ENHANCEMENT OF THE GLUCONEOGENIC FLUX OF HEPATIC GLYCOGEN REPLETION BY A PHENACYL IMIDAZOLIUM COMPOUND IN-VIVO

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-C-13]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 the C-13 isotopic enrichment in the C1 and C6 positions of hepatic glycogen and plasma glucose using C-13 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 mumol/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) mumol/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.