RESUMEN
BACKGROUND: Lipemic alterations are commonly seen in pediatric patients with acute lymphoblastic leukemia (ALL) treated with corticosteroids and L-asparaginase. OBJECTIVE: In these children, hypertriglyceridemia rarely causes symptoms and mostly responds well to a low-fat diet. Only few patients demand further therapy, which is not clearly approved in the literature to date. Therefore, it may be important to compile generally accepted standard procedures for lipid-lowering therapy in the pediatric ALL population. METHODS: We performed a study on 119 newly diagnosed pediatric patients with ALL, all treated according to the ALL-BFM 2000 protocol at our institution between the years 2000 and 2009, to evaluate the incidence of hypertriglyceridemia and the efficacy of a combination therapy with omega-3 fatty acids and acipimox in hypertriglyceridemic patients who did not respond to diet. RESULTS: We observed hypertriglyceridemia in 34.5% of patients in this collective. In the majority, normalization of triglycerides was successfully managed by administration of a low-fat diet. However, 7.6% of patients (related to total study population) with hypertriglyceridemia did not show diminished lipid levels during diet and/or presented with symptoms such as abdominal pain, dyspnea, or anginal chest pain. In these cases, we performed a lipid-lowering combination therapy with omega-3 fatty acids and acipimox. We observed a prompt decline of serum triglycerides to normal values and an improvement of symptoms within days after onset of this therapy without occurrence of any side effects. CONCLUSION: In summary, the combination treatment with omega-3 fatty acids and acipimox could represent an alternative to other reported lipid-lowering therapies without severe adverse reactions.
Asunto(s)
Ácidos Grasos Omega-3/farmacología , Hipertrigliceridemia/complicaciones , Hipertrigliceridemia/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Pirazinas/farmacología , Adolescente , Niño , Preescolar , Interacciones Farmacológicas , Ácidos Grasos Omega-3/uso terapéutico , Femenino , Humanos , Masculino , Pirazinas/uso terapéutico , Estudios RetrospectivosRESUMEN
Using L6 skeletal muscle cell line, rendered insulin resistant by incubation with triglyceride-rich lipoproteins (TGRLs), we sought to answer the question whether pioglitazone has direct effects on this cell line. Incubation of L6 cells with TGRLs led to an increase in the intramyocellular triglyceride content. Moreover, TGRLs led to a reduction in insulin-stimulated glycogen content and GSK-3 phosphorylation. All these changes induced by TGRLs could be antagonized by incubation of L6 cells with pioglitazone. The PPAR-γ antagonist GW9662 reversed the pioglitazone effects. We conclude that pioglitazone has direct insulin-sensitizing effects on the L6 skeletal muscle cell line, which are paralleled by a reduction in intramyocellular triglyceride accumulation.
Asunto(s)
Insulina/farmacología , Espacio Intracelular/efectos de los fármacos , Espacio Intracelular/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Células Musculares/metabolismo , Músculo Esquelético/citología , Tiazolidinedionas/farmacología , Animales , Línea Celular , Glucógeno/metabolismo , Insulina/metabolismo , Lipoproteínas/metabolismo , Células Musculares/efectos de los fármacos , Oxidación-Reducción/efectos de los fármacos , Pioglitazona , Ratas , Transducción de Señal/efectos de los fármacos , Triglicéridos/metabolismoRESUMEN
BACKGROUND AND AIMS: Several studies indicate that changes in the plasma concentrations of adipocyte-fatty acid binding protein (A-FABP), retinol binding protein-4 (RBP-4) and visfatin are associated with chronic states of insulin resistance. Recent studies have shown that postprandial lipemia induces an acute state of insulin resistance. The aim of this study was to investigate the effect of postprandial lipemia on the plasma concentrations of A-FABP, RBP-4 and visfatin. METHODS AND RESULTS: In a within-subject crossover study, we administered a standardized high-fat meal to 24 healthy subjects (12 males and 12 females). Plasma concentrations of adipocytokines were measured in the morning after an overnight fast and during postprandial lipemia, i.e. 2, 4 and 6 hours after meal ingestion (postprandial experiment). To exclude potential confounding factors affecting the adipocytokine plasma concentrations, a control experiment without meal ingestion was performed over the same time period (postabsorptive control experiment). Comparing plasma concentrations of A-FABP, RBP-4 and visfatin between the postprandial and the postabsorptive control experiments, we found no significant differences. Within either of the two experiments, a decrease of A-FABP was noted reaching, however, statistical significance only in the postprandial experiment, i.e. 2 and 4 hours after meal ingestion. CONCLUSION: Postprandial lipemia has no significant effect on the plasma concentrations of visfatin, A-FABP or RBP-4 in relation to their postabsorptive plasma profiles. We conclude that prolonged states of insulin resistance are required to affect plasma concentrations of these adipocytokines.
Asunto(s)
Proteínas de Unión a Ácidos Grasos/sangre , Alimentos , Hiperlipidemias/sangre , Nicotinamida Fosforribosiltransferasa/sangre , Proteínas Plasmáticas de Unión al Retinol/análisis , Adipoquinas/sangre , Adulto , Glucemia/análisis , HDL-Colesterol/sangre , Estudios Cruzados , Grasas de la Dieta/administración & dosificación , Ayuno , Ácidos Grasos no Esterificados/sangre , Femenino , Humanos , Insulina/sangre , Masculino , Triglicéridos/sangreRESUMEN
AIMS/HYPOTHESIS: Typical Western diets cause postprandial lipaemia for 18 h per day. We tested the hypothesis that postprandial lipaemia decreases insulin sensitivity. SUBJECTS, MATERIALS AND METHODS: Employing a randomised crossover design, we administered two types of virtually isocaloric meals to ten healthy volunteers on two separate occasions. The meals (Meals 1 and 2) were both designed to produce a rise in triglycerides, but only Meal 1 generated a rise in NEFA, too. Insulin sensitivity, as quantified by an IVGTT with minimal model analysis, was calculated postabsorptively at 08.00 h and postprandially at 13.00 h, i.e. 3 h after meal ingestion. RESULTS: Triglycerides rose from 0.91+/-0.31 mmol/l postabsorptively to 2.08+/-0.70 mmol/l postprandially with Meal 1 (p=0.005) and from 0.92+/-0.41 to 1.71+/-0.79 mmol/l with Meal 2 (p=0.005). Neither the triglyceride levels at 13.00 h, nor the post-meal AUCs for triglycerides were statistically different between Meal 1 and Meal 2. NEFA rose from 0.44+/-0.17 mmol/l postabsorptively to 0.69+/-0.16 mmol/l postprandially with Meal 1 (p=0.005) and showed no significant change with Meal 2 (0.46+/-0.31 mmol/l postabsorptively vs 0.36+/-0.32 mmol/l postprandially, p=0.09). Both the NEFA level at 13.00 h and the post-meal AUC for NEFA were significantly higher after Meal 1 than Meal 2. Compared with the postabsorptive state, insulin sensitivity decreased postprandially after each of the two meals to a comparable degree (Meal 1: -53%, p=0.02; Meal 2: -45%, p=0.005). CONCLUSIONS/INTERPRETATION: Our study reveals a drop in insulin sensitivity during postprandial lipaemia and strongly suggests that decreased insulin sensitivity is brought about by elevated plasma levels of triglyceride-rich lipoproteins independently of plasma NEFA levels.
Asunto(s)
Ácidos Grasos no Esterificados/sangre , Hiperlipidemias/complicaciones , Resistencia a la Insulina , Periodo Posprandial , Adulto , Glucemia/análisis , Estudios Cruzados , Prueba de Tolerancia a la Glucosa , Humanos , Hiperlipidemias/sangre , Insulina/sangre , Masculino , Triglicéridos/sangreRESUMEN
Second-generation antipsychotic agents (SGAs) are increasingly replacing first-generation antipsychotic agents due to their superior activity against the negative symptoms of schizophrenia, decreased extrapyramidal symptoms and better tolerability. However, some SGAs are associated with adverse metabolic effects as significant weight gain, lipid disorders and diabetes mellitus. The pathogenesis of SGA-induced disturbances of glucose homeostasis is unclear. In vivo studies suggest a direct influence of SGAs on peripheral insulin resistance. To this end, we analyzed whether olanzapine might alter glycogen synthesis and the insulin-signaling cascade in L6 myotubes. Glycogen content was diminished in a dose- and time-dependent manner. Within the insulin-signaling cascade IRS-1 tyrosine phosphorylation was induced several fold by insulin and was diminished by preincubation with olanzapine. IRS-1-associated PI3K activity was stimulated by insulin three-fold in L6 myotubes. Olanzapine inhibited insulin-stimulated IRS-1-associated PI3K activity in a dose-dependent manner. Protein mass of AKT, GSK-3 and GS was unaltered, whereas phosphorylation of AKT and GSK-3 was diminished, and pGS was increased. Finally, we compared olanzapine with amisulpride, an SGA clinically not associated with the induction of diabetes mellitus. Glycogen content was diminished in olanzapine-preincubated L6 cells, whereas this effect was not observed under the amisulpride conditions. We conclude that olanzapine impairs glycogen synthesis via inhibition of the classical insulin-signaling cascade and that this inhibitory effect may lead to the induction of insulin resistance in olanzapine-treated patients.
Asunto(s)
Antipsicóticos/farmacología , Glucógeno/biosíntesis , Insulina/metabolismo , Fibras Musculares Esqueléticas/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Animales , Antipsicóticos/efectos adversos , Benzodiazepinas/efectos adversos , Benzodiazepinas/farmacología , Línea Celular , Relación Dosis-Respuesta a Droga , Trastornos del Metabolismo de la Glucosa/inducido químicamente , Resistencia a la Insulina/fisiología , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/citología , Músculo Esquelético/metabolismo , Olanzapina , Ratas , Transducción de Señal/efectos de los fármacosRESUMEN
AIMS/HYPOTHESIS: Elevated fasting and postprandial plasma levels of triglyceride-rich lipoproteins (TGRLs), i.e. VLDL/remnants and chylomicrons/remnants, are a characteristic feature of insulin resistance and are considered a consequence of this state. The aim of this study was to investigate whether intact TGRL particles are capable of inducing insulin resistance. METHODS: We studied the effect of highly purified TGRLs on glycogen synthesis, glycogen synthase activity, glucose uptake, insulin signalling and intramyocellular lipid (IMCL) content using fully differentiated L6 skeletal muscle cells. RESULTS: Incubation with TGRLs diminished insulin-stimulated glycogen synthesis, glycogen synthase activity, glucose uptake and insulin-stimulated phosphorylation of Akt and glycogen synthase kinase 3. Insulin-stimulated tyrosine phosphorylation of IRS-1, and IRS-1- and IRS-2-associated phosphatidylinositol 3-kinase (PI3K) activity were not impaired by TGRLs, suggesting that these steps were not involved in the lipoprotein-induced effects on glucose metabolism. The overall observed effects were time- and dose-dependent and paralleled IMCL accumulation. NEFA concentration in the incubation media did not increase in the presence of TGRLs indicating that the effects observed were solely due to intact lipoprotein particles. Moreover, co-incubation of TGRLs with orlistat, a potent active-site inhibitor of various lipases, did not alter TGRL-induced effects, whereas co-incubation with receptor-associated protein (RAP), which inhibits interaction of TGRL particles with members of the LDL receptor family, reversed the TGRL-induced effects on glycogen synthesis and insulin signalling. CONCLUSIONS/INTERPRETATION: Our data suggest that the accumulation of TGRLs in the blood stream of insulin-resistant patients may not only be a consequence of insulin resistance but could also be a cause for it.
Asunto(s)
Ácidos Grasos no Esterificados/metabolismo , Glucosa/metabolismo , Insulina/metabolismo , Lipoproteínas/farmacología , Fibras Musculares Esqueléticas/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Transporte Biológico/efectos de los fármacos , Línea Celular , Glucógeno/biosíntesis , Glucógeno Sintasa/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Humanos , Proteínas Sustrato del Receptor de Insulina , Proteínas Relacionadas con Receptor de LDL/farmacología , Lactonas/farmacología , Lipasa/antagonistas & inhibidores , Metabolismo de los Lípidos , Fibras Musculares Esqueléticas/metabolismo , Orlistat , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfoproteínas/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt , Ratas , Triglicéridos/farmacologíaRESUMEN
The incline and length of guiding elements, i.e. marginal ridges and lingual surfaces of front teeth, marginal ridges and internal cusp slopes of premolars and molars, play an important role in dentistry. Since the so far reported values differ considerably, it was the purpose of the present investigation to replicate the measurements, including all the occlusal landmarks proposed and defined by previous investigators. The measurements were performed on 34 pairs of mounted casts from a selected group of untreated, naturally grown dentitions from adolescents of mean age 14 years. The upper casts were mounted with a face bow, the kinematic hinge axis and the left incisura infraorbitalis representing the posterior and anterior reference points. The lower pinned casts were mounted joint related. All measurements were carried out with a computer-aided, three-dimensional digitizer. The inclines were expressed as angles related to the axis-orbital-plane. Taking the proposed occlusal landmarks as a basis, the inclines of guiding elements were found to be in agreement with previously reported values, despite ethnic and racial differences of the various study-populations. The values, however, differed markedly when measurements based on individual, functional relevant landmarks were compared to measurements based on anatomical, easy identifiable or mathematically constructed landmarks. The successive decrease of the inclines of the guiding elements from the central incisors to the second molars could be confirmed, the molars displaying very flat inclines. Interestingly, 9% of the first molars and 21% of the second molars showed negative values, pointing to a functional arrangement characterized by a buccally oriented occlusal surface of those teeth. Combined with the finding that the length of the guiding elements of the anterior teeth was almost twice as long as that of the posterior teeth, the results corroborate the occlusal concept of an anterior-posterior sequence of the guiding elements, or a so-called sequential guidance with front-canine-dominance.