Miguel Valle

Elevated plasma total homocysteine levels in hyperinsulinemic obese subjects

Homocysteine has been associated with the oxidative stress in the pathogenesis of atherosclerosis. Oxidative stress caused by triglycerides and free fatty acids is known to cause insulin resistance and hyperinsulinemia. On the other hand, insulin resistance may increase homocysteine levels. Since obesity is associated with insulin resistance and hyperinsulinemia, we aimed to study the possible association of homocysteine with hyperinsulinemia in obese subjects. 20 obese male subjects (body mass index >29), aged 33--55 (mean 45 years old) were studied. A fasting blood sample was obtained for the study and the subjects undertook an oral glucose tolerance test with samples taken at 1 and 2 h after glucose. Subjects were divided in two groups according to the fasting insulin levels, < 9 &mgr;U/ml or normoinsulinemic (group 1) and >9 &mgr;U/ml or hyperinsulinemic (group 2). Glucose, insulin, homocysteine, folate, B(12,) total cholesterol, HDL-cholesterol and triglycerides levels were determined in fasting blood samples. In oral glucose tolerance test, glucose, insulin and homocysteine levels were measured. Hyperinsulinemic obese subjects (group 2) had higher levels of insulin and glucose at 1 h and 2 h postglucose, compared with group 1. Fasting total homocysteine and triglyceride levels were also increased in this group, whereas folate and B(12) levels were similar in both groups. Fasting homocysteine significantly correlated with fasting insulin (r = 0.6, p <0.01). Homocysteine levels slightly but significantly decreased after glucose loading in normoinsulinemic but not in hyperinsulinemic obese subjects. These results show that higher homocysteine levels are observed in the hyperinsulinemic obese subjects and suggest that homocysteine could play a role in the higher risk of cardiovascular disease in obesity.

Myeloperoxidase Is an Early Biomarker of Inflammation and Cardiovascular Risk in Prepubertal Obese Children

OBJECTIVE Obesity is associated with a state of chronic low-grade inflammation. Myeloperoxidase (MPO) plays an important role in the initiation and progression of acute and chronic inflammatory diseases, such as cardiovascular disease (CVD). The objectives of the current study were to evaluate plasma MPO levels in prepubertal obese children and to determine whether MPO could be an early biomarker of inflammation and CVD risk. RESEARCH DESIGN AND METHODS In a prospective multicenter case-control study paired by age and sex of 446 Caucasian prepubertal children ages 6–12 years, 223 normal-weight and 223 obese children were recruited. Blood pressure, waist circumference, weight, and height were measured. In addition to MPO, glucose, insulin, metabolic lipid parameters, oxidized low-density lipoproteins, adiponectin, leptin, resistin, C-reactive protein (CRP), interleukin 6, tumor necrosis factor α, matrix metalloproteinase-9 (MMP-9), and plasminogen activator inhibitor 1 were determined. RESULTS We found that MPO was elevated in prepubertal obese children and that this enzyme was associated with such proinflammatory and cardiovascular risk biomarkers as CRP, MMP-9, and resistin. Insulin resistance calculated by the homeostatic assessment model was the best predictor of MPO. CONCLUSIONS MPO is an early biomarker of inflammation associated with CVD risk in obese children at the prepubertal age.

Presence of the Metabolic Syndrome in Obese Children at Prepubertal Age

Background/Aims: There is a strong debate on the diagnosis and early phenotypic expression of the metabolic syndrome in children. The aim of the present study was to examine the frequency of the metabolic syndrome using various definitions in obese prepubertal and pubertal children. Methods: 478 (213 females and 265 males) obese children were recruited in three provinces of Spain. Blood pressure (BP), waist circumference, and weight and height were measured, and body mass index was calculated. Glucose, insulin, high-density lipoprotein cholesterol and triacylglycerols were determined. We classified the children according to seven different proposed definitions of the metabolic syndrome. Results: Regardless of the definition used, the prevalence of the metabolic syndrome (8.3–34.2%) was relatively high in obese children in the prepubertal period as well as in pubertal children (9.7–41.2%). We performed a principal-factor analysis to explain correlations among features of the metabolic syndrome and found that glucose metabolism (factor 1), dyslipidemia (factor 2) and obesity/BP (factor 3) explained 72% of the total variance. Conclusion: Irrespective of the classification used, the metabolic syndrome is not only present in pubertal but also in prepubertal children. International definitions of the metabolic syndrome should also consider criteria specific for children in the prepubertal period, i.e. children aged <10 years.

Infantile obesity: A situation of atherothrombotic risk?

Obesity is a major risk factor for cardiovascular disease frequently associated with hypertension, dyslipidemia, and diabetes. In recent years, alterations in the hemostatic system have been added to these dysfunctions. We analyzed some of these alterations in coagulation and fibrinolysis in obese children (6 to 9 years old) of both sexes. We studied 61 obese children (mean body mass index [BMI], 22.35 kg/m2; 95% confidence interval [CI], 21.82 to 22.87) and 70 non-obese children (mean BMI, 16.58 kg/m2; 95% CI, 16.24 to 16.93) as a control group. The obese subjects presented significantly elevated values for insulin (P < .001), tissue-plasminogen activator ([t-PA] P < .001), plasminogen activator inhibitor-1 ([PAI-1] P < .001), and fibrinogen (P < .001) with respect to the control group. We found no significant differences in the concentration of glucose and fragment 1 + 2 of prothrombin (F1 + 2). In the obese subjects, insulin, PAI-1, and F1 + 2 were positively correlated with the BMI. On the other hand, t-PA was correlated with insulin and PAI-1 but not with the BMI. Therefore, in the obese children, there was an increment of the risk factors for cardiovascular disease.

Increased plasma pancreastatin-like immunoreactivity levels in non-obese patients with essential hypertension.

Design Pancreastatin, a novel peptide, is known to inhibit insulin secretion and to have a glycogenolytic effect, and is present in many endocrine and chromaffin cells. Both the plasma insulin levels and the adrenergic activity accompanying insulin resistance have been shown to be increased in hypertensive subjects. Our working hypothesis was that pancreastatin might play a role in these pathological phenomena. Methods We studied the plasma pancreastatin level in non-obese essential hypertensive patients in response to an intravenous glucose load. We further measured the responses to the glucose challenge of insulin, glucagon, catecholamines and free fatty acids, as well as other factors related to insulin resistance (i.e. lipoproteins and apolipoproteins). We separated the hypertensive patients into three groups according to their response to an oral glucose-tolerance test: normoinsulinaemic, hyperinsulinaemic and glucose-intolerant. Matched normotensive control subjects were also studied. Results Pancreastatin levels did not change in the control group after the glucose challenge. However, all hypertensive patients showed an increase in plasma pancreastatin levels after glucose loading. The normoinsulinaemic hypertensive patients also had elevated basal pancreastatin levels. The increase in pancreastatin levels was in the ranking: normoinsulinaemic hyperinsulinaemic glucose-intolerant. The pancreastatin: insulin ratio showed that the secretion of pancreastatin and insulin may be regulated differently. Basal free fatty acid and glucagon levels were found to be elevated both in the hyperinsulinaemic and in the glucose-intolerant group. Fasting triglycerides levels were increased in all of the hypertensive patients. Other risk factors for coronary artery disease were also found to be altered: elevated very low-density lipoprotein-cholesterol and decreased high-density lipoprotein-cholesterol, with ranking: normoinsulinaemic hyperinsulinaemic glucose-intolerant. Conclusions These results show an increase in pancreastatin levels in hypertensive patients, suggesting that pancreastatin might play a role in the pathophysiology of essential hypertension.

Changes in body mass index are associated with changes in inflammatory and endothelial dysfunction biomarkers in obese prepubertal children after 9 months of body mass index SD score loss

The metabolic syndrome is associated with insulin resistance, a systemic low-grade inflammatory state, and endothelial dysfunction. These disorders may arise at a very early age in obese children. The aim of this study was to confirm changes in endothelial dysfunction and inflammatory biomarkers in obese prepubertal children and to evaluate the effect of body mass index (BMI) modification on these biomarkers. Biomarkers for inflammation, endothelial dysfunction, and insulin resistance were measured in obese children (47) and healthy controls (47). Baseline pretreatment levels of insulin (P = .019), homeostasis model assessment of insulin resistance (P = .004), soluble intercellular adhesion molecule (sICAM) (P = .003), and C-reactive protein (CRP) (P < .001) were significantly higher in obese children than in controls. After 9 months of treatment, obese children with lowered BMI SD score (SDS-BMI) displayed a significant decrease in insulin (P = .011), homeostasis model assessment of insulin resistance (P = .012), CRP (P = .006), and interleukin-6 (IL-6) (P = .045) levels compared with obese children with stable SDS-BMI; they also displayed a nonsignificant drop in sICAM levels. Similarly, obese children with lowered SDS-BMI displayed a decrease in CRP (P = .005) and IL-6 (P = .065) compared with baseline levels before treatment. In the total obese group, changes in SDS-BMI correlated positively with changes in CRP (P = .035), IL-6 (P = .027), and sICAM-1 (P = .038) levels. Only SDS-BMI was an independent predictive factor for CRP (P = .031), IL-6 (P = .027), and sICAM-1 (P = .033). Prepubertal obese children displayed alterations indicative of endothelial dysfunction, insulin resistance, and inflammatory state. Lowering of the SDS-BMI after 9 months of treatment was associated with an improvement in these variables compared with those in obese children with stable SDS-BMI status.

Plasma pancreastatin-like immunoreactivity correlates with plasma norepinephrine levels in essential hypertension.

Pancreastatin (PST), a 49 amino acid peptide originally isolated from porcine pancreas, is derived from chromogranin A (Cg A), an acidic protein co-released with catecholamines from sympathetic nerve terminals and chromaffin cells. Extracellular processing of Cg A yields PST as well as other biological active peptides. Measurement of Cg A and PST-like immunoreactivity (PST-LI) has been used to investigate patients with pheochromocytoma and other neuroendocrine neoplasia. Some studies have found increased plasma norepinephrine (NE) levels in essential hypertension. We therefore measured venous plasma PST-LI and catecholamines in patients with essential hypertension. We employed a radioimmunoassay developed with commercially available reagents for measuring plasma PST-like immunoreactivity, and HPLC with electrochemical detection for measurement of plasma catecholamines. The correlation of PST-LI with epinephrine (E) was very weak. However, its correlation with NE was highly significant. Thus, venous plasma PST-LI immunoreactivity may reflect sympathetic nerve activity in essential hypertension.

Waist-to-height ratio, inflammation and CVD risk in obese children

OBJECTIVE To evaluate the association between waist-to-height ratio (WHtR) and specific biomarkers of inflammation, CVD risk and endothelial dysfunction in prepubertal obese children. DESIGN Prospective, multicentre case-control study matched by age and sex. SETTING Children were recruited between May 2007 and May 2010 from primary-care centres and schools in three cities in Spain (Cordoba, Santiago de Compostela and Zaragoza). SUBJECTS Four hundred and forty-six (223 normal weight and 223 obese) Caucasian prepubertal children aged 6-12 years. RESULTS WHtR was higher in the obese than in the normal-weight children. Blood pressure, waist circumference, weight, height, insulin, plasma lipids, leptin, resistin, abnormal neutrophil and monocyte counts, C-reactive protein, IL-6, IL-8, TNF-α, myeloperoxidase, soluble intercellular adhesion molecule-1, selectin and plasminogen activator inhibitor-1 levels were higher in the obese than in the normal-weight group. Adiponectin and HDL-cholesterol were lower and glucose and metalloproteinase-9 showed no differences. Resistin, TNF-α and active plasminogen activator inhibitor-1 were associated with WHtR, a sensitive indicator of central obesity. CONCLUSIONS Our results lead to the hypothesis that changes in biomarker levels of insulin resistance, inflammation and CVD risk before puberty might induce metabolic consequences of obesity in obese children before reaching adulthood.

A Continuous Metabolic Syndrome Score Is Associated with Specific Biomarkers of Inflammation and CVD Risk in Prepubertal Children

Background/Aims: We aimed to evaluate the use of a continuous metabolic syndrome (MetS) score and to assess the associations of this score with risk biomarkers of inflammation, endothelial damage and cardiovascular disease (CVD) in prepubertal children. Methods: A total of 677 prepubertal children (295 obese, 146 overweight, and 236 normal-weight) were recruited. MetS traits, markers of inflammation, endothelial damage and CVD risk were measured, and a continuous MetS score was calculated, consisting of the sum/5 of the standardised scores of the MetS components. Results: The continuous MetS score was significantly associated with active plasminogen activator inhibitor-1 (r = 0.406, p < 0.001), adiponectin (r = -0.212, p < 0.001), resistin (r = 0.263, p < 0.001), C-reactive protein (r = 0.254, p < 0.001), tumour necrosis factor alpha (r = 0.120, p = 0.003), myeloperoxidase (r = 0.188, p < 0.001) and sE-selectin (r = 0.278, p < 0.001). Children in the normal-weight, overweight and obese groups with MetS totalled 0 (0%), 1 (0.7%) and 24 (8.7%), respectively, whereas the at-risk children identified using the continuous MetS score in each group totalled 2 (0.85%), 17 (11.6%) and 167 (56.6%), respectively. Conclusions: The association of the continuous MetS score with specific risk biomarkers of inflammation, endothelial damage and CVD supports its use in the early identification of children at increased risk of metabolic dysfunction.

Short-term effects of GH treatment on coagulation, fibrinolysis, inflammation biomarkers, and insulin resistance status in prepubertal children with GH deficiency

OBJECTIVE The aims of this study was to determine whether prepubertal GH deficiency (GHD) children showed any impairment in coagulation- and fibrinolysis-related parameters and in inflammatory and insulin resistance markers and to evaluate the effect of short-term GH therapy on these parameters. DESIGN This was a 6-month, prospective, observational, case-control study (36 prepubertal children with GHD and 38 healthy prepubertal children with no differences in BMI). Comparison of study parameter values in GHD AND control groups at baseline and after 6 months of GH treatment in the GHD group. The following were analyzed: glucose, insulin, fibrinogen, absolute plasminogen activator inhibitor type 1 (aPAI-1), von Willebrand factor (vWF), homeostasis model assessment for insulin resistance (HOMA-IR) index, C-reactive protein (CRP), and interleukin 6 (IL6) levels. RESULTS Children with GHD showed higher baseline levels of aPAI-1 and fibrinogen and lower levels of glucose, insulin, and HOMA-IR index than healthy controls. No intergroup differences were found for vWF. After 6 months of treatment, aPAI-1 levels were lower but no changes were observed in fibrinogen or vWF levels, which were similar to those of controls. Glucose levels increased, though not significantly, while insulin levels and HOMA-IR index rose to normal levels. A positive correlation was found between changes in insulin status/HOMA-IR index and levels of aPAI-1, fibrinogen, vWF, CRP, and IL6. CONCLUSIONS At early ages, GH therapy appears to exert beneficial effects on the amount of aPAI-1. At the same time, it increases the state of insulin resistance (HOMA-IR index) without modifying the levels of fibrinogen, vWF, CRP, and IL6.