RESUMEN
Genetic defects are often still regarded as a life-long fate, which one has to cope with. It is true that in many cases an inherited disposition may lead to a severe disease; however, it is also true that the number of genetic defects with a treatment option is continuously increasing and in some of them the onset of disease symptoms can even be totally prevented. Knowledge of the precise molecular pathomechanism is often the basis for a treatment concept. Genome-wide sequencing has tremendously increased the possibility to identify a genetic defect and its broad application has meanwhile made a decisive contribution in routine diagnostics. After identifying a genetic alteration, it is still necessary to investigate the pathobiochemical consequences on the cellular and systemic level. This can be a time-consuming process since not all functional consequences can be immediately recognized. In the case of metabolic defects the treatment strategy can either be a supplementation of missing products or a removal of toxic substrates. The residual function of affected pathways can also often be improved. Recently, the direct correction of the affected genetic defects has become a treatment option for a selected number of diseases. As the first symptoms of disease usually occur early in life, pediatrics has a pioneering role in developing treatment strategies.
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BACKGROUND: Pharmacological treatment options for adolescents with obesity are very limited. Glucagon-like-peptide-1 (GLP-1) receptor agonist could be a treatment option for adolescent obesity. OBJECTIVE: To investigate the effect of exenatide extended release on body mass index (BMI)-SDS as primary outcome, and glucose metabolism, cardiometabolic risk factors, liver steatosis, and other BMI metrics as secondary outcomes, and its safety and tolerability in adolescents with obesity. METHODS: Six-month, randomized, double-blinded, parallel, placebo-controlled clinical trial in patients (n = 44, 10-18 years, females n = 22) with BMI-SDS > 2.0 or age-adapted-BMI > 30 kg/m2 according to WHO were included. Patients received lifestyle intervention and were randomized to exenatide extended release 2 mg (n = 22) or placebo (n = 22) subcutaneous injections given once weekly. Oral glucose tolerance tests (OGTT) were conducted at the beginning and end of the intervention. RESULTS: Exenatide reduced (P < .05) BMI-SDS (-0.09; -0.18, 0.00), % BMI 95th percentile (-2.9%; -5.4, -0.3), weight (-3 kg; -5.8, -0.1), waist circumference (-3.2 cm; -5.8, -0.7), subcutaneous adipose tissue (-552 cm3 ; -989, -114), 2-hour-glucose during OGTT (-15.3 mg/dL; -27.5, -3.1), total cholesterol (11.6 mg/dL; -21.7, -1.5), and BMI (-0.83 kg/m2 ; -1.68, 0.01) without significant change in liver fat content (-1.36; -3.12, 0.4; P = .06) in comparison to placebo. Safety and tolerability profiles were comparable to placebo with the exception of mild adverse events being more frequent in exenatide-treated patients. CONCLUSIONS: Treatment of adolescents with severe obesity with extended-release exenatide is generally well tolerated and leads to a modest reduction in BMI metrics and improvement in glucose tolerance and cholesterol. The study indicates that the treatment provides additional beneficial effects beyond BMI reduction for the patient group.
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Fármacos Antiobesidad/uso terapéutico , Exenatida/uso terapéutico , Obesidad Infantil/tratamiento farmacológico , Adolescente , Índice de Masa Corporal , Niño , Método Doble Ciego , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Masculino , Obesidad Infantil/metabolismoRESUMEN
INTRODUCTION: As a small proportion of obese individuals do not develop metabolic complications and non-alcoholic fatty liver disease (NAFLD), this study aimed to provide a comprehensive clinical, metabolic and genetic description of obese subjects with healthy livers. METHODS: A total of 183 subjects were stratified, according to BMI, presence of metabolic syndrome, biochemical liver tests and hepatic steatosis on ultrasound, into: (i) lean controls (n = 69); (ii) obese healthy (n = 50); and (iii)obese NAFLD (n = 62) groups. Detailed clinical, genetic and metabolic evaluations were then performed. RESULTS: Obese healthy subjects did not differ in glucose parameters from lean controls, and had a lower rate of minor TM6SF2 gene variants compared with obese NAFLD (2/49 vs. 11/60, respectively; P = 0.035) and lean controls (13/64; P = 0.035), but significantly higher leptin concentrations than lean controls (P < 0.001); they also higher adiponectin concentrations (P < 0.001), and lower TNF-α and IL-6 concentrations (P = 0.01 and P < 0.001, respectively), than obese NAFLD subjects. Also, metabolomic studies identified ether- and ester-containing phospholipids [PC ae C44:6, PC ae C42:5, PC aa C40:4; P < 0.001, corrected by the false discovery rate (FDR) method] and found that the amino-acids lysine, glycine and isoleucine (FDR < 0.001) differed between the two obese groups, but not between lean controls and obese healthy subjects. CONCLUSION: Obese people with healthy livers are characterized by intact glucose homoeostasis, lower pro-inflammatory cytokine levels, and higher adiponectin and leptin concentrations compared with obese people with NAFLD. In addition, the major allele of TM6SF2, a set of phosphatidylcholines and several amino acids are associated with healthy livers in obesity.
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Síndrome Metabólico/metabolismo , Metaboloma , Metabolómica/métodos , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Obesidad Metabólica Benigna/metabolismo , Obesidad/metabolismo , Anciano , Estudios de Casos y Controles , Conducta Alimentaria , Femenino , Humanos , Estilo de Vida , Masculino , Síndrome Metabólico/complicaciones , Síndrome Metabólico/epidemiología , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Obesidad/complicaciones , Obesidad/epidemiología , Obesidad Metabólica Benigna/epidemiología , Obesidad Metabólica Benigna/patologíaRESUMEN
BACKGROUND: Obesity is associated with non-alcoholic fatty liver disease (NAFLD), and the patatin-like phospholipase 3 (PNPLA3) rs738409 (Ile148Met, C>G) gene polymorphism is one of the most important genetic determinants of NAFLD. Carriers have been reported to better respond to lifestyle modification. AIM: To investigate the effect of rs738409 on overweight/obese adolescents and adults with and without metabolic syndrome (MetS). METHODS: Two hundred and eighty-eight overweight/obese and 209 normal weight participants of the STYJOBS/EDECTA cohort (NCT00482924) were analysed for PNPLA3 genotypes. RESULTS: Compared to overweight/obese without MetS, in overweight/obese study participants with MetS, the presence of the G allele (148Met) was significantly higher (CC: 5.0% vs. 9.2%, Spearman's correlation, 0.12; P = 0.038). Persons with CG (heterozygote for the risk allele) and with GG (homozygote for the risk allele) genotypes showed significantly higher ALT levels than those with CC genotypes. Even young individuals aged below 20 years had significantly increased ALT levels if they were homozygote with the G allele. CONCLUSIONS: The PNPLA3 rs738409 polymorphism is associated already in youths with increased ALT, and is more frequent in obese with MetS of all ages. Hence, overweight/obese rs738409 carriers should be identified early in life and treated with a rigorous life style intervention.
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Lipasa/genética , Proteínas de la Membrana/genética , Síndrome Metabólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/genética , Obesidad/genética , Adolescente , Adulto , Anciano , Alelos , Estudios de Casos y Controles , Niño , Femenino , Genotipo , Heterocigoto , Humanos , Estilo de Vida , Masculino , Síndrome Metabólico/genética , Persona de Mediana Edad , Obesidad/complicaciones , Polimorfismo Genético , Estudios Prospectivos , Adulto JovenRESUMEN
OBJECTIVE: Obesity triggers an inflammatory response characterized by elevated circulating pro-inflammatory adipokines that predisposes to T2DM and cardiovascular disease. The objective of our study was to determine a potential association of adipokine plasma profile and the presence of a MetS in obese children and adolescents compared to adults. DESIGN AND METHODS: We determined serum levels of the adipokines soluble CD163 (sCD163), fetuin-A, osteopontin (OPN) and interleukin-1 receptor antagonist (IL-1 Ra) in 30 pediatric and 36 adult obese patients in a cross-sectional study. RESULTS: Serum concentrations of all tested adipokines except sCD163 were significantly elevated in the pediatric cohort compared to adults. Patients with MetS showed increased serum levels of sCD163, fetuin-A and IL-1 Ra levels compared to those without MetS. Fetuin-A and sCD163 remained significantly elevated by MetS within the juvenile group and borderline significant in the adults when tested separately. In the pediatric cohort we found correlations between sCD163 and fetuin-A as well as OPN and IL-1 Ra whereas correlations of sCD163 and both fetuin-A and IL-1 Ra were found in the adult group. CONCLUSION: Our results indicate that adipokine profiles related to the presence of MetS significantly differ between pediatric and adult patients which may point to different underlying mechanisms.
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Adipoquinas/sangre , Síndrome Metabólico/sangre , Obesidad/sangre , Adolescente , Adulto , Factores de Edad , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Atherosclerosis (AS), a major pathologic consequence of obesity, is the main etiological factor of cardiovascular disease (CVD), which is the most common cause of death in the western world. A systemic chronic low grade immune- mediated inflammation (scLGI) is substantially implicated in AS and its consequences. In particular, proinflammatory cytokines play a major role, with Th1-type cytokine interferon-γ (IFN-γ) being a key mediator. Among various other molecular and cellular effects, IFN-γ activates the enzyme indoleamine 2,3-dioxygenase (IDO) in monocyte-derived macrophages, dendritic, and other cells, which, in turn, decreases serum levels of the essential amino acid tryptophan (TRP). Thus, people with CVD often have increased serum kynurenine to tryptophan ratios (KYN/TRP), a result of an increased TRP breakdown. Importantly, increased KYN/TRP is associated with a higher likelihood of fatal cardiovascular events. A scLGI with increased production of the proinflammatory adipokine leptin, in combination with IFN-γ and interleukin-6 (IL-6), represents another central link between obesity, AS, and CVD. Leptin has also been shown to contribute to Th1-type immunity shifting, with abdominal fat being thus a direct contributor to KYN/TRP ratio. However, TRP is not only an important source for protein production but also for the generation of one of the most important neurotransmitters, 5-hydroxytryptamine (serotonin), by the tetrahydrobiopterin-dependent TRP 5-hydroxylase. In prolonged states of scLGI, availability of free serum TRP is strongly diminished, affecting serotonin synthesis, particularly in the brain. Additionally, accumulation of neurotoxic KYN metabolites such as quinolinic acid produced by microglia, can contribute to the development of depression via NMDA glutamatergic stimulation. Depression had been reported to be associated with CVD endpoints, but it most likely represents only a secondary loop connecting excess adipose tissue, scLGI and cardiovascular morbidity and mortality. Accelerated catabolism of TRP is further involved in the pathogenesis of the anemia of scLGI. The pro-inflammatory cytokine IFN-γ suppresses growth and differentiation of erythroid progenitor cells, and the depletion of TRP limits protein synthesis and thus hemoglobin production, and, through reduction in oxygen supply, may contribute to ischemic vascular disease. In this review we discuss the impact of TRP breakdown and the related complex mechanisms on the prognosis and individual course of CVD. Measurement of TRP, KYN concentrations, and calculation of the KYN/TRYP ratio will contribute to a better understanding of the interplay between inflammation, metabolic syndrome, mood disturbance, and anemia, all previously described as significant predictors of an unfavorable outcome in patients with CVD. The review leads to a novel framework for successful therapeutic modification of several cardinal pathophysiological processes leading to adverse cardiovascular outcome.
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Enfermedades Cardiovasculares/metabolismo , Triptófano/metabolismo , Envejecimiento , Animales , Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/fisiopatología , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatología , Humanos , Inflamación/complicaciones , Inflamación/metabolismo , Trastornos del Humor/complicaciones , Trastornos del Humor/metabolismo , Sepsis/complicaciones , Sepsis/metabolismoRESUMEN
UNLABELLED: The present study was conducted to evaluate the burden of pneumococcal meningitis in Austrian children between 2001 and 2008. Clinical outcome was retrospectively analyzed both on discharge and on follow-up investigations. This study was based on a prospective multicentre surveillance study on hospitalized invasive pneumococcal infections in Austrian children with a total annual "study population" of about 399,000 children aged below 5 years per year. Between 2001 and 2008, 74 cases of pneumococcal meningitis were identified in children aged below 5 years. The mean annual incidence rate for pneumococcal meningitis was 2.3 per 100,000 children in this age group. In 57/74 children (mean age on admission 14.5 ± 13.3 months), outcome data on hospital discharge were available: 5 deaths (8.8%), 20 children (35.1%) with sequelae and 32 children (56.1%) without sequelae were observed. Sequelae on discharge included motor impairment in 8 children (14.0%), hearing impairment in 9 children (15.8%) and/or other complications in 14 children (24.6%). In 7/8 children with motor deficits, matching cerebral lesions were identified by neuroimaging: cerebral infarction in five children, cerebral vasculitis and cerebral abscess in one child each. In 40/57 children, long-term outcome (18.9 ± 20.2 months after discharge) could be assessed: 1 child (2.5%) died 9 months after hospital discharge, 11 children (27.5%) had one or two long-term sequelae and 28 children (70.0%) had no sequelae. Long-term sequelae included motor impairment in three children (7.5%), hearing impairment in nine children (22.5%) and other deficits in two children (5.0%). CONCLUSION: Our study confirms that pneumococcal meningitis causes high mortality and severe long-term sequelae. On long-term follow-up, we observed improvements of motor impairment, but not of hearing impairment.
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Meningitis Neumocócica/epidemiología , Streptococcus pneumoniae/aislamiento & purificación , Adolescente , Austria/epidemiología , Niño , Preescolar , Femenino , Estudios de Seguimiento , Hospitalización , Humanos , Incidencia , Lactante , Masculino , Meningitis Neumocócica/microbiología , Meningitis Neumocócica/mortalidad , Pronóstico , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
The obesity prevalence is growing worldwide and largely responsible for the increased incidence of cardiovascular disease, the most common cause of death in the western world. Excessive food intake along with insufficient physical exercise is the basic impetus for this development. The obese state is commonly associated with an increase in leptin levels and chronic immune-mediated inflammation. Despite high leptin levels, the leptin response, normally associated with satiety and satiation, seems to be impaired and individuals continue to consume calorie-rich food. Antioxidant food additives such as sodium sulphite, sodium benzoate and curcumin were shown to suppress the leptin release in lipopolysaccharide- treated murine adipocytes. Based on this, we hypothesize that the insufficient leptin release, caused by excessive consumption of food additives, may lead to a reduced exposure of the central nervous system to leptin and ultimately propagate obesity. On the other hand, leptin has been shown to favor Th1-type activity, which ultimately decreases tryptophan levels. Tryptophan derivatives, serotonin and melatonin, induce satiety/satiation through several mechanisms. In this context, the antioxidant suppression of leptin release and Th1-type activity is beneficial to increase serotonin and melatonin levels. The molecules in the mechanism described in this review are highly integrated in the reward system, and have been implicated in the addiction behavior of obesity. Based on these facts, the involvement of antioxidant food supplements in the mechanisms of the reward-deficiency syndrome which perpetuates obesity will be discussed.
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Antioxidantes/efectos adversos , Aditivos Alimentarios/efectos adversos , Leptina/inmunología , Obesidad/inmunología , Inmunidad Adaptativa , Animales , Humanos , Inflamación/complicaciones , Inflamación/etiología , Inflamación/inmunología , Obesidad/complicaciones , Obesidad/etiologíaRESUMEN
BACKGROUND: Since obesity and its associated co-morbidities do not only have effect on the individual patient, but also on society and the health system, it is of great importance to investigate this lifestyle-disease. The rationale of this study was to distinguish metabolically healthy from unhealthy overweight/obese patients as compared to healthy normal weight children and adolescents by means of a comprehensive anthropometric, laboratory and sonomorphological vascular assessment. MATERIALS AND METHODS: 299 study participants were derived from the prospective, observational study STYJOBS/EDECTA (STYrian Juvenile Obesity Study/Early DEteCTion of Arteriosclerosis). Standard anthropometric data were obtained for each subject. This study comprised different diagnostic steps: extended anthropometry (Lipometer®), carotid artery ultrasound, various laboratory measurements, blood pressure measurement, oral glucose tolerance test. Ow/ob juveniles were classified as "metabolically healthy" (no laboratory criteria of metabolic syndrome fulfilled) vs. "metabolically unhealthy" (≥ 3 criteria of metabolic syndrome). Results underwent statistical evaluation, including t-test or Mann-Whitney U-test, regression analysis and a p-value < 0.05 was considered statistically significant. RESULTS AND DISCUSSION: In the study's central European cohort only about 16% (n=48/299) of the overweight/obese juveniles can be regarded as metabolically healthy. About 36% (n=108/299) of the overweight/obese patients fulfilled the criteria for metabolic syndrome. High visceral fat stores (p<0.001) and their clinical surrogate waist circumference (p<0.001) determine an adverse metabolic phenotype. Several parameters, including uric acid (p<0.001), adiponectin (p<0.05), insulin resistance (HOMA-Index, p<0.001), nuchal SAT thickness (p<0.001), arteriosclerosis of the carotids (p<0.001), and others are responsible for the distinction between -metabolically healthy and unhealthy juveniles. Nevertheless, "healthy obesity" only defines a sub-phenotype of a disease effecting rising numbers of young patients. CONCLUSIONS: Since obesity in children and adolescents is not a consistent entity, it remains crucial to differ between metabolically healthy and unhealthy obese children in order to achieve appropriate intervention and prevention for our patients.
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Cuello/patología , Obesidad/sangre , Obesidad/patología , Grasa Subcutánea/metabolismo , Grasa Subcutánea/patología , Ácido Úrico/sangre , Adiponectina/sangre , Adolescente , Enfermedades de las Arterias Carótidas/sangre , Enfermedades de las Arterias Carótidas/patología , Niño , Preescolar , Femenino , Humanos , Resistencia a la Insulina , Masculino , Obesidad/prevención & control , Estudios ProspectivosRESUMEN
BACKGROUND: Bariatric surgery is the most effective treatment to reduce weight permanently which is essential to avoid, to improve or even to cure life-threatening comorbidities. Little is known about changes of the psychological etiology and risk factors. METHODS: The present study concentrated on psychological variables which are considered to cause or promote obesity. The changes of symptoms were measured by the AD-EVA test inventory. A total of 60 patients (24 male/36 female, age 18-71 years) were tested prior to gastric bypass or gastric banding (body mass index BMI M=44.95, SD=6.91) and postoperatively (BMI M=33.92, SD=7.23). RESULTS: Following surgery the variables addiction (t=11.15, p<0.01) and binge eating disorder (t=2.13, p<0.05) showed significant changes across all patients and therefore confirmed a positive effect but restrained eating and bulimia remained unmodified after surgery. There were significant differences between the two bariatric methods (p<0.01). DISCUSSION: A precise interdisciplinary evaluation is a prerequisite for deciding between gastric banding and the bypass technique as well as to define the need for preoperative and postoperative psychotherapy.
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Conducta Adictiva/diagnóstico , Conducta Adictiva/psicología , Trastornos de Alimentación y de la Ingestión de Alimentos/diagnóstico , Trastornos de Alimentación y de la Ingestión de Alimentos/psicología , Derivación Gástrica , Gastroplastia , Hiperfagia/diagnóstico , Hiperfagia/psicología , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/psicología , Adolescente , Adulto , Anciano , Índice de Masa Corporal , Conducta Cooperativa , Femenino , Humanos , Comunicación Interdisciplinaria , Masculino , Persona de Mediana Edad , Obesidad/psicología , Cuidados Posoperatorios , Psicoterapia , Factores de Riesgo , Encuestas y Cuestionarios , Adulto JovenRESUMEN
In glycogen storage disease type 1 (GSD1), children present with severe hypoglycemia, whereas the propensity for hypoglycemia may decrease with age in these patients. It was the aim of this study to elucidate the mechanisms for milder hypoglycemia symptoms in young adult GSD1 patients. Four patients with GSD1 [body mass index (BMI) 23.2 +/- 6.3 kg/m, age 21.3 +/- 2.9 yr] and four healthy controls matched for BMI (23.1 +/- 3.0 kg/m) and age (24.0 +/- 3.1 yr) were studied. Combined (1)H/(31)P nuclear magnetic resonance spectroscopy (NMRS) was used to assess brain metabolism. Before and after administration of 1 mg glucagon, endogenous glucose production (EGP) was measured with d-[6,6-(2)H(2)]glucose and hepatic glucose metabolism was examined by (1)H/(13)C/(31)P NMRS. At baseline, GSD1 patients exhibited significantly lower rates of EGP (0.53 +/- 0.04 vs. 1.74 +/- 0.03 mg.kg(-1).min(-1); P < 0.01) but an increased intrahepatic glycogen (502 +/- 89 vs. 236 +/- 11 mmol/l; P = 0.05) and lipid content (16.3 +/- 1.1 vs. 1.4 +/- 0.4%; P < 0.001). After glucagon challenge, EGP did not change in GSD1 patients (0.53 +/- 0.04 vs. 0.59 +/- 0.24 mg.kg(-1).min(-1); P = not significant) but increased in healthy controls (1.74 +/- 0.03 vs. 3.95 +/- 1.34; P < 0.0001). In GSD1 patients, we found an exaggerated increase of intrahepatic phosphomonoesters (0.23 +/- 0.08 vs. 0.86 +/- 0.19 arbitrary units; P < 0.001), whereas inorganic phosphate decreased (0.36 +/- 0.08 vs. -0.43 +/- 0.17 arbitrary units; P < 0.01). Intracerebral ratios of glucose and lactate to creatine were higher in GSD1 patients (P < 0.05 vs. control). Therefore, hepatic defects of glucose metabolism persist in young adult GSD1 patients. Upregulation of the glucose and lactate transport at the blood-brain barrier could be responsible for the amelioration of hypoglycemic symptoms.
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Encéfalo/metabolismo , Glucosa/metabolismo , Enfermedad del Almacenamiento de Glucógeno Tipo I/metabolismo , Hígado/metabolismo , Espectroscopía de Resonancia Magnética/métodos , Adulto , Glucemia/metabolismo , Butiratos/sangre , Proteína C-Reactiva/metabolismo , Ácidos Grasos no Esterificados/sangre , Femenino , Glucógeno/metabolismo , Enfermedad del Almacenamiento de Glucógeno Tipo I/sangre , Humanos , Insulina/sangre , Lactatos/sangre , Masculino , Fosfatos/metabolismoRESUMEN
To test Randle's hypothesis we examined whether free fatty acids (FFAs) affect glucose-stimulated glucose transport/phosphorylation and allosteric mediators of muscle glucose metabolism under conditions of fasting peripheral insulinemia. Seven healthy men were studied during somatostatin-glucose-insulin clamp tests [plasma insulin, 50 pmol/L; plasma glucose, 5 mmol/L (0-180 min), 10 mmol/L (180-300 min)] in the presence of low (0.05 mmol/L) and increased (2.6 mmol/L) plasma FFA concentrations. (31)P and (1)H nuclear magnetic resonance spectroscopy was used to determine intracellular concentrations of glucose-6-phosphate (G6P), inorganic phosphate, phosphocreatine, ADP, pH, and intramyocellular lipids. Rates of glucose turnover were measured using D-[6,6-(2)H(2)]glucose. Plasma FFA elevation reduced rates of glucose uptake at the end of the euglycemic period (R(d 150-180 min): 8.6 +/- 0.5 vs. 12.6 +/- 1.6 micromol/kg.min, P < 0.05) and during hyperglycemia (R(d 270-300 min): 9.9 +/- 0.6 vs. 22.3 +/- 1.7 micromol/kg.min, P < 0.01). Similarly, intramuscular G6P was lower at the end of both euglycemic (G6P(167-180 min): -22 +/- 7 vs. +24 +/- 7 micromol/L, P < 0.05) and hyperglycemic periods (G6P(287-300 min): -7 +/- 9 vs. +28 +/- 7 micromol/L, P < 0.05). Changes in intracellular inorganic phosphate exhibited a similar pattern, whereas FFA did not affect phosphocreatine, ADP, pH, and intramyocellular lipid contents. In conclusion, the lack of an increase in muscular G6P along with reduction of whole body glucose clearance indicates that FFA might directly inhibit glucose transport/phosphorylation in skeletal muscle.
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Ácidos Grasos no Esterificados/fisiología , Glucosa-6-Fosfato/análisis , Glucosa/metabolismo , Músculo Esquelético/metabolismo , Adulto , Glucemia/análisis , Humanos , Insulina/sangre , Masculino , Fosfatos/análisisRESUMEN
BACKGROUND: Metabolic effects of free fatty acids (FFAs) frequently are tested using combined infusion of triglycerides and heparin, which stimulates lipolysis in vivo. Ongoing in vitro lipolysis, however, probably produces falsely high plasma FFA concentrations under these conditions. Therefore, this study aims to assess the efficacy of tetrahydrolipstatin (THL) in inhibiting plasma lipolytic activity and to improve plasma FFA determination. METHODS: Plasma concentrations of FFAs and glycerol were measured in five healthy subjects in the presence and absence of THL. Blood was drawn at baseline, during infusion of a triglyceride emulsion (1.5 mL/min), and during infusion of triglycerides plus heparin (0.2 IU. kg(-1). min(-1)). In addition, the effects of storage temperature of the samples were analyzed. RESULTS: In samples frozen immediately after collection, plasma FFAs were 28% lower in the presence of THL than in its absence (P = 0.008). When THL-free plasma was incubated for 3 h on ice or at room temperature, plasma FFAs were 22% (P = 0.02) and 91% (P = 0.0004) higher, respectively, than in samples frozen immediately. The addition of THL blunted temperature-dependent in vitro lipolysis by 88% (P<0.01) and 89% (P <0.001) after incubation on ice and at room temperature, respectively. Changes in plasma glycerol concentrations exhibited similar behavior. CONCLUSIONS: THL, which is safe and easy to handle, is a potent inhibitor of in vitro lipolysis and could, therefore, be added to blood samples drawn during triglyceride/heparin infusions to allow more accurate determination of plasma FFA concentrations.