Late-onset Bartter syndrome type II.

Mutations in the ROMK1 potassium channel gene () cause antenatal/neonatal Bartter syndrome type II (aBS II), a renal disorder that begins , accounting for the polyhydramnios and premature delivery that is typical in affected infants, who develop massive renal salt wasting, hypokalaemic metabolic alkalosis, secondary hyperreninaemic hyperaldosteronism, hypercalciuria and nephrocalcinosis. This BS type is believed to represent a disorder of the infancy, but not in adulthood. We herein describe a female patient with a remarkably late-onset and mild clinical manifestation of BS II with compound heterozygous missense mutations, consisting of a novel c.

Branched-chain amino acid catabolism rather than amino acids plasma concentrations is associated with diet-induced changes in insulin resistance in overweight to obese individuals.

Background & Aims: 3-Hydroxyisobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, which stimulates muscle fatty acid uptake, has been implicated in the pathogenesis of insulin resistance. We tested the hypothesis that circulating 3-HIB herald insulin resistance and that metabolic improvement with weight loss are related to changes in BCAAs and 3-HIB.

Methods And Results: We analyzed plasma and urine in 109 overweight to obese individuals before and after six months on hypocaloric diets reduced in either carbohydrates or fat.

Branched-chain and aromatic amino acids, insulin resistance and liver specific ectopic fat storage in overweight to obese subjects.

Background & Aims: Amino acids may interfere with insulin action, particularly in obese individuals. We hypothesized that increased circulating branched-chain and aromatic amino acids herald insulin resistance and ectopic fat storage, particularly hepatic fat accumulation.

Methods And Results: We measured fasting branched-chain and aromatic amino acids (tryptophan, tyrosine, and phenylalanine) by mass spectrometry in 111 overweight to obese subjects.

Aliskiren penetrates adipose and skeletal muscle tissue and reduces renin-angiotensin system activity in obese hypertensive patients.

Objective: In animals, the direct renin inhibitor aliskiren showed extensive tissue binding in the kidney and long-lasting renal effects. Aliskiren provides prolonged blood pressure-lowering effects following treatment discontinuation in patients. Therefore, we investigated whether aliskiren attains tissue concentrations sufficient to inhibit local renin-angiotensin system (RAS) activity in patients.

Left ventricular mass and function with reduced-fat or reduced-carbohydrate hypocaloric diets in overweight and obese subjects.

In animals, carbohydrate and fat composition during dietary interventions influenced cardiac metabolism, structure, and function. Because reduced-carbohydrate and reduced-fat hypocaloric diets are commonly used in the treatment of obesity, we investigated whether these interventions differentially affect left ventricular mass, cardiac function, and blood pressure. We randomized 170 overweight and obese subjects (body mass index, 32.

Variations in truncal body circumferences affect fat mass quantification with bioimpedance analysis.

Objective: To test the hypothesis that variations in trunk circumferences influence the accuracy of bioimpedance analysis (BIA) for assessment of percent fat mass (%FM).

Subjects And Methods: %FM was predicted with BIA, and compared with air-displacement plethysmography (ADP) in a small sample of 35 overweight (OW), 21 normal weight and 8 underweight volunteers. Waist and hip circumferences were assessed, and 15 of the OW subjects were measured before and after weight reduction.

Cardiorespiratory fitness and insulin sensitivity in overweight or obese subjects may be linked through intrahepatic lipid content.

Objective: Low cardiorespiratory fitness (CRF) predisposes one to cardiovascular disease and type 2 diabetes in part independently of body weight. Given the close relationship between intrahepatic lipid content (IHL) and insulin sensitivity, we hypothesized that the direct relationship between fitness and insulin sensitivity may be explained by IHL.

Research Design And Methods: We included 138 overweight to obese, otherwise healthy subjects (aged 43.

Neurohumoral and metabolic response to exercise in water.

Atrial natriuretic peptide (ANP) stimulates lipid mobilization and lipid oxidation in humans. The mechanism appears to promote lipid mobilization during exercise. We tested the hypothesis that water immersion augments exercise-induced ANP release and that the change in ANP availability is associated with increased lipid mobilization and lipid oxidation.

LMNA mutations, skeletal muscle lipid metabolism, and insulin resistance.

Context: Type 2 familial partial lipodystrophy (FPLD) is an autosomal-dominant lamin A/C-related disease associated with exercise intolerance, muscular pain, and insulin resistance. The symptoms may all be explained by defective metabolism; however, metabolism at the tissue level has not been investigated.

Objective: We hypothesized that in FPLD, insulin resistance and impaired aerobic exercise capacity are explained by a common underlying mechanism, presumably a muscular metabolic defect.

Determinants of exercise-induced fat oxidation in obese women and men.

Endurance training at an intensity eliciting maximal fat oxidation may have a beneficial effect on body weight and glucose metabolism in obese patients. However, the exercise intensity at which maximal fat oxidation occurs and the factors limiting fat oxidation are not well studied in this population. Obese, otherwise healthy men (n=38) and women (n=91) performed an incremental exercise test up to exhaustion on a cycle ergometer.

Circulating endocannabinoid concentrations during orthostatic stress.

Background: In animals, the endocannabinoid system is activated during hemodynamic insults and restrains blood pressure in part through sympathetic inhibition.

Materials And Methods: We tested the hypothesis that hemodynamic stress elicited by head-up tilt testing increases systemic endocannabinoid concentrations in humans and that excessive endocannabinoid availability predisposes to presyncope.

Results: With head-up tilt, 2-arachidonoylglycerol increased, whereas anandamide remained unchanged.

Influences of normobaric hypoxia training on physical fitness and metabolic risk markers in overweight to obese subjects.

Previous studies suggested that hypoxia and exercise may have a synergistic effect on cardiovascular and metabolic risk factors. We conducted a single blind study in overweight to obese subjects to test the hypothesis that training under hypoxia (HG, n = 24, FiO(2) = 15%) results in similar or even greater improvement in body weight and metabolic risk markers compared with exercise under normoxia (NG, n = 21, FiO(2) = 21%). After an initial metabolic evaluation including incremental exercise testing, subjects trained in normoxic or hypoxic conditions thrice weekly over a 4-week period at a heart rate corresponding to 65% of maximum oxygen uptake (VO(2max)).

Energy metabolism in human renin-gene transgenic rats: does renin contribute to obesity?

Renin initiates angiotensin II formation and has no other known functions. We observed that transgenic rats (TGR) overexpressing the human renin gene (hREN) developed moderate obesity with increased body fat mass and glucose intolerance compared with nontransgenic Sprague-Dawley (SD) rats. The metabolic changes were not reversed by an angiotensin-converting enzyme inhibitor, a direct renin inhibitor, or by (pro)renin receptor blocker treatment.

Dipeptidyl-peptidase-IV inhibition augments postprandial lipid mobilization and oxidation in type 2 diabetic patients.

Context: Dipeptidyl-peptidase-IV (DPP-4) inhibition increases endogenous GLP-1 activity, resulting in improved glycemic control in patients with type 2 diabetes mellitus. The metabolic response may be explained in part by extrapancreatic mechanisms.

Objective: We tested the hypothesis that DPP-4 inhibition with vildagliptin elicits changes in adipose tissue and skeletal muscle metabolism.

The Valsalva maneuver: screening for drug-induced baroreflex dysfunction.

Objective: Many drugs can interfere with baroreflex mechanisms thereby impairing blood pressure control, but few have undergone sufficient testing. The state of affairs may be explained by the lack of simple and inexpensive screening tests.

Methods: In eleven healthy men, we tested the hypothesis that a simple Valsalva maneuver could detect drug-induced changes in baroreflex function that have previously been described using more elaborate and invasive methodologies.

Influences of normobaric hypoxia training on metabolic risk markers in human subjects.

Purpose: Endurance exercise and hypoxia regulate pathways that are crucial to glucose and lipid metabolism. We hypothesized that training under hypoxia results in similar or even greater metabolic improvement compared with exercise under normoxia at a lower workload.

Methods: We randomly assigned 20 healthy men to single blind training under hypoxia (FiO2 = 15%) or normoxia (FiO2 = 21%).

Dysregulation of the endocannabinoid system in obesity.

An activation of the endocannabinoid system (ECS) in obesity with increased concentrations of endocannabinoids in several tissues and in the circulation is described in this review. This increased availability of endocannabinoids might stimulate cannabinoid receptors in a pathophysiological manner. The successful use of the cannabinoid receptor CB(1) inverse agonists rimonabant and taranabant for weight loss and the treatment of obesity-associated metabolic disorders might well be through blocking this overstimulation of cannabinoid receptors.

Peripheral endocannabinoid system activity in patients treated with sibutramine.

Objective: The endocannabinoid system (ECS) promotes weight gain and obesity-associated metabolic changes. Weight loss interventions may influence obesity-associated risk indirectly through modulation of the peripheral ECS. We investigated the effect of acute and chronic treatment with sibutramine on components of the peripheral ECS.

Hormonal influences on cardiovascular norepinephrine transporter responses in healthy women.

Gender differences in human cardiovascular norepinephrine transporter function may be mediated through female sex hormones. We studied 16 healthy eumenorrheic women (25+/-1 years) during the early follicular phase (day 5+/-0) and midluteal phase (day 22+/-0) of the menstrual cycle. In a randomized, crossover, double-blind fashion, subjects ingested 8 mg of the selective norepinephrine transporter inhibitor reboxetine or placebo.

Norepinephrine transporter inhibition alters the hemodynamic response to hypergravitation.

Sympathetically mediated tachycardia and vasoconstriction maintain blood pressure during hypergravitational stress, thereby preventing gravitation-induced loss of consciousness. Norepinephrine transporter (NET) inhibition prevents neurally mediated (pre)syncope during gravitational stress imposed by head-up tilt testing. Thus it seems reasonable that NET inhibition could increase tolerance to hypergravitational stress.

Peripheral metabolic effects of endocannabinoids and cannabinoid receptor blockade.

The endocannabinoid system consists of endogenous arachidonic acid derivates that activate cannabinoid receptors. The two most prominent endocannabinoids are anandamide and 2-arachidonoyl glycerol. In obesity, increased concentrations of circulating and tissue endocannabinoid levels have been described, suggesting increased activity of the endocannabinoid system.

Yohimbine attenuates baroreflex-mediated bradycardia in humans.

Alpha-2 adrenoreceptor stimulation profoundly augments baroreflex-mediated bradycardia presumably through parasympathetic activation. We tested the hypothesis that endogenous alpha-2 adrenergic tone mediates a similar response. In 10 healthy men (age: 33+/-3 years; body mass index: 24+/-1.

Metabolic regulation: effects of natriuretic peptide interactions.

In addition to their well-established effects on blood pressure and volume homeostasis, natriuretic peptides have complex effects on carbohydrate and lipid metabolism. In vivo, pharmacological and physiological concentrations of atrial natriuretic peptides induce lipolysis in a concentration-dependent manner and increase the lipid oxidation rate. The response appears to be mediated through the stimulation of natriuretic peptide receptor-A.

Stimulation of cholecystokinin-A receptors with GI181771X does not cause weight loss in overweight or obese patients.

Cholecystokinin (CCK) decreases meal size through activation of CCK-A receptors on vagal afferents. We tested the hypothesis that the selective CCK-A agonist GI181771X induces weight loss in obese patients. Patients with body mass index > or = 30 or > or = 27 kg/m2 with concomitant risk factors were randomized to 24-week, double-blind treatment with different GI181771X doses or matching placebo together with a hypocaloric diet.

Water drinking induces thermogenesis through osmosensitive mechanisms.

Context: Recently, we showed that drinking 500 ml water induces thermogenesis in normal-weight men and women.

Objective: We now repeated these studies in a randomized, controlled, crossover trial in overweight or obese otherwise healthy subjects (eight men and eight women), comparing also the effects of 500 ml isoosmotic saline or 50 ml water.

Results: Only 500 ml water increased energy expenditure by 24% over the course of 60 min after ingestion, whereas isoosmotic saline and 50 ml water had no effect.