Enhancement of the gluconeogenic flux of hepatic glycogen repletion by a phenacyl imidazolium compound in vivo

Abstract

The effect of a phenacyl imidazolium compound (LY177507 or Proglycosyn, Eli Lilly) on the direct (glucose→glucose-6-phosphate→glycogen) and indirect (three-carbon compounds→glucose-6-phosphate→glycogen) pathways of liver glycogen synthesis was studied in conscious rats. [1-¹³C]Glucose (99% enriched) was infused intraduodenally into chronically catheterized Proglycosyn-treated (n=7) and saline-treated (n=7) rats for 120 min. Net hepatic glycogen synthetic rates were increased twofold in drug-treated rats compared with saline-treated controls. The percentage of liver glycogen synthesized by the direct pathway was calculated by comparing the¹³C isotopic enrichment in the C1 and C6 positions of hepatic glycogen and plasma glucose using¹³C nuclear magnetic resonance spectroscopy and gas chromatography-mass spectroscopy techniques and was found to be 59±5% and 39±2% (P<0.05) in the saline treated and Proglycosyn-treated groups, respectively. Net flux rates for the direct and indirect pathways were calculated to be 0.24±0.04 and 0.17±0.03 μmol/g liver per min, respectively, in the saline-treated group and 0.30±0.04 (P=NS) and 0.46±0.06 (P<0.05) μmol/g liver per min, respectively, in the Proglycosyn-treated group. Thus, Proglycosyn increases net hepatic glycogen synthesis in vivo exclusively through augmentation of the indirect pathway.