Abstract: Background Salivary cortisol is unaffected by cortisol binding globulin and reflects free serum cortisol as compared to total serum cortisol. Aim The aim of the present study was to compare the salivary cortisol response with the serum cortisol response in a low-dose-(1 microg)-ACTH test in a clinical setting and to determine the optimal cut-off value of salivary cortisol as an alternative to serum cortisol. Material/Subjects and Methods We measured serum and salivary cortisol responses to i.v. administration of 1-microg ACTH in 51 patients (17 males) referred to the Department of Clinical Chemistry for ACTH-testing. Serum cortisol was assessed before, 20 minutes and 30 minutes after ACTH-administration, and salivary cortisol was assessed before and 30 minutes after ACTH administration. Results Mean cortisol at baseline, 20 and 30 minutes were 0.44 micromol/l (SD:0.22), 0.64 micromol/l (SD:0.24) and 0.70 micromol/l (SD:0.25), respectively. Median basal salivary cortisol was 8.4 nmol/l (interquartile range [IQR]:3.8-14.2). Salivary cortisol at 30 minutes equaled 35.9 nmol/l (IQR:21.1-46.2). Basal salivary cortisol was significantly correlated with salivary cortisol at 30 minutes (r=0.53;P<0.001). Salivary cortisol at 30 minutes of 23.5 nmol/l had a sensitivity and specificity of 78.1% and 70.0%, respectively as compared to the serum cortisol cut-off values of >0.50 micromol/l. Conclusions The salivary low-dose-ACTH-test yields more dynamic responses than serum sortisol. However, the sensitivity and specificity of salivary cortisol are too low to be adequate as an alternative to the serum cortisol measurements. In women on estrogen therapy, however, the use of salivary cortisol might be superior to serum cortisol.
Abstract: BACKGROUND/OBJECTIVE: Early insulin secretion following a meal is representative for normal physiology and may depend on meal composition. To compare the effects of a fat-rich and a carbohydrate-rich mixed meal on insulinogenic index as a measure of early insulin secretion in normoglycemic women (NGM) and in women with type 2 diabetes mellitus (DM2), and to assess the relationship of anthropometric and metabolic factors with insulinogenic index. SUBJECTS/METHODS: Postmenopausal women, 76 with NGM and 64 with DM2, received a fat-rich meal and a carbohydrate-rich meal on separate occasions. Early insulin response was estimated as insulinogenic index ( big up tri, Deltainsulin(0-30 min)/ big up tri, Deltaglucose(0-30 min)) for each meal. Associations of fasting and postprandial triglycerides, body mass index, waist and hip circumference and alanine aminotransferase with insulinogenic indices were determined. RESULTS: Women with NGM present with higher insulinogenic index than women with DM2. The insulinogenic index following the fat-rich meal ( big up tri, DeltaI(30)/ big up tri, DeltaG(30) (fat)) was higher than the index following the carbohydrate-rich meal (big up tri, DeltaI(30)/ big up tri, DeltaG(30) (CH)) (P<0.05 in women with DM2, and not significant in women with NGM). In women with DM2, homeostasis model assessment for insulin resistance was positively associated with big up tri, DeltaI(30)/ big up tri, DeltaG(30) (CH). In women with NGM, waist circumference was independently and inversely associated with big up tri, DeltaI(30)/ big up tri, DeltaG(30) (fat) and with big up tri, DeltaI(30)/ big up tri, DeltaG(30) (CH); hip circumference was positively associated with big up tri, DeltaI(30)/ big up tri, DeltaG(30) (fat). CONCLUSIONS: The insulinogenic index following the fat-rich meal was higher than following the isocaloric carbohydrate-rich meal, which might favorably affect postprandial glucose excursions, especially in women with DM2. The association between a larger waist circumference and a lower meal-induced insulinogenic index in women with NGM requires further mechanistic studies.
Abstract: BACKGROUND: Differences in prevalence of cardiometabolic risk factors between different ethnic groups are largely unknown. We determined the variation in cardiometabolic risk profile according to ethnicity in a cohort overweight/obese Dutch children. METHODS: An oral glucose tolerance test was performed in 516 overweight/obese Dutch children of multi-ethnic origin, attending an obesity out-patient clinic of an urban general hospital (mean age 10.6 +/- 3.2; 55.2% boys). Anthropometric parameters and blood samples were collected, and the prevalence of (components of) the metabolic syndrome (MetS) and insulin resistance were determined in each ethnic group. RESULTS: Major ethnic groups were Dutch native (18.4%), Turkish (28.1%), and Moroccan (25.8%). The remaining group (27.7%) consisted of children with other ethnicities. Turkish children had the highest mean standardized BMI compared to Dutch native children (P < 0.05). As compared to Moroccan children, they had a higher prevalence of MetS (22.8% vs. 12.8%), low HDL-cholesterol (37.9% vs. 25.8%), hypertension (29.7% vs. 18.0%) and insulin resistance (54.9% vs. 37.4%, all P < 0.05). Although Turkish children also had higher prevalences of forementioned risk factors than Dutch native children, these differences were not statistically significant. Insulin resistance was associated with MetS in the Turkish and Moroccan subgroup (OR 6.6; 95%CI, 2.4-18.3 and OR 7.0; 95%CI, 2.1-23.1, respectively). CONCLUSION: In a Dutch cohort of overweight/obese children, Turkish children showed significantly higher prevalences of cardiometabolic risk factors relative to their peers of Moroccan descent. The prospective value of these findings needs to be established as this may warrant the need for differential ethnic-specific preventive measures.
Abstract: We studied the association between alanine aminotransferase (ALT) and features of the metabolic syndrome in a cohort of overweight and obese children aged 3-18 years. An oral glucose tolerance test was performed in 443 consecutive children from an obesity out-patient clinic (median age 11.2, range 3.1-18.0 years; n=240 boys) of multi-ethnic origin. The prevalence of the metabolic syndrome, insulin resistance, elevated ALT (>30 IU/L), and the association of ALT with (components of) the metabolic syndrome was assessed. The metabolic syndrome was present in 26.9%. Elevated ALT levels were found in 20.3%, with a higher prevalence in boys than in girls (25.8% versus 13.8%, P<0.001). ALT was associated with the prevalence of the metabolic syndrome, insulin resistance, high triglycerides, and low HDL-cholesterol after adjustment for gender, age, and BMI. In conclusion, elevated ALT levels were highly prevalent and associated with the metabolic syndrome, insulin resistance, high triglycerides, and low HDL-cholesterol in an obese multiethnic pediatric population.
Abstract: BACKGROUND: Inflammation and oxidative stress are associated with atherosclerosis. Myeloperoxidase (MPO) is linked to both inflammation and oxidative stress by its location in leukocytes and its role in catalyzing the formation of oxidizing agents. Recent evidence suggests that MPO activity precipitates atherogenesis. Measurement of MPO in plasma may therefore contribute to cardiovascular disease (CVD) risk stratification. CONTENT: Cross-sectional studies, case-control studies, and prospective-cohort studies investigating the relation between MPO and CVD have been evaluated. Differences in study populations, sample materials, sample handling, and assays were ascertained. Potential causal mechanisms linking MPO to accelerated atherosclerosis are discussed here. A majority of studies indicate that measurement of MPO in plasma was associated with improved CVD risk stratification above and beyond risk stratification results obtained with markers used in routine clinical practice. However, comparison of these epidemiological studies with regard to MPO and outcome is hampered because the reported MPO concentration depends on the assay method, sampling material, and preanalytical and analytical procedures. The link between MPO and CVD can, at least partly, be explained by MPO-dependent oxidation of LDL and HDL, subsequently leading to cholesterol accumulation in the arterial wall. Furthermore, MPO may reduce the bioavailability of nitric oxide, resulting in endothelial dysfunction. Finally, MPO destabilizes atherosclerotic plaques. SUMMARY: Increasing evidence suggests that MPO is causally linked to atherosclerosis and its measurement may improve CVD risk estimation. Before MPO can be used in routine clinical practice, however, standardization of sampling and laboratory procedures is needed.
Abstract: OBJECTIVES: To assess the prevalence of the metabolic syndrome (MetS) in overweight/obese children and adolescents of an out-patient clinic, and to compare two definitions of MetS in adolescents. METHODS: In total, 528 overweight / obese children (3-16 years), of multi-ethnic origin, underwent an oral glucose tolerance test, blood collections and anthropometric measurements. In children <10 years, MetS was assessed according to child-specific cut-off values (MetS-child). In adolescents, MetS-child and MetS-adolescent (the recommendation of the International Diabetes Federation for adolescents) were compared. RESULTS: The prevalence of MetS-child within the cohort (median age 11.3, range 3.1-16.4 yrs) was 18.6% (children <10 years vs. adolescents: 14.1% vs. 20.7%, P=0.073). Insulin resistance was present in 47.7% (children <10 years vs. adolescents: 21.8% vs. 60.1%, P<0.001). MetS-child was highly prevalent, and not statistically significant between age groups. In adolescents, the prevalence of MetS-adolescent was higher than MetS-child (33.2% vs. 20.7%, P<0.001). The agreement between the MetS definitions was moderate (kappa =0.51), with the agreement for the MetS-criteria for abnormal lipid levels being substantial to very good (kappa =0.71 to 0.80). CONCLUSIONS: MetS-child was highly prevalent in overweight/obese children and adolescents. A higher prevalence of MetS according to adolescent- as compared to child-specific criteria was found.
Abstract: OBJECTIVES: To examine the effect of blood anticoagulation type on the myeloperoxidase (MPO) concentration. DESIGN AND METHODS: MPO was measured in EDTA-plasma and matched heparin-plasma and serum samples collected from healthy volunteers. RESULTS: MPO concentrations in heparin-plasma and serum were higher than in EDTA-plasma (both P<0.001). MPO in EDTA-plasma was not significantly correlated with MPO in either heparin-plasma or serum. CONCLUSIONS: For MPO measurements, EDTA-plasma is the preferred specimen as it appears unaffected by ex vivo release of MPO from leukocytes.
Abstract: The present study aimed to compare the associations of postprandial glucose (ppGL) and postprandial triglycerides (ppTG) with carotid intima media thickness (cIMT) in women with normal glucose metabolism (NGM) and type 2 diabetes (DM2). Post-menopausal women (76 with NGM, 78 with DM2), received two consecutive fat-rich and two consecutive carbohydrate-rich meals on separate occasions. Blood samples were taken before and 1, 2, 4, 6 and 8h following breakfast; lunch was given at t=4. Ultrasound imaging of the carotid artery was performed to measure cIMT. In women with NGM, an increase of 1.0 mmol/l glucose following the fat-rich meals was associated with a 50 microm cIMT increase (p=0.04), and following the carbohydrate meals, an increase of 1.8 mmol/l glucose was associated with a 50 microm larger cIMT (p=0.08). These associations were not explained by classical cardiovascular risk factors. However, no association between ppGL and cIMT was found in women with DM2 and ppTG were not associated with cIMT. The association between ppGL and cIMT in normoglycaemic women suggests that ppGL in the normal range is a marker or a risk factor for atherosclerosis. Postprandial glucose levels might be a better indicator of risk than post-OGTT glucose levels or triglyceride levels.
Abstract: Patients with type 2 diabetes mellitus (DM2) have an increased risk of cardiovascular disease (CVD). Myeloperoxidase (MPO), expressed in leukocytes and released upon activation, is associated with CVD and endothelial dysfunction. Postprandial leukocyte recruitment and activation with subsequent MPO release may contribute to atherosclerosis and CVD. We hypothesized that MPO may increase in the postprandial state because of postprandial leukocyte recruitment and/or activation, especially in subjects with DM2. One hundred postmenopausal women, aged 50 to 65 years (66 with normal glucose metabolism [NGM] and 34 with DM2), received 2 consecutive fat-rich meals and 2 consecutive carbohydrate-rich meals on separate occasions. Blood samples were taken before (t = 0) and at 2, 4, and 8 hours after breakfast; lunch was given at t = 4. Plasma MPO concentration was measured by sandwich enzyme-linked immunosorbent assay. The number of leukocytes in fasting blood samples was higher in DM2 compared with NGM (6.1 +/- 1.4 and 5.4 +/- 1.2 x 10(9)/L, respectively; P < .05). Baseline MPO concentration did not significantly differ between NGM and DM2 (51.4 +/- 12.9 and 54.5 +/- 18.4 mug/L, respectively; P = .39). Baseline MPO was positively associated with leukocytes (r = 0.20, P < .05) and inversely associated with high-density lipoprotein cholesterol (r = -0.22, P < .05). Leukocytes increased from 5.0 +/- 1.5 to 6.1 +/- 1.5 x 10(9)/L and from 5.8 +/- 1.4 to 6.6 +/- 1.4 x 10(9)/L in NGM and DM2, respectively (both P < .01), after the fat-rich meals. In contrast to our hypothesized increase in MPO, we found a significant decrease in MPO in NGM (both meal types) and DM2 (fat-rich meals only). Our findings provide no support to our initial hypothesis that meal-induced release of MPO might be a mechanism that contributes to CVD risk.
Abstract: Both postprandial hyperglycemia and hypertriglyceridemia have been identified as risk markers for cardiovascular disease, but parameters associated with these postprandial responses are largely unknown. The objective was to assess whether usually measured clinical and biochemical parameters can predict postprandial glucose and triglyceride responses and whether these responses are associated with each other. Postmenopausal women, 76 with normal glucose metabolism (NGM) and 41 with type 2 diabetes mellitus (T2DM), received 2 consecutive fat-rich meals and carbohydrate-rich meals on separate occasions. Blood samples were taken before and at t = 1, 2, 4, 6, and 8 hours after breakfast; lunch was given at t = 4 hours. Regression analysis was performed with incremental area under the postprandial triglyceride curve (triglyceride-iAUC) and glucose curve (glucose-iAUC) after fat-rich and carbohydrate-rich meals, respectively. In women with NGM, fasting triglycerides, hemoglobin A(1c), total cholesterol, and, inversely, high-density lipoprotein cholesterol were independently associated with triglyceride-iAUC; and age and fasting triglycerides were independently associated with glucose-iAUC. In women with T2DM, fasting triglycerides were independently associated with triglyceride-iAUC, whereas hemoglobin A(1c) and fasting glucose were stronger than fasting triglycerides associated with glucose-iAUC. Glucose-iAUC and triglyceride-iAUC were associated with each other in women with T2DM, but not in those with NGM. The association between glucose-iAUC and triglyceride-iAUC in women with T2DM and the association of fasting triglycerides with both glucose-iAUC and triglyceride-iAUC in NGM and T2DM suggest a common underlying mechanism for postprandial increments in glucose and triglycerides, especially in T2DM. Commonly measured clinical and biochemical parameters can only partly explain postprandial glucose and triglyceride excursions.
Abstract: AIMS: To study the association between alanine aminotransferase (ALT) and the 6-year risk of the metabolic syndrome in a population-based study in Caucasian men and women. METHODS: The association of ALT with the 6-year risk of the metabolic syndrome in 1097 subjects, aged 50-75 years, was assessed in the Hoorn Study with logistic regression analysis. Subjects with the metabolic syndrome at baseline, defined according to the Adult Treatment Panel III of the National Cholesterol Education Program, were excluded. RESULTS: After 6.4 (range 4.4-8.1) years follow-up, 226 subjects (20.6%) had developed the metabolic syndrome. The odds ratio (95% confidence interval) for developing the metabolic syndrome, adjusted for age, sex, alcohol intake and follow-up duration was 2.25 (1.50-3.37) for subjects in the upper tertile compared with those in the lower tertile of ALT. This association persisted after additional adjustment for all the baseline metabolic syndrome features [1.62 (1.02-2.58)]. Among the individual components of the metabolic syndrome, ALT was significantly associated only with fasting plasma glucose at follow-up. CONCLUSIONS: These data suggest that ALT is associated with risk of the metabolic syndrome in a general population of middle-aged Caucasian men and women, further strengthening the role of ALT as an indicator for future metabolic derangement. These findings warrant further studies to elucidate the role of non-adipose tissue fat accumulation in the pathogenesis of complications related to the metabolic syndrome.
Abstract: Alanine aminotransferase (ALT) is a marker of non-alcoholic fatty liver disease (NAFLD) and predicts incident type 2 diabetes mellitus (DM2). Recently, ALT was shown to be also associated with endothelial dysfunction and carotid atherosclerosis. We studied the predictive value of ALT for all-cause mortality, incident cardiovascular disease (CVD) and coronary heart disease (CHD) events in a population-based cohort of Caucasian men and women aged 50-75 years, at baseline. The 10-year risk of all-cause mortality, fatal and non-fatal CVD and CHD events in relation to ALT was assessed in 1439 subjects participating in the Hoorn Study, using Cox survival analysis. Subjects with prevalent CVD/CHD and missing data were excluded. As compared with the first tertile, the age- and sex-adjusted hazard ratios (95% confidence intervals) for all-cause mortality, CVD events and CHD events were 1.30 (0.92-1.83), 1.40 (1.09-1.81) and 2.04 (1.35-3.10), respectively, for subjects in the upper tertile of ALT. After adjustment for components of the metabolic syndrome and traditional risk factors, the association of ALT and CHD events remained significant for subjects in the third relative to those in the first tertile, with a hazard ratio of 1.88 (1.21-2.92) and 1.75 (1.12-2.73), respectively. In conclusion, the predictive value of ALT for coronary events, seems independent of traditional risk factors and the features of the metabolic syndrome in a population-based cohort. Further studies should confirm these findings and elucidate the pathophysiological mechanisms.
Abstract: Nonalcoholic fatty liver disease (NAFLD) is prevalent in people with the metabolic syndrome and type 2 diabetes. Evidence is now accumulating that NAFLD is associated with obesity and diabetes and may serve as a predictor of cardiovascular disease. Although at present, treatment of the individual risk factors pertinent to NAFLD is advocated, novel therapies are emerging that may target steatosis and/or inflammation, thus ameliorating the overall cardiovascular disease risk. Long-term outcome studies need to establish whether treatment of NAFLD (and in particular which therapy) will affect the long-term outcome.
Abstract: OBJECTIVE: Insulin resistance, associated with increased lipolysis, results in a high exposure of nonadipose tissue to lipids. Experimental data indicate that fatty infiltration of pancreatic islets may also contribute to beta-cell dysfunction, but whether this occurs in humans in vivo is unknown. RESEARCH DESIGN AND METHODS: Using proton magnetic resonance spectroscopy and oral glucose tolerance tests, we studied the association of pancreatic lipid accumulation in vivo and various aspects of beta-cell function in 12 insulin-naive type 2 diabetic and 24 age- and BMI-matched nondiabetic men. RESULTS: Patients versus control subjects had higher A1C, fasting plasma glucose, and insulin and triglyceride levels and lower HDL cholesterol, but similar waist circumference. Median (interquartile range) pancreatic fat content in patients and control subjects was 20.4% (13.4-43.6) and 9.7% (7.0-20.2), respectively (P = 0.032). Pancreatic fat correlated negatively with beta-cell function parameters, including the insulinogenic index adjusted for insulin resistance, early glucose-stimulated insulin secretion, beta-cell glucose sensitivity, and rate sensitivity (all P < 0.05), but not potentiation. However, these associations were significantly affected by the diabetic state, such that a significant association of pancreatic fat with beta-cell dysfunction was only present in the nondiabetic group (all P < 0.01), suggesting that once diabetes occurs, factors additional to pancreatic fat account for further beta-cell function decline. In control subjects, the association of pancreatic fat and beta-cell function remained significant after correction for BMI, fasting plasma glucose, and triglycerides (P = 0.006). CONCLUSIONS: These findings indicate that pancreatic lipid content may contribute to beta-cell dysfunction and possibly to the subsequent development of type 2 diabetes in susceptible humans.
Abstract: OBJECTIVE: We studied acute changes in markers of glycoxidative and lipoxidative stress, including oxidized LDL, N(epsilon)-(carboxyethyl)-lysine (CEL), N(epsilon)-(carboxymethyl)-lysine (CML), and 3-deoxyglucosone (3DG), following two consecutive meals. RESEARCH DESIGN AND METHODS: Postmenopausal women (27 with normal glucose metabolism [NGM], 26 with type 2 diabetes) received two consecutive fat-rich meals and two consecutive carbohydrate-rich meals on two occasions. Glucose and triglyceride concentrations were measured at baseline and 1, 2, 4, 6, and 8 h following breakfast; lunch was given at 4 h. Oxidized LDL-to-LDL cholesterol ratio, CEL, CML, and 3DG were measured at baseline and at 8 h. RESULTS: Fasting oxidized LDL-to-LDL cholesterol ratio, 3DG, and CML were higher in women with type 2 diabetes compared with women with NGM and were comparable to the postprandial values at 8 h in NGM. Postprandial rises in the oxidized LDL-to-LDL cholesterol ratio and 3DG were similar in both groups. However, the oxidized LDL-to-LDL cholesterol ratio increased more after the fat-rich meals, whereas CML and 3DG increased more after the carbohydrate-rich meals. After the fat-rich meals, the increase in the oxidized LDL-to-LDL cholesterol ratio correlated with postprandial triglycerides, whereas the increase in 3DG was correlated with postprandial glucose. CONCLUSIONS: The acute changes in markers of glycoxidative and lipoxidative stress in both type 2 diabetes and NGM suggest that postabsorptive oxidative stress may partly underlie the association of postprandial derangements and cardiovascular risk.
Abstract: For a long time, hepatic steatosis was believed to be a benign condition. Only recently, liver steatosis, also termed non-alcoholic fatty liver disease (NAFLD), has gained much interest. In most cases of NAFLD, a condition regarded as the hepatic component of the metabolic syndrome, the enzyme alanine aminotransferase (ALT) is elevated and consequently has been used as a marker for NAFLD. More recently, several cross-sectional and prospective studies have demonstrated associations of this liver enzyme with features of the metabolic syndrome and type 2 diabetes mellitus. This review discusses the biochemical and metabolic properties of ALT, its applicability as a marker of NAFLD and describes its possible role in the pathogenesis of the metabolic syndrome and type 2 diabetes mellitus and subsequent cardiovascular disease. In addition, treatment strategies to ameliorate NAFLD and the associated risks are discussed.
Abstract: BACKGROUND: Plasma levels of liver transaminases, including alanine aminotransferase (ALT), are elevated in most cases of nonalcoholic fatty liver disease (NAFLD). Elevated ALT levels are associated with insulin resistance, and subjects with NAFLD have features of the metabolic syndrome that confer high-risk cardiovascular disease. Alanine aminotransferase predicts the development of type 2 diabetes (DM2) in subjects with the metabolic syndrome. However, the role of elevated ALT levels in subjects with overt DM2 has yet not been explored. MATERIALS AND METHODS: In a cross-sectional study, 64 normotriglyceridaemic subjects with DM2 were studied with regard to the relation between liver transaminases with whole-body insulin sensitivity, measured with the euglycaemic hyperinsulinaemic clamp and with brachial artery flow-mediated dilation (FMD) as a marker of endothelial dysfunction. RESULTS: On average, patients were normotriglyceridaemic (plasma triglycerides 1.3 +/- 0.4 mmol L-1) and had good glycaemic control (HbA1c 6.2 +/- 0.8%). The mean ALT level was 15.0 +/- 7.5 U L-1, and the mean aspartate aminotransferase concentration equalled 10.6 +/- 2.6 U L-1. Alanine aminotransferase levels were negatively associated with whole-body insulin sensitivity as well as with FMD (both P = 0.03, in multivariate analyses; regression coefficients beta [95%CI]: -0.76 [-1.4 to -0.08] and -0.31 [-0.58 to -0.03] respectively). CONCLUSIONS: In metabolically well-controlled patients with DM2, ALT levels are related to decreased insulin-sensitivity and an impaired conduit vessel vascular function.
Abstract: This study examined the difference in sequence of coming-out and first same-sex experience in relation to risk-taking behavior in a sample of Dutch gay and bisexual men. A questionnaire assessed age of disclosure (coming-out) and age of first same-sex experience, and information on sexual history, sexual relationships, and sexual behavior. It was found that 68% of respondents engaged in their first same-sex experience before coming-out. This proportion increased with age. Men who had sex with men before coming-out reported more lifetime sex partners and more casual sex partners in the past 6 months than men in which this sequence was reversed. In addition, among this group a higher proportion of men reported STDs, engaging in anal intercourse with casual partners in the previous 6 months, and unprotected anal sex with casual sex partners in the recent past, compared to men who came out before having their first same-sex experience. The extent to which external factors (such as tolerance toward homosexuals) or internal factors (such as personality factors) can account for the difference in sexual behaviors in general and sexual risk-taking behavior in particular could be subject of further study.
