HEPATIC GLUCONEOGENIC FLUXES AND GLYCOGEN TURNOVER DURING FASTING IN HUMANS - A STABLE-ISOTOPE STUDY

Fluxes through intrahepatic glucose-producing metabolic pathways were measured in normal humans during over-night or prolonged (60 h) fastin g. The glucuronate probe was used to measure the turnover and sources of hepatic UDP-glucose; mass isotopomer distribution analysis from [2- C-13(1)]glycerol for gluconeogenesis and UDP-gIuconeogenesis; [U-C-13( 6)]glucose for glucose production (GP) and the direct UDP-glucose path way; and [1-H-2(1)]galactose for UDP-glucose flux and retention in hep atic glycogen. After overnight fasting, GP (fluxes in milligram per ki logram per minute) was 2.19+/-0.09, of which 0.79 (36%) was from gluco neogenesis, 1.40 was from glycogenolysis, 0.30 was retained in glycoge n via UDP-gluconeogenesis, and 0.17 entered hepatic UDP-glucose by the direct pathway. Thus, total flux through the gluconeogenic pathway (1 .09) represented 54% of extrahepatic glucose disposal (2.02) and the n et hepatic glycogen depletion rate was 0.93 (46%). Prolonging [2-C-13( 1)]glycerol infusion slowly increased measured fractional gluconeogene sis. In response to prolonged fasting, GP was lower (1.43+/-0.06) and fractional and absolute gluconeogenesis were higher (78+/-2% and 1.11/-0.07, respectively). The small but nonzero glycogen input to plasma glucose (0.32+/-0.03) was completely balanced by retained UDP-gluconeo genesis (0.31+/-0.02). Total gluconeogenic pathway flux therefore acco unted for 99+/-2% of GP, but with a glycogen cycle interposed. Prolong ing isotope infusion to 10 h increased measured fractional gluconeogen esis and UDP-gluconeogenesis to 84-96%, implying replacement of glycog en by gluconeogenic-labeled glucose. Moreover, after glucagon administ ration, GP (1.65), recovery of [l-H-2(1)]galactose label in plasma glu cose (25%) and fractional gluconeogenesis (91%) increased, such that 7 8% (0.45/0.59) of glycogen released was labeled (i.e., of recent gluco neogenic origin). In conclusion, hepatic gluconeogenic flux into glyco gen and glycogen turnover persist during fasting in humans, reconcilin g inconsistencies in the literature and interposing another locus of c ontrol in the normal pathway of GP.