in other family members.

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.

Mannose binding lectin deficiency and triglyceride-rich lipoprotein metabolism in normolipidemic subjects.

Mannose binding lectin (MBL) is one of the three initiators of complement activation and is therefore closely linked to inflammation. MBL deficiency has been associated with the generation of atherosclerosis. Since atherosclerosis, the complement system and postprandial lipemia are linked to inflammation, we studied postprandial lipoprotein metabolism in MBL deficiency. An observational study was carried out in 107 volunteers (21% MBL deficient). Classical cardiovascular risk factors were not different between subjects with and without MBL deficiency. Oral fat loading tests in 8 MBL deficient and 14 MBL sufficient subjects showed similar postprandial triglyceride, free fatty acid, hydroxybutyric acid and complement component 3 concentrations. MBL deficient subjects had 2.4 times lower postprandial Sf>400 (chylomicron)-apoB48 concentrations, but in contrast a 2-3.5 times increased Sf 60-400 (VLDL1-TG) and Sf 60-400-apoB100 response. MBL activity was inversely related to the postprandial Sf 60-400-TG increase. Despite lower postprandial Sf>400-apoB48 concentrations, MBL deficient subjects show an accumulation of Sf 60-400 lipoproteins.

Comparison of different methods to investigate postprandial lipaemia.

Postprandial hyperlipidaemia has been associated with coronary artery disease (CAD). We investigated which of the generally used methods to test postprandial lipaemia differentiated best between patients with premature CAD (50+/-4 years, n=20) and healthy controls. Furthermore, the effects of rosuvastatin 40 mg/day on postprandial parameters were assessed. Standardised oral fat-loading tests (OFLT) and ambulant self-measurements of daylong capillary triglycerides (TGc) were performed. Total responses of individual lipoproteins, plasma TG (TGp) and remnant-like particle cholesterol (RLP-C) were estimated as area under the curve (AUC). Most AUCs were highest in untreated patients and reached control levels after rosuvastatin. From all AUCs, RLP-C-AUC was best associated to TGp-AUC in untreated patients and controls (adjusted R2=0.84, beta=0.92, p.

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.

[Effect of gender and obesity on postprandial lipemia in non-diabetic normolipidemic subjects and subjects with familial combined hyperlipidemia]. / Efecto del género y de la obesidad en la lipemia posprandial en sujetos sanos normolipidémicos no diabéticos y sujetos con hiperlipemia familiar combinada.

INTRODUCTION: A new method based on self-measurement of diurnal capillary triglycerides (TG) facilitates the study of postprandial lipemia (PL). The objectives of our study are: to evaluate the effect of gender and obesity on PL measured by self-determination of diurnal capillary TG with Accutrend GCT in normolipidemic non-diabetic subjects and subjects with familial combined hyperlipidemia (FCH). MATERIAL AND METHODS: We studied 23 FCH subjects (10 males) and 45 normolipidemic non-diabetic subjects (29 males). All subjects self-determine 3 diurnal capillary TG profiles during a week. RESULTS: In normolipidemic non diabetic subjects significantly higher diurnal TG profiles and area under the curve of TG (AUCTGc) (25.25 +/-9.09 vs 19.71 +/- 6.16 mmolh/l) were found in males compared to females. In FCH subjects these differences were not found and the AUCTGc correlated with BMI (r = 0.510, p < 0.05) and waist circumference (r = 0.453, p < 0.05). Obese subjects (BMI >or= 27 kg/m2) showed diurnal TG profiles and AUCTGc significantly higher than the non-obese. DISCUSSION: Normolipidemic non diabetic females showed a lower PL compared to males, probably due to the effect of estrogens in PL metabolism. Obesity negatively influences PL in normolipidemic non diabetic subjects and subjects with FCH.

Metabolic dysregulation in diabetes and HIV-associated insulin resistance: from fatty acids to fat distribution

Insulin resistance is one of the most important aspects of the metabolic dysregulation in diabetes and the metabolic syndrome. While most experts agree on the disturbed glucose-insulin axis in insulin resistance, the effects on lipid metabolism have received much less attention. Generally, fasting plasma triglycerides are slightly elevated and HDL cholesterol is diminished in the insulin resistance syndromes. Especially, the postprandial state seems to be one of the most important phases in which all the metabolic dysregulations come together. Postprandial lipemia itself is one of the causes of insulin resistance, and since postprandial lipemia is exaggerated in these syndromes, postprandial studies may be the best situation to investigate insulin resistance. Furthermore, postprandial hyperlipidemia has been closely linked to atherosclerosis making this the major risk factor in insulin resistance. One of the less well studied aspects of postprandial lipemia, which is closely related to insulin resistance, is peripheral fatty acid trapping and adipose tissue distribution. In HIV lipodystrophy, aberrant adipose tissue deposition and impaired peripheral fatty acid trapping are important determinants of many of the metabolic disturbances seen in this disorder. Therefore, HIV lipodystrophy is an interesting model to elucidate the molecular mechanisms regulating fatty acid trapping and adipose tissue distribution. Recent studies have clearly shown that components of the complement system play an important role in lipoprotein metabolism and fatty acid regulation. Especial attention has been drawn to the complement component 3 (C3) which is also a strong predictor of the metabolic syndrome. C3 is synthesized by adipose tissue during lipolysis of triglyceride rich lipoproteins. This process seems to be disturbed in different situations of insulin resistance like the metabolic syndrome, type 2 diabetes and familial combined hyperlipidemia. C3 may be a potential link between inflammation and lipoprotein dysmetabolism. Surprisingly, C3 concentrations are also modulated by several interventions designed to treat the me metabolic syndrome, like statins. Other inflammatory markers like leukocyte count and activation behave similar to C3 concentrations, especially during the postprandial phase. In this overview we will discuss several metabolic aspects of two examples of the insulin resistance syndrome, type 2 diabetes and HIV lipodystrophy

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