The mechanism of action of clofibrate and tetranicotinoylfructose (Bradilan) on the kinetics of plasma free fatty acid and triglyceride transport in type IV and type V hypertriglyceridaemia

Abstract. The kinetics of plasma free fatty acid and triglyceride transport were assessed in 20 patients with idiopathic hypertriglyceridaemia. These patients were subdivided according to lipoprotein pattern into Type IV and Type V patients. The effects of clofibrate therapy on plasma free fatty acid and triglyceride kinetics were assessed in these patients. Clofibrate produced a marked reduction in serum triglyceride associated with a significant reduction in triglyceride turnover as well as enhancement of triglyceride clearance. The reduction in triglyceride concentration produced by clofibrate was found to correlate with the reduction in free fatty acid turnover indicating that this drug decreased the availability of free fatty acid turnover indicating that this drug decreased the availability of free fatty acids for hepatic esterification. Clearance of endogenous plasma triglyceride was markedly enhanced in those patients in whom it was markedly impaired before treatment.—Having discontinued clofibrate for six weeks the same patients received bradilan (tetranicotinoylfructose) and kinetic measurements were repeated. It was evident that bradilan had a greater hypotriglyceridaemic effect than clofibrate in both groups of patients. The effect of bradilan was the result of inhibition of free fatty acid turnover and consequently a marked reduction in triglyceride turnover. Bradilan, unlike clofibrate, did not affect the mechanisms responsible for the clearance of plasma triglycerides.     

Immuno-endocrine and metabolic responses to long distance ski racing in world-class male and female cross-country skiers

The purpose of this study was to characterize the extent of immune, endocrine, substrate and metabolic changes during a long-distance cross-country ski race in extremely well-trained athletes and evaluate if the blood perturbations would indicate signs of health risk. Ten male (M) and six female (F) national team skiers were investigated as they followed their usual routines of race preparations. Blood samples were drawn before and immediately after a World Cup 50-km M and 30-km F ski race with a mean finish time of 142 and 104 min, respectively. Hemoglobin, electrolytes, and C-reactive protein remained unchanged for both M and F. Serum testosterone remained unchanged in M, but doubled in F. Significant increases were observed in concentrations of granulocytes (F: 5 x, M: 5 x), natural killer cells (F: 2 x, M: 1.5 x), adrenaline (F: 12 x, M:10 x), noradrenaline (F: 7 x, M:5 x), growth hormone (F: 30 x, M: 2 x), cortisol (F: 1.5 x, M:2 x), glucose (F: 2 x, M:1.5 x), creatine kinase (F: 2 x, M:2 x), uric acid (F: 1.5 x, M: 1.5 x) and non-organic phosphate (F:2 x, M:2 x), while insulin concentration decreased (F: 0.5x, M: 0.8 x). Free fatty acid (FFA) concentration increased (F:2 x, M: 3 x). In conclusion, we observed substantial changes in several immuno-endocrine, substrate and metabolic measurements after long distance cross-country ski racing and suggest that some of these marked changes may reflect the large amount of muscle mass involved during skiing.     

CONCENTRATIONS OF TRIGLYCERIDES, FREE FATTY ACIDS AND GLYCEROL IN CORD BLOOD OF NEWBORN INFANTS WITH A BIRTH WEIGHT OF ≤2700 GRAMS

Abstract Concentrations of triglycerides, free fatty acids (FFA) and glycerol were measured in umbilical venous blood from 99 infants with a birth weight of between 1100–2700 g and a gestational age of 27–41 weeks. Thirty infants were small for gestational age (SGA), 58 were appropriate (AGA) and 11 were of uncertain gestational age. In AGA infants with a gestational age of ≥35 weeks, FFA values were lower than in those with a gestational age of>35 weeks; otherwise concentrations of triglycerides, FFA and glycerol were independent of birth weight and gestational age in AGA infants. In SGA infants, higher FFA values were found compared with both AGA and term infants of normal birth weight. Triglyceride values were higher in SGA than in AGA infants. In SGA infants, a significant positive correlation was found between gestational age and concentrations of both FFA and triglycerides. No differences in FFA, glycerol and triglyceride concentrations were seen between asphyxiated and non-asphyxiated AGA infants.     

THE EFFECT OF FEEDING ON OXYGEN CONSUMPTION, RQ AND PLASMA LEVELS OF GLUCOSE, FFA, AND D-β-HYDROXYBUTYRATE IN NEWBORN INFANTS OF DIABETIC MOTHERS AND SMALL FOR GESTATIONAL AGE INFANTS

Abstract. Eight infants of strictly controlled diabetic mothers (IDM), 8 infants of gestational diabetic mothers (IGDM) and 6 small for gestational age infants (SGA) were studied before the first feeding and during an early feeding regimen. In IDMs and IGDMs continuous monitoring from 2 hours up to 7 1/2 hours after birth before feeding revealed no consistent changes of Vo₂ and RQ. The groups of infants were studied on 4 different occasions: (I) 2 to 16 hours, (II) 1 to 2 days, (III) 3 to 4 days, and (IV) 7 to 11 days. Prefeeding Vo₂-values were not significantly different between each of the groups, but mean RQ was higher in IGDMs than in IDMs. Age of the infant and prefeeding RQ were inversely correlated (r=-0.537, p<0.02). With increasing age and milk intake Vo₂ increased significantly in all groups. RQ decreased during the first 24 to 48 hours in all groups and rose thereafter with highest values at 7 to 11 days. Plasma levels of glucose, FFA, and D-β-hydroxybutyrate were not significantly different between each of the groups. The highest values for D-β-hydroxybutyrate were found at 1–2 days when the lowest RQ values were also recorded. D-β-hydroxybutyrate concentrations and RQ values (r= -0.648, p<0.001) were inversely correlated suggesting increasing oxidation of fat. Feeding resulted in a marked rise in RQ to values around unity, which preceded a distinct increase in Vo₂ that reached a maximum at 1 to 1 1/2 hours after the feed, then slowly returned to pretest values. The rise in Vo₂ was accompanied by an increase in rectal temperature (0.4 to 1.5°C). Vo₂, RQ, and plasma levels of glucose, FFA, and D-β-hydroxybutyrate, were almost identical for each of the groups. We suggest: 1) That differences in feeding practice is the most likely explanation for the discrepancy between reported values for Vo₂, RQ, and circulating substrates in normal and low birth weight newborns. 2) That the rise in Vo₂ during the neonatal period, caused by feeding, reflects the cost of growth.     

Accumulation of lipids and oxidatively damaged DNA in hepatocytes exposed to particles

Exposure to particles has been suggested to generate hepatosteatosis by oxidative stress mechanisms. We investigated lipid accumulation in cultured human hepatocytes (HepG2) and rat liver after exposure to four different carbon-based particles. HepG2 cells were exposed to particles for 3 h and subsequently incubated for another 18 h to manifest lipid accumulation. In an animal model of metabolic syndrome we investigated the association between intake of carbon black (CB, 14 nm) particles and hepatic lipid accumulation, inflammation and gene expression of Srebp-1, Fasn and Scd-1 involved in lipid synthesis. There was a concentration-dependent increase in intracellular lipid content after exposure to CB in HepG2 cells, which was only observed after co-exposure to oleic/palmitic acid. Similar results were observed in HepG2 cells after exposure to diesel exhaust particles, fullerenes C₆₀ or pristine single-walled carbon nanotubes. All four types of particles also generated oxidatively damaged DNA, assessed as formamidopyrimidine DNA glycosylase (FPG) sensitive sites, in HepG2 cells after 3 h exposure. The animal model of metabolic syndrome showed increased lipid load in the liver after one oral exposure to 6.4 mg/kg of CB in lean Zucker rats. This was not associated with increased iNOS staining in the liver, indicating that the oral CB exposure was associated with hepatic steatosis rather than steatohepatitis. The lipid accumulation did not seem to be related to increased lipogenesis because there were unaltered gene expression levels in both the HepG2 cells and rat livers. Collectively, exposure to particles is associated with oxidative stress and steatosis in hepatocytes.     

Optimization of GPR40 Agonists for Type 2 Diabetes

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Soy β-conglycinin improves glucose uptake in skeletal muscle and ameliorates hepatic insulin resistance in Goto-Kakizaki rats

Although the underlying mechanism is unclear, β-conglycinin (βCG), the major component of soy proteins, regulates blood glucose levels. Here, we hypothesized that consumption of βCG would normalize blood glucose levels by ameliorating insulin resistance and stimulating glucose uptake in skeletal muscles. To test our hypothesis, we investigated the antidiabetic action of βCG in spontaneously diabetic Goto-Kakizaki (GK) rats. Our results revealed that plasma adiponectin levels and adiponectin receptor 1 messenger RNA expression in skeletal muscle were higher in βCG-fed rats than in casein-fed rats. Phosphorylation of adenosine monophosphate–activated protein kinase (AMP kinase) but not phosphatidylinositol-3 kinase was activated in βCG-fed GK rats. Subsequently, βCG increased translocation of glucose transporter 4 to the plasma membrane. Unlike the results in skeletal muscle, the increase in adiponectin receptor 1 did not lead to AMP kinase activation in the liver of βCG-fed rats. The down-regulation of sterol regulatory element-binding factor 1, which is induced by low insulin levels, promoted the increase in hepatic insulin receptor substrate 2 expression. Based on these findings, we concluded that consumption of soy βCG improves glucose uptake in skeletal muscle via AMP kinase activation and ameliorates hepatic insulin resistance and that these actions may help normalize blood glucose levels in GK rats.     

磷酸二脂酶抑制剂米力农对大鼠胰岛素分泌的影响

 目的探讨米力农(milrinone)对大鼠胰岛素分泌的影响。方法在0时静脉给予3组大鼠不同剂量的磷酸二酯酶抑制剂milrinone(剂量为：1,5,25 μmol·kg^-1)，并在给药前后观察其血糖、血浆胰岛素和游离脂肪酸(FFA)随时间变化的过程。结果给予milrinone的3组大鼠血浆FFA和胰岛素水平明显高于给药前和对照组，而仅25 μmol·kg^-1组血糖明显升高。结论Milrinone 通过抑制磷酸二酯酶Ⅲ(PDE-3)，使细胞内cAMP浓度升高而促进了胰岛β细胞分泌。但其也抑制了胰岛素的抗酯解作用，因而可能诱导了胰岛素抵抗。     

Omega-3 fatty acids induce Ca2+ mobilization responses in human colon epithelial cell lines endogenously expressing FFA4

Aim:

Free fatty acid receptor 4 (FFA4; formerly known as GPR120) is the G protein-coupled receptor (GPCR) for omega-3 polyunsaturated fatty acids. FFA4 has been found to express in the small intestines and colons of mice and humans. In this study we investigate the effects of omega-3 polyunsaturated fatty acids on FFA4 in human colon epithelial cells in vitro.

Methods:

HCT116 and HT-29 human colon epithelial cell lines endogenously expressing FFA4 were used. Intracellular Ca²⁺ concentration ([Ca²⁺]_i) was measured in fura 2-AM-loaded cells with fluorescence spectrophotometry. RT-PCR and immunohistochemistry were used to detect FFA4.

Results:

Ten to 100 μmol/L of omega-3 polyunsaturated fatty acids α-linolenic acid (αLA) or eicosapentaenoic acid (EPA) induced dose-dependent [Ca²⁺]_i increase in HCT116 and HT-29 cells, whereas docosahexaenoic acid (DHA) had no effect. In addition, the omega-6 fatty acids linoleic acid and γ-linoleic acid also dose-dependently increase [Ca²⁺]_i, but the mono-unsaturated fatty acid oleic acid and saturated fatty acids such as stearic acid and palmitic acid had no effect. In HCT116 and HT-29 cells, the αLA-induced [Ca²⁺]_i increase was partially inhibited by pretreatment with EGTA, phospholipase C inhibitor edelfosine, cADPR inhibitors 8-bro-cADPR or DAB, and abolished by pretreatment with Ca²⁺ATPase inhibitor thapsigargin, but was not affected by G_i/o protein inhibitor PTX or IP₃R inhibitor 2-APB.

Conclusion:

Omega-3 and omega-6 long-chain polyunsaturated fatty acids (C18-20) induce Ca²⁺ mobilization responses in human colonic epithelial cells in vitro through activation of FFA4 and PTX-insensitive G_i/o protein, followed by Ca²⁺ release from thapsigargin-sensitive Ca²⁺ stores and Ca²⁺ influx across the plasma membrane.