S-15261, a new anti-hyperglycemic agent, reduces hepatic glucose production through direct and insulin-sensitizing effects

S-15261 is a new oral anti-hyperglycemic agent that increases Insulin sensitivity in various insulin-resistant animal models. The aim of this study was to determine the short- and long-term effects of S-15261 and its metabolites (S-15511 and Y-415) on fatty acid and glucose metabolism in hepatocytes isolated from 24-h starved rats. During short-term exposure (1h) neither S-15261 nor its metabolites affected fatty acid oxidation whatever the concentration used. By contrast, S-15261 and its two metabolites reduced the rates of glucose production from lactate/pyruvate and dihydroxyacetone. Using crossover plot analysis, it was shown that Y-415 reduced hepatic gluconeogenesis upstream the formation of dihydroxyacetone phosphate. After 48 h in culture, S-15261 and its two metabolites reduced the rates of glucose production from lactate/pyruvate secondarily to a decrease in PEPCK and Glc-6-Pase mRNA levels. A part of these effects on gene expression could be due to a drug-induced reduction in PGC-1 gene expression. When hepatocytes were cultured in the presence of a submaximal concentration of Insulin (10(-9)M), S-15261, through its metabolite S-15511, enhanced Insulin sensitivity both on gene expression (PEPCK, Glc-6-Pase, PGC-1) and on gluconeogenesis. Furthermore, S-15261 and S-15511 induced the expression of GK and FAS genes as the result of an increased in SREBP-1c mRNA levels. Finally, S-15511 enhanced the stimulatory effect of Insulin on GK mRNA level through an additional increase in SREBP-1c gene expression. In conclusion, this work reveals that S-15261 via its metabolites reduces hepatic glucose production through direct and insulin-sensitizing effects on genes encoding regulatory proteins of hepatic glucose metabolism.