Differential effect of hyperglycemia and hyperinsulinemia on pathways of hepatic glycogen repletion

To delineate the roles of hyperglycemia and insulin on the direct vs. indirect pathways of liver glycogen synthesis, we performed euglycemic (group I; n = 8), hyperglycemic (group II; n = 9), and euglycemic pharmacological hyperinsulinemic clamp studies (120 min) with an infusion of [1-¹³C]glucose in chronically catheterized conscious rats after a 24-h fast. Portal vein plasma glucose concentrations and portal vein plasma insulin concentrations, respectively, obtained at the end of the study in groups I-III were as follows: group I 110 ± 4 mg/dl, 29 ± 7 ng/ml; group III 219 ± 7 mg/dl, 24 ± 7 ng/ml; and group III 112 ± 9 mg/dl, 174 ± 25 ng/ml. Mean liver glycogen concentrations at the end of the three studies were 0.68 ± 0.07, 1.22 ± 0.08 (P < 0.001 compared with groups I and III), and 0.60 ± 0.17 g/100 g wet wt liver in groups I-III respectively, which yielded hepatic glycogen synthetic rates of 0.16 ± 0.03, 0.41 ± 0.04 (P < 0.001 compared with groups I and III), and 0.13 ± 0.08 μmol glucosyl U·g liver^-1·min^-1 in groups I-III, respectively. From the enrichments of ¹³C in the C-1 and C-6 positions of the glucosyl unit in glycogen compared with the enrichment in the C-1 position in portal vein glucose as determined by ¹³C- and ¹H-NMR, the amount of glycogen synthesized by the direct pathway was calculated to be 18 ± 2, 41 ± 3 (P < 0.0001 compared with groups I and III), and 17 ± 3% in groups I-III, respectively. In conclusion, during the insulinized state, hyperglycemia 1) markedly increased the percent of hepatic glycogen synthesized by the direct pathway and 2) played a major role in augmenting hepatic glycogen synthesis.