The effect of dietary phytosphingosine on cholesterol levels and insulin sensitivity in subjects with the metabolic syndrome

Background: Sphingolipids, like phytosphingosine (PS) are part of cellular membranes of yeasts, vegetables and fruits. Addition of PS to the diet decreases serum cholesterol and free fatty acid (FFA) levels in rodents and improves insulin sensitivity. Objective: To study the effect of dietary supplementation with PS on cholesterol and glucose metabolism in humans. Methods: Twelve men with the metabolic syndrome (MetS) (according to the International Diabetes Federation (IDF) criteria; age 51 +/- 2 years (mean +/- s.e.m.); body mass index (BMI) 32 +/- 1 kg/m(2)) were randomly assigned to 4 weeks of PS (500mg twice daily) and 4 weeks of placebo (P) in a double-blind cross-over study, with a 4-week wash-out period between both interventions. At the end of each intervention anthropometric measures and serum lipids were measured and an intravenous glucose tolerance test (IVGTT) was performed. Results: Phytosphingosine did not affect body weight and fat mass compared with P. PS decreased serum total cholesterol (5.1 +/- 0.3 (PS) vs 5.4 +/- 0.3 (P) mmol/l; P<0.05) and low-density lipoprotein (LDL)-cholesterol levels (3.1 +/- 0.3 (PS) vs 3.4 +/- 0.3 (P) mmol/l; P<0.05), whereas it did not alter serum triglyceride and high-density lipoprotein (HDL)-cholesterol levels. In addition, PS lowered fasting plasma glucose levels (6.2 +/- 0.3 (PS) vs 6.5 +/- 0.3 (P) mmol/l; P<0.05). PS increased the glucose disappearance rate (K-value) by 9.9% during the IVGTT (0.91 +/- 0.06 (PS) vs 0.82 +/- 0.05 (P) %/min; P<0.05) at similar insulin levels, compared with P, thus implying enhanced insulin sensitivity. PS induced only minor gastrointestinal side effects. Conclusion: Dietary supplementation of PS decreases plasma cholesterol levels and enhances insulin sensitivity in men with the MetS. European Journal of Clinical Nutrition (2010) 64, 419-423; doi: 10.1038/ejcn.2009.154; published online 24 February 2010Diabetes mellitus: pathophysiological changes and therap

Hyperlipidaemia is associated with increased insulin-mediated glucose metabolism, reduced fatty acid metabolism and normal blood pressure in transgenic mice overexpressing human apolipoprotein C1

Aims/hypothesis. Insulin resistance for glucose metabolism is associated with hyperlipidaemia and high blood pressure. In this study we investigated the effect of primary hyperlipidaemia on basal and insulin-mediated glucose and on non-esterified fatty acid (NEFA) metabolism and mean arterial pressure in hyperlipidaemic transgenic mice overexpressing apolipoprotein C1 (APOC1). Previous studies have shown that APOC1 transgenic mice develop hyperlipidaemia primarily because of an impaired hepatic uptake of very low density lipoprotein (VLDL). Methods. Basal and hyperinsulinaemic (6 mU ? kg-1 ? min-1), euglycaemic (7 mmol/l) clamps with 3-3H-glucose or 9,10-3H-palmitic acid infusions and in situ freeze clamped tissue collection were carried out. Results. The APOC1 mice showed increased basal plasma cholesterol, triglyceride, NEFA and decreased glucose concentrations compared with wild-type mice (7.0 ± 1.2 vs 1.6 ± 0.1, 9.1 ± 2.3 vs 0.6 ± 0.1, 1.9 ± 0.2 vs 0.9 ± 0.1 and 7.0 ± 1.0 vs 10.0 ± 1.1 mmol/l, respectively, p < 0.05). Basal whole body glucose clearance was increased twofold in APOC1 mice compared with wild-type mice (18 ± 2 vs 10 ± 1 ml ? kg-1 ? min-1, p < 0.05). Insulin-mediated whole body glucose uptake, glycolysis (generation of 3H2O) and glucose storage increased in APOC1 mice compared with wild-type mice (339 ± 28 vs 200 ± 11; 183 ± 39 vs 128 ± 17 and 156 ± 44 vs 72 ± 17 μmol ? kg-1 ? min-1, p < 0.05, respectively), corresponding with a twofold to three-fold increase in skeletal muscle glycogenesis and de novo lipogenesis from 3-3H-glucose in skeletal muscle and adipose tissue (p < 0.05). Basal whole body NEFA clearance was decreased threefold in APOC1 mice compared with wild-type mice (98 ± 21 vs 314 ± 88 ml ? kg-1 ? min-1, p < 0.05). Insulin-mediated whole body NEFA uptake, NEFA oxidation (generation of 3H2O) and NEFA storage were lower in APOC1 mice than in wild-type mice (15 ± 3 vs 33 ± 6; 3 ± 2 vs 11 ± 4 and 12 ± 2 vs 22 ± 4 μmol ? kg-1? min-1, p < 0.05) in the face of higher plasma NEFA concentrations (1.3 ± 0.3 vs 0.5 ± 0.1 mmol/l, p < 0.05), respectively. Mean arterial pressure and heart rate were similar in APOC1 vs wild-type mice (82 ±4 vs 85 ± 3 mm Hg and 459 ± 14 vs 484 ± 11 beats, min-1). Conclusions/interpretation. 1) Hyperlipidaemic APOC1 mice show reduced NEFA and increased glucose metabolism under both basal and insulin-mediated conditions, suggesting an intrinsic defect in NEFA metabolism. Primary hyperlipidaemia alone in APOC1 mice does not lead to insulin resistance for glucose metabolism and high blood pressure

Synthetic Approaches to Neurobiology: Review and Case Study in the Control of Anguiliform Locomotion

. This paper briefly reviews synthetic approaches to neurobiology and presents results of two experiments on the use of evolutionary algorithms for the design of neural controllers for locomotion. The first experiment consists in using the evolutionary algorithm for instantiating low level parameters of a connectionist simulation of the lamprey&apos;s locomotor circuitry. The second experiment develops potential neural circuits for the swimming and trotting of the salamander; an animal whose locomotor circuitry has currently not been decoded. In both cases, biologically plausible control circuits are developed which produce a neural activity with many similarities to that measured in the real animals. 1 Synthetic approaches to neurobiology The fields of artificial life and artificial intelligence have developed tools and methods which have the potential to significantly help computational neurobiology. Synthetic approaches to neurobiology can indeed increase our understanding of ..

A 3-D biomechanical model of the salamander

. This article describes a 3D biomechanical simulation of a salamander to be used in experiments in computational neuroethology. The physically-based simulation represents the salamander as an articulated body, actuated by muscles simulated as springs and dampers, in interaction with a simple environment. The aim of the simulation is to investigate the neural circuits underlying the aquatic and terrestrial locomotion of the real salamander, as well as to serve as test bed for investigating vertebrate sensorimotor coordination in silico. 1 Computational neuroethology This article describes the design of a 3D biomechanical model for experiments in computational neuroethology [1, 2], a field which studies how behaviors of an autonomous agent (a simulated animal or a robot) arise from neural circuits. A central aspect of computational neuroethology is that it integrates the simulated central nervous system into a body and an environment, and that it investigates behavior as the re..

Calcium handling by vascular myocytes in hypertension

Calcium ions (Ca2+) trigger the contraction of vascular myocytes and the level of free intracellular Ca2+ within the myocyte is precisely regulated by sequestration and extrusion mechanisms. Extensive evidence indicates that a defect in the regulation of intracellular Ca2+ plays a role in the augmented vascular reactivity characteristic of clinical and experimental hypertension. For example, arteries from spontaneously hypertensive rats (SHR) have an increased contractile sensitivity to extracellular Ca2+ and intracellular Ca2+ levels are elevated in aortic smooth muscle cells of SHR. We hypothesize that these changes are due to an increase in membrane Ca2+ channel density and possibly function in vascular myocytes from hypertensive animals. Several observations using various experimental approaches support this hypothesis: 1) the contractile activity in response to depolarizing stimuli is increased in arteries from hypertensive animals demonstrating increased voltage-dependent Ca2+ channel activity in hypertension; 2) Ca2+ channel agonists such as Bay K 8644 produce contractions in isolated arterial segments from hypertensive rats and minimal contraction in those from normotensive rats; 3) intracellular Ca2+ concentration is abnormally increased in vascular myocytes from hypertensive animals following treatment with Ca2+ channel agonists and depolarizing interventions, and 4) using the voltage-clamp technique, the inward Ca2+ current in arterial myocytes from hypertensive rats is nearly twice as large as that from myocytes of normotensive rats. We suggest that an alteration in Ca2+ channel function and/or an increase in Ca2+ channel density, resulting from increased channel synthesis or reduced turnover, underlies the increased vascular reactivity characteristic of hypertensio