Association of traits of metabolic syndrome with glucose abnormalities.

The association of glucose abnormalities (GAs) with the early appearance of traits of the metabolic syndrome (MS) was studied in an unselected sample of apparently healthy Urban Hispanics. GAs were defined as impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and newly diagnosed diabetes mellitus (DM). Overall, GAs were associated with older age, abdominal obesity, low high-density lipoprotein cholesterol levels, hypertriglyceridemia, hyperinsulinemia, hypertension, and MS. Prevalence of MS defined as per NCPE-ATPIII was the greatest in subjects with DM (54.3%) and with combined abnormalities (IFG + IGT) (54.1%; P > 0.5). Similar prevalence of MS was found in subjects with isolated IFG (34.3%) and isolated IGT (36.8%) but higher than in normal fasting-glucose tolerant individuals (23.3%) (P < 0.01). The average number of traits of the MS coexisting in normal fasting glucose-tolerant individuals was 1.6 [95% confidence interval (CI), 1.5-1.8; median 2], in isolated IFG: 2.05 (95% CI, 1.8-2.2; median 2); isolated IGT: 2.16 (95% CI, 1.8-2.3; median 2); combined IFG + IGT: 2.7 (95% CI, 2.3-3.1; median 3); and DM: 2.7 (95% CI, 2.25-3.1; median 3) (P < 0.01). Postload insulin levels were higher in isolated IGT than in isolated IFG, whereas HOMA-IR was higher in IFG. Indices of early and total insulin secretion were markedly reduced in DM, IFG-IGT, and IGT. In conclusion, GAs are strongly associated with the number and severity of traits of the MS, defects in insulin secretion, and sustained hyperinsulinemia in response to oral glucose. Subjects with combined GA and newly diagnosed type 2 DM had not only an increased prevalence of MS, but also the MS was characterized by the presence of more than 3 traits, and by a greater severity of each of the coexisting traits.

Prevalence of glucose abnormalities and diagnostic value of fasting glucose and fasting insulin in urban Hispanics.

The prevalence of glucose abnormalities (GAs) and the diagnostic value of fasting plasma glucose and insulin in detecting impaired glucose tolerance (IGT) and diabetes mellitus (DM) were determined in urban Latin Americans. An oral glucose tolerance test was conducted in 592 subjects after administration of 75 g of glucose. Employing American Diabetes Association (ADA) and World Health Organization guidelines, GAs were found in 34% of the subjects, defined as impaired fasting glucose (IFG) (13.3%), IGT (6.9%), combined IFG + IGT (7.8%), and newly diagnosed type-2-DM (6.5%). All newly diagnosed diabetics had 2-hour glucose levels ≥200 mg/dL, but only 46.1% had fasting glucose ≥126 mg/dL. In addition, nearly half of the subjects with IGT (47%) had fasting glucose levels <100 mg/dL. The sensitivity, specificity, positive and negative predictive values of IFG in predicting IGT was 52.9%, 83%, 36.8%, and 90.4 %, respectively. Fasting insulin levels were not sensitive for differentiating glucose tolerant, from IFG and IGT; only the subjects with combined IFG + IGT had increased fasting insulin levels (22% above IFG) (P < 0.01). Two-hour insulin was increased by 30% in IGT and newly diagnosed diabetics, and by 46% in the subjects with combined IFG + IGT. In summary, the very high prevalence of undetected GA encountered in "healthy" subjects living in Caracas, Venezuela, requires immediate sanitary attention. With 50% of diabetic patients being unaware of their condition, half of IGT and DM not detected by ADA guidelines, and the poor sensitivity/specificity of fasting glucose in predicting 2-hour abnormalities, we recommend that 2-hour postload glucose be included when screening for GAs. Measurements of fasting and/or postload insulin are not cost effective for the diagnosis of GA, because they provide little additional clinical information in this context.

Metabolic syndrome: an all or none or a continuum load of risk?

OBJECTIVE: The aim of this study was to determine if an increasing number of traits of metabolic syndrome was associated with an increased severity of each of the traits. METHODS: A cohort of otherwise healthy 387 Latin-American subjects was evaluated for traits of metabolic syndrome according to National Cholesterol Education Program Adult Treatment Panel III (NECP ATP III) guidelines. Waist cricumference and triglyceride, high-density lipoprotein cholesterol (HDL-C), and blood pressure (BP) levels were measured. Glucose and insulin levels were obtained after 75 g of oral glucose. RESULTS: The prevalence of subjects with no traits and 1, 2, 3, and 4-5 traits was 10.1%, 27.1%, 36.7%, 20.9%, and 5.1%, respectively. Low HDL-C accounted for 55.2% and larger waist circumference for 30.5% of all cases with one trait. High BP and high glucose contributed mainly as the 4th or 5th trait. Higher values for obesity, abdominal obesity, dyslipidemia, BP, hyperglycemia, and hyperinsulinemia were observed as the number of traits increased from 0 to 4-5 traits. More traits meant more severe traits, even after adjusting by age. Subjects with metabolic syndrome but with 4-5 traits had a much higher risk load than those with 3 traits, due to more traits and more severe traits. CONCLUSIONS: We found that with an increasing number of traits of the metabolic syndrome that the severity of each trait increased. A gradual increase in risk load defined by trait clustering and severity was observed when moving from no traits to fully blown metabolic syndrome. Such a continuum of risk was also observed among subjects with metabolic syndrome, implying that subjects diagnosed with the syndrome may be at quite different risk load.

Salt and the metabolic syndrome.

BACKGROUND AND AIMS: High blood pressure in subjects with the metabolic syndrome (MS) is largely related to dietary salt. We investigated in free-living men and women whether increase in dietary salt intake is associated with the presence and severity of the MS. METHODS AND RESULTS: A total of 766 subjects (251M, 515F) of 44.9+/-0.5 years/age and SBP/DBP of 120+/-0.6/77+/-0.4 mmHg were studied. Twenty-four hour urinary sodium (UNa(+)) and potassium (UK(+)) excretions were 143+/-2.5 mmol (median: 131.5) and 48+/-0.9 mmol (median: 44). UNa(+) was higher in men than in women (median: 155.5 vs. 119.8 mmol/day; P<0.0001). UK(+) (r=0.34; P<0.0001), measures of obesity (r=0.26; P<0.0001) and BP (r=0.15; P<0.0001) were significantly associated with UNa(+). The association with BP was lost after adjusting for weight. Of the 766 subjects, 256 (33.4%) met the NCEP-ATPIII criteria for the MS. Median UNa(+) in men and women with no traits of the MS was 140 and 116.7 mmol/day, respectively (P<0.001), increasing to 176 in men and 135 mmol/day in women with 4-5 components of the syndrome (P<0.001). Weight, BMI and waist increased significantly across the quartiles of UNa(+) both in men and women; whereas, age, lipids and fasting glucose did not. SBP and DBP were associated with UNa(+) in men but not in women. UK(+) correlated with age in men and women (r=023; P<0.0001) and with obesity in women (r=0.14; P=0.001). CONCLUSIONS: UNa(+) a measure of dietary sodium intake in free-living subjects was markedly increased in subjects with the MS. Higher UNa(+) was associated with obesity and higher BP, but not with age, dyslipidemia or fasting glucose.

Óxido nítritico: sensibilidad a la sal y la obesidad / Nitric oxide: salt sensitivity and obesity

El óxido nítrico es una molécula neurotransmisora, mediadora de importantes funciones como la vasodilatación, estimulación de la síntesis de músculo liso vascular y antiagregación plaquetaria. El óxido nítrico es continuamente sintetizado y liberado desde el endotelio en condiciones fisiológicas. La inhibición crónica de la producción de óxido nítrico conduce a hipertensión arterial severa; por otra parte la hipertensión arterial se asocia con otros factores de riesgo, como lo es la sensibilidad a la sal. A pesar de que la hipertensión arterial inducida por sodio fue descrita hace medio siglo, aún se desconoce su etiología en humanos, y las implicaciones del óxido nítrico en su aparición. a) La ingesta elevada de sodio inhibe la producción del óxido nítrico; este efecto se revierte con la ingestión de sal. b) en sujetos obesos, la corrección de alteraciones metabólicas asociadas es capaz de corregir la sensibilidad a la sal y por lo tanto, de disminuir la hipertensión arterial en los individuos sal sensibles. También restablece la bioactividad normal del óxido nítrico. Estos hallazgos permiten afirmar que los factores de riesgo adquiridos juegan un papel importante en la patogénesis de la sensibilidad a la sal asociada a la obesidad, y que la corrección de la adiposidad abdominal mejora las anomalías metabólicas asociadas, reduce la reactividad de la presión arterial al sodio y mejora la producción de óxido nítrico.

Nitric oxide, as a neurotransmitter molecule, is a mediator of important functions including vasodilatation, synthesis of vascular smooth muscle and anti-aggregation of platelets. Under physiological conditions nitric oxide is synthesized and released from the endothelium. The chronic inhibition of nitric oxide production leads to severe hypertension; moreover hypertension is associated with other risk factors, such as salt sensitivity. Although hypertension induced by sodium was described half a century ago, its etiology remains unclear as well as the involvement of nitric oxide. A) high sodium intake inhibits the production of nitric oxide; this effect is reversed by reducing salt intake. B) in obese subjects, the reduction of central adiposity and the correction of related metabolic abnormalities can alter the salt sensitivy, and thereby decrease blood pressure in salt-sensitive individuals. It also restores the normal bioactivity of nitric oxide. These findings confirm the important role of risk factors in the pathogenesis of salt sensitivy associated with obesity, and that the correction of abdominal fat improves metabolic abnormalities, leading to the lowering of salt sensitivy and to an improvement in the production of nitric oxide.

Lowering the threshold for defining microalbuminuria: effects of a lifestyle-metformin intervention in obese "normoalbuminuric" non-diabetic subjects.

BACKGROUND: We investigated whether levels of albuminuria (urinary albumin excretion (UAE)) below those conventionally accepted as microalbuminuria (<30 mg/day) are sensitive to correction of obesity and obesity-related risk factors. METHODS: The effects of a 12-month lifestyle modification-metformin program were evaluated in otherwise healthy overweight/obese "normoalbuminuric" subjects: group I with UAE of <10 mg/day (n = 23) and group II with UAE of 10-29 mg/day (n = 18). RESULTS: The subjects of group II were older and heavier, and had higher blood pressure (BP) and lower high-density lipoprotein (HDL) levels, than those of group I. Creatinine clearances were also higher in group II (148 +/- 14 ml/min) than in group I (108 +/- 9 ml/min). Although the intervention induced comparable reductions in obesity, BP, lipids and insulin levels in both groups, UAE was significantly reduced in group II (9.1 +/- 1.8 mg/24 h; 60% reduction; P < 0.001), and non-significantly in group I (0.75 +/- 0.5 mg/day; 12% reduction; P > 0.1). Additionally, greater reduction in creatinine clearance was observed in subjects with higher UAE rates. After the intervention, both groups achieved similar UAE rates (5.7 +/- 0.9 and 5.2 +/- 1.0 mg/day; P > 0.10). Basal UAE was related to the subjects' creatinine clearance (r = 0.38; P = 0.04). For both groups together, intervention-induced changes in UAE rates were not significantly related to BP, age, or body weight. However, for group II subjects, BP and UAE reduction were positively associated (r = 0.44; P = 0.03). CONCLUSIONS: UAE of 10-29 mg/day (hyperalbuminuria), below the conventionally used limit to define microalbuminuria, is already associated with a more adverse cardiovascular risk profile, and is exquisitely sensitive to interventions that reduce obesity, BP, and insulin resistance.

Alpha-adducin polymorphism, salt sensitivity, nitric oxide excretion, and cardiovascular risk factors in normotensive Hispanics.

BACKGROUND: Genetic and environmental factors determine the blood pressure (BP) response to changes in salt intake. Mutations in the alpha-adducin gene may be associated with hypertension and salt-sensitive hypertension. We investigated whether one alpha-adducin polymorphism, the Gly460Trp (G/T) variant, was associated with salt sensitivity, nitric oxide (NO) production; and cardiovascular risk factors in healthy adult normotensive Venezuelans. METHODS AND RESULTS: Subjects (n = 126) were screened for salt sensitivity. The alpha-Adducin polymorphism was tested in salt-sensitive (SS) and salt-resistant (SR) subjects. The G/T and G/G (wild gene) groups had similar BP levels. The G/T subjects had higher LDL-cholesterol (P =.01) and postload glucose AUC (P =.03) than G/G individuals. Genotype frequencies were not associated with BP or salt sensitivity (G/G, 38.1% SS and 61.9% SR vs G/T, 40.7% SS and 59.3% SR). Shifting from high salt to low salt diet produced comparable reductions in systolic BP and diastolic BP in G/T and G/G groups. The G/G and G/T groups excreted similar amounts of sodium on high and low salt diets. The SR subjects carrying the wild or the mutated gene showed no changes in NO metabolite excretion at different levels of salt intake. In SS subjects, the level of NO metabolite excretion was highly dependent on salt intake. A combination of SS and 460Trp mutation enhanced the sodium-dependent modulation of NO production. CONCLUSIONS: In normotensive Venezuelans, the alpha-adducin G/T polymorphism was not associated with BP, salt sensitivity, or with sodium excretion during sodium loading or restriction. G/T was associated with increased LDL-cholesterol and postload glucose levels. In SS, G/T was associated with greater salt-dependent modulation of NO excretion. However, this larger increase in NO excretion was not associated with a larger decrease in BP.

QT prolongation and fatal arrhythmias: a review of clinical implications and effects of drugs.

A long QT interval due to prolonged repolarization may be associated with a polymorphic ventricular tachycardia known as torsades de pointes. During marked prolongation of the action potential (long QT) early after depolarizations may occur, which when propagated may trigger an arrhythmia. The duration of QTc interval is the major determinant of the risk of drug-induced torsades. Congenital long QT syndrome, female gender, hypokalemia and use of sympathomimetics increase the risk of torsades, and potentiate the QT prolonging effects of drugs. Antiarrhythmics that block the potassium channel prolong the QT and increase the risk for torsades (amiodarone, sotalol, quinidine, procainamide, ibutilide, disopyramide). Additionally, some macrolide and fluoroquinolone antibiotics, antipsychotic and antidepressant drugs, serotonin agonists of the triptan class, cisapride, dolasetron and others have been reported to be associated with QT prolongation or cases of torsades. Drug-induced effects on the QT interval with the associated possibility of inducing fatal arrhythmias have become a new challenge for the practitioner, the drug development process and the regulatory agencies.

Ondansetron and metformin-induced gastrointestinal side effects.

Treatment with metformin is associated with a high incidence of gastrointestinal side effects of unknown mechanism. Metformin is a biguanide derivative, which resembles 5-HT3-receptor agonists in its structure. Activation of 5-HT3 receptors is known to induce nausea, vomiting, and diarrhea. In this study, we investigated if the gastrointestinal side effects produced by metformin were antagonized by ondansetron, a selective antagonist of 5-HT3 receptors. Patients experiencing gastrointestinal side effects were randomized to ondansetron (4 mg bid p.o.) or placebo while maintained on metformin (double-blind, parallel-group design). If side effects persisted or worsened, metformin was discontinued and the patient considered a therapeutic failure. Of the 98 subjects treated with metformin, 22 developed side effects to match the study entry criteria. Diarrhea was the most frequent side effect. Subjects were randomized to ondansetron (10/2 F/M, 42.8 +/- 2.3 years, 28.6 +/- 1.1 kg/m2, 2585 +/- 35 mg/d metformin) or placebo (9/1 F/M, 43 +/- 4.3 years, 29.7 +/- 1.8 kg/m2, 2715 +/- 71 mg/d metformin). Ondansetron showed no efficacy against metformin-induced side effects. A comparable number of therapeutic failures were observed in ondansetron (8/12; 66%) and placebo-treated subjects (5/10; 50%) (P<0.1). Mean nausea scores (numeric analog scale) before and during treatment with ondansetron were 6.3 +/- 1 and 6.9 +/- 1 cm, respectively. Nausea scores averaged 7.3 +/- 1.5 and 5.9 +/- 1.5 cm, before and during treatment with placebo (P>0.1). In conclusion, 5-HT3 receptors do not seem to play a role in metformin-induced gastrointestinal side effects.

Role of salt sensitivity, blood pressure, and hyperinsulinemia in determining high upper normal levels of urinary albumin excretion in a healthy adult population.

BACKGROUND: The objective of this study was to investigate the role of blood pressure (BP), salt sensitivity (SS), and the cardiovascular metabolic syndrome in determining the urinary albumin excretion (UAE) in glucose-tolerant, normoalbuminuric (<20 mg/day) healthy adults. METHODS AND RESULTS: We evaluated 177 healthy subjects (age, 38.3 +/- 0.9 years; weight, 75.2 +/- 1.1 kg; body mass index, 28.8 +/- 0.4 kg/m(2); systolic BP, 117 +/- 1 mm Hg; diastolic BP, 77.5 +/- 0.8 mm Hg; UAE, 8.2 +/- 0.3 mg/24 h). Subjects with UAE levels of 15 to 20 mg/day had higher systolic BP, diastolic BP, and pulse pressures than those with UAE levels less than 15 mg/day (P <.0001). Hypertension (HT) and SS were more prevalent in the high normal UAE group (15 to 20 mg/day) than in groups with lower UAE (47% v 8% for HT and 67% v 24% for SS). In normotensives (n = 156), no differences in BP were observed among the different UAE strata; yet, the prevalence of SS was greater in the high (57%) compared to the low normal (17% to 21%) UAE groups. Similar levels of UAE, BP, and similar prevalence of SS were found in men with and without abdominal obesity, despite the fact that obesity was associated with hypertriglyceridemia and hyperinsulinemia. CONCLUSIONS: In healthy normoalbuminuric adults, high normal UAE is associated with SS in normotensives and with SS and higher BP in a mixed population (88% normotensive and 12% hypertensive). Abdominal obesity, hypertriglyceridemia, and hyperinsulinemia were not related to UAE. Therefore, UAE levels of 15 to 20 mg/day should be accepted as microalbuminuria, and these subjects may benefit from early intervention (ie, salt restriction and BP lowering).

The selective serotonin reuptake inhibitor citalopram induces the storage of serotonin in catecholaminergic terminals.

We investigated whether selective inhibition of serotonin (5-hydroxytryptamine; 5-HT) transporter with citalopram leads to accumulation of 5-HT in catecholaminergic neurons. In the rabbit olfactory tubercle, citalopram (1-10 microM) inhibited [(3)H]5-HT uptake; however, the maximal degree of inhibition achieved was 70%. Addition of nomifensine (1-10 microM) was required for complete inhibition of [(3)H]5-HT uptake. In slices labeled with 0.1 microM [(3)H]5-HT, cold 5-HT (0.03-1 microM) induced a large increase in the efflux (release) of stored [(3)H]5-HT, an effect blocked by coperfusion with 1 microM citalopram. Similar concentrations (0.03-1 microM) of norepinephrine (NE) or dopamine (DA) failed to release [(3)H]5-HT. When labeling with 0.1 microM [(3)H]5-HT was carried out in the presence of citalopram, 1) low concentrations of 5-HT failed to release [(3)H]5-HT; 2) DA and NE were more potent and effective in releasing [(3)H]5-HT than in control slices; 3) coperfusion of NE, DA, or 5-HT with citalopram enhanced the release of [(3)H]5-HT induced by the catecholamines but not by 5-HT; and 4) coperfusion of NE or DA with nomifensine antagonized NE- and DA-evoked [(3)H]5-HT release, with a greater effect on NE than on DA. These results suggest that in the rabbit olfactory tubercle, where there is coexistence of 5-HT, NE, and DA neurons, inhibition of the 5-HT transporter led to accumulation of 5-HT in catecholaminergic terminals. Thus, during treatment with selective serotonin uptake inhibitors (SSRIs), 5-HT may be stored in catecholaminergic neurons acting as a false neurotransmitter and/or affecting the disposition of DA and/or NE. Transmitter relocation may be involved in the antidepressant action of SSRIs.

Treatment with 7-nitroindazole enhances kainic acid induced cholinergic neurotoxicity in the rat striatum: a neuroprotective role for neuronal nitric oxide.

1. In this study we investigated the effect of 7-nitroindazole (7-NI), a preferential inhibitor of neuronal nitric oxide synthase (nNOS), on kainic acid (KA) induced neurotoxicity in rats. Choline acetyltransferase activity (CAT), a cholinergic marker, and histological changes were employed to assess neurotoxicity. 2. In control rats, the local intrastriatal injection of 0.5 microg of KA reduced CAT from 22.9 +/- 2.2 to 14.7 +/- 2.0 nmol/h/mg tissue ((38 +/- 6)% reduction) (P < 0.001). Greater reductions in CAT were observed with 1 and 2 microg of KA ((70 +/- 6)% and (80 +/- 3)%, respectively). 7-NI aggravated KA-induced cholinergic and histological damage. KA reduced CAT by (68.2 +/- 4)% in 7-NI-treated rats, by (38 +/- 6)% in saline-treated controls, and by (41 +/- 4)% in peanut-oil- (7-NI-vehicle-) treated rats (P = 0.0047). 3. After KA, CAT activity averaged 14.3 +/- 2.0 in peanut-oil-treated rats and 7.9 +/- 1.0 nmol/h/mg tissue in 7-NI- (peanut-oil-) treated rats (P = 0.015). Similarly to changes in CAT, 7-NI treatment aggravated KA-induced histological changes indicative of neuronal damage (acute ischemic neuronal changes, disorganization of myelinated fibers bundle, and vacuolation changes of the neuropil). Treatment with 7-NI was not associated with increased mortality. 4. Our findings suggest that neuronal NO plays a neuroprotective action on excitotoxicity.

Lesion of caudate-putamen interneurons with kainic acid alters dopamine and serotonin metabolism in the olfactory tubercle of the rat.

1. The existence of functional interrelationships between dorsal and ventral regions of the rat striatum was investigated. Kainic acid (KA) was employed to induce neuronal lesions in the more dorsal striatum, the caudate-putamen (CP). Only one CP (one side) received KA. KA-induced neurotoxicity at the site of injection (CP) was evidenced by reductions in choline-acetyltransferase activity and in GABA levels, and by increases in the ratios metabolite/monoamine for dopamine (DA) and serotonin (5-HT). 2. In addition to the well-known local effects, direct stereotaxic injection of KA into the CP produced distant effects in the ipsilateral olfactory tubercle (OT). A dose-dependent increase in the levels of 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) and decreases in DA and 5-HT concentrations were observed in the OT ipsilateral to the CP injected with KA. With 1, 2, 3, and 4 microg of KA, the ratio DOPAC+HVA/DA in the OT was 30, 79, 140, and 173% higher, respectively, than control levels. With 2, 3, and 4 microg of KA, the levels of 5-HIAA were approximately 30, 60, and 120% higher than control values, and the changes in 5-HIAA were associated with significant reductions in 5-HT concentrations. 3. Our results suggest that the dorsal part of the striatum exerts important regulatory functions over the most ventral striatal region, the OT. Destruction of CP interneurons by KA leads to disinhibition of DA and 5-HT activities to the OT. The functional interactions between dorsal and ventral striatal regions may play a role in the integration of fundamental life-preserving, motivational, and goal-directed olfactory motor behaviors of rodents.