Interaction of carnitine with insulin-stimulated glucose metabolism in humans.

To characterize the interactions of carnitine with glucose metabolism, we administered L-carnitine as a primed (3 mmol) constant (17 mumol/min) intravenous infusion to healthy young volunteers during short-term (2 h) euglycemic hyperinsulinemia. In comparison with a control (saline) infusion, exogenous carnitine administration resulted in a stable, fourfold increase in basal serum carnitine levels (160 +/- 14 vs. 36 +/- 2 microM, P less than 0.001). At similar steady-state plasma insulin levels (75 microU/ml), carnitine infusion was associated with a 17 +/- 3% stimulation of whole body glucose utilization (6.56 +/- 0.60 vs. 5.57 +/- 0.44 mg.min-1.kg-1, P less than 0.001). This effect was more pronounced in the subjects with higher rates of glucose disposal (r = 0.65, P less than 0.05). Net rates of insulin-induced glucose oxidation (measured by continuous, computerized indirect calorimetry) were similar with or without carnitine (1.67 +/- 0.23 vs. 1.65 +/- 0.10 mg.min-1.kg-1, respectively). As a consequence, the carnitine-induced enhancement of total glucose metabolism was quantitatively accounted for by a 50% increase in nonoxidative glucose disposal (2.89 +/- 0.81 vs. 1.92 +/- 0.51 mg.min-1.kg-1, P less than 0.05). The inhibitory effect of insulin on net lipid oxidation was not altered by carnitine (-0.67 +/- 0.09 vs. -0.62 +/- 0.06 mg.min-1.kg-1). Circulating levels of free fatty acids (FFA), glycerol, and beta-hydroxybutyrate fell in parallel during insulin infusion in the test and control study, and blood lactate concentrations rose by similar amounts (approximately 0.35 mM).(ABSTRACT TRUNCATED AT 250 WORDS)

Independent stimulation of glucose metabolism and Na+-K+ exchange by insulin in the human forearm.

Insulin promotes potassium uptake into skeletal muscle by stimulating the activity of the Na+-K+ pump. To test whether insulin-induced glucose and potassium uptake are linked processes in vivo, we used the perfused forearm technique in healthy volunteers. Local hyperinsulinemia (125 +/- 11 microU/ml for 100 min) induced a net uptake of glucose and potassium (4.79 +/- 0.61 and 0.76 +/- 0.22 mumol.min-1.100 ml-1 of forearm volume, respectively). When an intra-arterial ouabain infusion (0.72 microgram.min-1.100 ml-1, producing local levels of approximately 0.5 mM) was superimposed on the insulin infusion, potassium uptake was blocked (0.026 +/- 0.190 ml.min-1.100 ml-1, P less than 0.02), and glucose uptake was decreased (to 3.31 +/- 0.34 mumol.min-1.100 ml-1, P less than 0.03). The latter change was explained by a 30% fall in forearm blood flow (from 2.95 +/- 0.10 to 2.01 +/- 0.18 ml.min-1.100 ml-1, P less than 0.001). To separate out the effect of blood flow, in another series of studies forearm blood flow was clamped by co-infusing propranolol and phentolamine (7 and 8 micrograms.min-1.100 ml-1, respectively). Under these conditions of fixed flow (7.0 +/- 0.8 ml.min-1.100 ml-1), ouabain still abolished the stimulatory effect of insulin on potassium uptake but had only a small (and statistically insignificant) effect on forearm glucose extraction (from 20 +/- 2 to 16 +/- 2%, P = N>). We conclude that in human forearm muscle ouabain inhibits Na+-K+ exchange and depresses insulin-induced glucose uptake via an adrenergic-mediated limitation of blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Methylglyoxal: genotoxicity studies and its effect in vivo on the hepatic microsomal mono-oxygenase system of the mouse.

The genotoxic potential of methylglyoxal (MG) was studied in Saccharomyces cerevisiae D7 and in Salmonella typhimurium TA97 and TA102 in the presence and in the absence of metabolic activation system (S9 fraction) prepared from mouse liver induced with beta-naphthoflavone (beta-NF) and sodium phenobarbital (PB). The in vivo effects on the hepatic microsomal mixed function mono-oxygenase system induced by MG were studied in untreated, beta-NF or PB pre-treated mice. MG was a direct-acting mutagen in S. typhimurium TA97 and TA102 when tested up to a maximum concentration of 0.47 mg/plate. Mitotic gene conversion was also induced by MG in the yeast S. cerevisiae D7. A weak but significant effect on reverse point mutation was also found in S. cerevisiae. Genetic activity was lower in the presence of S9 fraction in yeast test. In the in vivo studies, MG (at the total dose of 600 mg/kg) was shown to increase the aminopyrine N-demethylase (APD) and p-nitroanisole O-demethylase (p-NAD) activities in uninduced mice. Cytochrome P-450 content (cyt P-450) and ethoxycoumarin O-deethylase activity (ECD) were also weakly enhanced by MG treatment. In contrast, no significant changes in mono-oxygenase activities were seen in beta-NF- or PB-treated mice after MG injection.