Pathway and carbon sources for hepatic glycogen repletion in dogs

Abstract

The present studies were undertaken to quantitate the relative contributions of the indirect and direct pathways for hepatic glycogen repletion and to determine the role of splanchnic tissues in provision of C precursors used for the indirect pathway. For this purpose, we administered oral glucose (1.4 g/kg) enriched with [1-14C]glucose to 18-h fasted dogs and measured net hepatic and net gastrointestinal glucose, lactate, and alanine balance, hepatic and gastrointestinal fractional extraction [( 3H]lactate), release and uptake of lactate, as well as the total amount of hepatic glycogen formed from the oral glucose and the 14C labeling pattern of the glycogen-glucose C. Although net hepatic glucose uptake (8.7 +/- 0.6 g, 27% of the oral load) exceeded the amount of glycogen formed from the oral glucose (6.3 +/- 1.1 g), analysis of radioactivity in C-1 of the glycogen glucose indicated that nearly 50% of the glycogen was formed by the indirect pathway. Net hepatic uptake of lactate (1.4 +/- 0.1 g) and alanine (1.5 +/- 0.1 g) could account for greater than 90% of glycogen formed by the indirect pathway if all of the lactate and alanine taken up by the liver had been incorporated into glycogen. Release of lactate and alanine by splanchnic tissues approximated the amount of lactate and alanine taken up by the liver. However, in addition to taking up lactate, the liver also produced nearly as much lactate as the gastrointestinal tract (1.8 +/- 0.2 vs. 2.0 +/- 0.3 g, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Glycogen: its mode of formation and contribution to hepatic glucose output in postabsorptive humans

“…With the direct pathway, glycogen is formed from glucose 6-phosphate originating from glucose taken up and phosphorylated within the liver and then directly incorpor-ated into glycogen whereas with the indirect pathway, glycogen is formed from glucose 6-phosphate originating from gluconeogenic precursors generated either within the liver or extrahepatic tissues [10,11]. In vitro studies and experiments in rats have generally indicated that the indirect pathway is the major route for glycogen synthesis [9] but their validity and physiologic significance have been questioned [8].…”

“…Regarding this assumption, the studies of Radziuk [14] and Jackson et al [25] indicate that absorption of ingested glucose would be complete by 4.5-5 h. Furthermore, the data of Jackson et al [25], Mitrakou et al [10], and Kelley et al [24] indicate that at least 80 % of the ingested glucose would have been removed from plasma within 5 h of its ingestion. Given a half-life in plasma of 44.4 min for glucose [25], it can be calculated that less than 0.15 % of the last ingested glucose load would not have been removed from plasma.…”

“…The validity of the first assumption is supported by the studies of Devos and Hers [26] and the branching structure of glycogen in which additional glucose moieties are added to peripheral branches and degradation proceeds centripedally. Regarding the second assumption, the studies of Mitrakou et al [10] and Kelley et al [24] indicate that hepatic glucose output is maximally suppressed for at least 3 h after glucose is ingested. Thus, ingestion of glucose at 2-h intervals should have resulted in deposition of glycogen at a near uniform specific activity.…”

Inclusion of Low Amounts of Fructose With an Intraduodenal Glucose Load Markedly Reduces Postprandial Hyperglycemia and Hyperinsulinemia in the Conscious Dog

“…After oral glucose ingestion in the healthy human, 50 -77% of the liver glycogen synthesized is derived via the direct pathway (3)(4)(5)(6). The response of the conscious dog is similar to that of humans, with 25-40% of a gastrointestinal glucose load being taken up by the liver and 50 -62% of accumulated hepatic glycogen being synthesized via the direct pathway (7)(8)(9).…”

Comparison of the time courses of insulin and the portal signal on hepatic glucose and glycogen metabolism in the conscious dog.

“…In the dog, arterial plasma glucose levels of 160-290 mg/dl and insulin levels of 35-384 U/ml resulted in rates of NHGU of 1.0-2.9 mg/kg/min (1). These results demonstrate that the combination of hyperinsulinemia and hyperglycemia cannot account for the peak rates of NHGU (up to 7.5 mg/kg/min) present after the ingestion of glucose in either humans or the dog (1,(4)(5)(6)(7)(8)(9). In addition to the rise in insulin and glucose, meal ingestion also produces a rise in the portal vein glucose level that is greater than the glucose level in the arterial circulation.…”