1. Investigación

Rats chronically treated with two daily doses of tolbutamide, glibenclamide or glipentide were compared with animals treated with placebo. Plasma individual amino acids were determined at 0, 3, 7, 10, 12, 14, 17, 24, 27 and 29 days of treatment 16 hours after the administration of the drug. Rats were fasted for 48 h periods at days 10 to 12 and 27 to 29 of the experiment. Sulfonylurea treated animals show minor changes in the plasma aminogram, although glipentide and glibenclamide produced greater effects than tolbutamide. At the 3rd day after the onset of the treatment, plasma levels of glutamate+ glutamine, arginine and histidine appeared significantly reduced in glipentide and glibenclamide treated animals. When plasma samples were collected 3 h after the drug administration at the 24th day of treatment, the only observed change was a decrease in the levels of arginine in the glipentide treated animals. Fasting produced decreases in plasma levels of alanine, pro line, cysteine, tyrosine, methionine +ornithine and tryptophan, there were no changes in serine, aspartate + asparagine, threonine citruline, arginine and lysine; and glycine, glutamate+ glutamine and leucine + isoleucine show increases. These changes were rapidly compensated with refeeding, appearing a "rebound effect" in certain amino acids. Both fasting and refeeding affect very little the effect of sultonylureas on plasma amino acid levels, although for some individual amino acid they reduce or enhance the effect of the fasting. These small effect of sulfonylureas on plasma amino acid levels could be the result of the juxtaposition of different factors, including the effects of these drugs on circulating insulin levels, on protein biosynthesis and amino acids transamination and hepatic gluconeogenesis.

The effect of glucose, arginine, pyruvate and palmitate administration on levels of circulating glucose and RIA-insulin was studied in fed and 48 h-fasted rats. The rise in blood glucose level after oral glucose load was greater in fasted than in fed rats, whereas plasma insulin level increase was similar in both groups. When glucose was given intravenously, plasma RIA-insulin rose only in the fed animals. Arginine administration produced minor changes in these parameters in both fed and fasted rats. Oral pyruvate produced greater enhancement in blood glucose concentration in fasted than in fed animals while plasma insulin levels rose only in the fed rats. After palmitate load, blood glucose levels increased only in the fed animals in which there was also an increase in plasma insulin levels following intravenous administration of fatty acid. These results suggest that none of the metabolites used except glucose has a physiological role in insulin secretion in the fed or fasted animals; in the latter group sensitivity to glucose stimulus was greatly reduced while the release of insulinotropic gastrointestinal factors after administration of oral glucose appeared less affected. The changes in blood glucose levels observed after addition of pyruvate or palmitate are discussed in terms of the role of pyruvate as a gluconeogenetic substrate and of the effect of palmitate on glucose metabolism.