A decreased mobilization of triglycerides may contribute to fat accumulation in adipocytes, leading to obesity. However, this hypothesis remains to be proven. In this study, epinephrine-induced lipid mobilization was investigated in vivo in nine markedly obese children (160 Ϯ 5% ideal body weight) aged 12.1 Ϯ 0.1 yr during the dynamic phase of fat deposition, compared with six age-matched nonobese children. As an in vivo index of lipolysis, we measured glycerol flux using a nonradioactive tracer dilution approach, and plasma free fatty acid concentrations. In the basal state, the obese children had a 30% lower rate of glycerol release per unit fat mass than the lean children. To study the regulation of lipolysis, epinephrine was infused stepwise at fixed doses of 0.75 and then 1.50 g/min in both groups. In lean children, glycerol flux and plasma free fatty acid increased to an average of 249-246% of basal values, respectively, in response to a mean plasma epinephrine of 396 Ϯ 41 pg/ml. The corresponding increase was only 55-72% in the obese children, although their mean plasma epinephrine reached 606 Ϯ 68 pg/ml. All obese and nonobese children, except an Arg64Trp heterozygote, were homozygotes for Trp at position 64 of their beta 3 -adrenoreceptor. The resistance of lipolysis to epinephrine showed no relationship with the Arg64 polymorphism of the beta 3 -adrenoreceptor gene.In summary, in vivo lipolysis, which mostly reflects the mobilization of lipid stores from subcutaneous adipose tissue, shows a decreased sensitivity to epinephrine in childhood onset obesity. Since our study was carried out in obese children during the dynamic phase of fat accumulation, the observed resistance to catecholamines might possibly be causative rather than the result of obesity. ( J. Clin. Invest. 1997. 99:2568-2573.)
We investigated the effect of a 48 h triglyceride infusion on the subsequent insulin secretion in response to glucose in healthy men. We measured the variations in plasma concentration and urinary excretion of catecholamines as an indirect estimation of sympathetic tone. For 48 h, 20 volunteers received a triglyceride/heparin or a saline solution, separated by a 1-month interval. At time 48 h, insulin secretion in response to glucose was investigated by a single iv glucose injection (0.5 g/kg(-1)) followed by an hyperglycemic clamp (10 mg.kg(-1).min(-1), during 50 min). The triglyceride infusion resulted in a 3-fold elevation in plasma free fatty acids and an increase in insulin and C-peptide plasma concentrations (1.5- and 2.5-fold, respectively, P < 0.05), compared with saline. At time 48 h of lipid infusion, plasma norepinephrine (NE) concentration and urinary excretion levels were lowered compared with saline (plasma NE: 0.65 +/- 0.08 vs. 0.42 +/- 0.06 ng/ml, P < 0.05; urinary excretion: 800 +/- 70 vs. 620 +/- 25 nmol/24 h, P < 0.05). In response to glucose loading, insulin and C-peptide plasma concentrations were higher in lipid compared with saline infusion (plasma insulin: 600 +/- 98 vs. 310 +/- 45 pM, P < 0.05; plasma C-peptide 3.5 +/- 0.2 vs. 1.7 +/- 0.2 nM, P < 0.05). In conclusion, in healthy subjects, a 48-h lipid infusion induces basal hyperinsulinemia and exaggerated insulin secretion in response to glucose which may be partly related to a decrease in sympathetic tone.
The localization, distribution and elimination of l4C_Tienilic acid, a new diuretic and hypouricemic drug has been described.This study was carried out using l4C labelled compound on four different animal species: mice, rats, pigs and dogs. The blood level is expressed as f.1g/ml equivalents of the administered product. After oral administration, the absorption rate of this product in doses of 5 mg/kg for rats, pigs and dogs was between 50 and 80 %, depending on the species.Tienilic acid was rapidly distributed in most of the essential organs and tissues with the exception of the brain. In the blood the product was found only at the plasmatic level with high plasmatic protein binding, around 72-95 %.Biliary and particularly urinary elimination was fast and practically complete in 48 hours.
The metabolic fate of a new diuretic, tienilic acid, was investigated in Wistar rats, Swiss mice, Beagle dogs, and large white pigs using the 14C-labelled compound. Tienilic acid and its metabolites were determined in bile, urine, and plasma following intravenous and oral administration. In general, only a small amount of unmetabolized drug is excreted. Biotransformation consists of two major metabolic routes; one is reduction and the other is oxidative hydrolysis of the molecule at the level of the carbonyl group. These two routes co-exist in all species studied, but the reduction route is prominent in the dog. Mass spectrometry was used to elucidate the structure of two metabolites and confirm it for the third.
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