To determine the effect of increased glycogen stores on hepatic carbohydrate metabolism, 15 nondiabetic volunteers were studied before and after 4 d of progressive overfeeding. Glucose production and gluconeogenesis were assessed with glucose (Study I, n = 6) or [3-3H] glucose and [U-4C I -alanine (Study H, n = 9) and substrate oxidation was determined by indirect calorimetry. Overfeeding was associated with significant (P < 0.01) increases in plasma glucose (4.97±0.10 to 5.09±0.11 mmol/ liter), insulin (18.8±1.5 to 46.6±+10.0 pmol/liter) and carbohydrate oxidation (4.7±1.4 to 18.0±1.5 ,Imol -kg'-* min -1) and a decrease in lipid oxidation (1.2+0.2 to 0.3±0.1 ,umol kg -1. min-'). Hepatic glucose output (HGO) increased in Study I (10.2±0.5 to 13.1+0.9 ,umol -kg-' min-', P < 0.01) and Study 11 (11.17+0.67 to 13.33±0.83 ,umol * kg'-. min-, P < 0.01), and gluconeogenesis decreased (57.6+6.4 to 33.4±4.9 ,umol/min, P < 0.01), indicating an increase in glycogenolysis. The increase in glycogenolysis was only partly compensated by an increase in glucose cycle activity (2.2±0.2 to 3.4±0.4 ,umol kg-1min-1, P < 0.01) and the fall in gluconeogenesis, thus resulting in increased HGO. The suppression of gluconeogenesis despite increased lactate and alanine (glycerol was decreased) was associated with decreased free fatty acid (FFA) oxidation and negligible FFA enhanced gluconeogenesis. These studies suggest that increased liver glycogen stores alone can overwhelm normal intrahepatic mechanisms regulating carbohydrate metabolism resulting in increased HGO in nondiabetic man. (J.
We previously reported a fall in hepatic glucose output (HGO) during sleep accompanied by reductions in glucose utilization (Rd) and free fatty acids (FFAs). This study was undertaken to determine the potential role of changes in Rd and FFA on HGO in nondiabetic men. To determine if the fall in HGO during sleep could be reversed by FFA elevation, seven nondiabetic men underwent [3-3H]glucose infusions from 2200 to 0800, with heparin (90 mU.kg-1.min-1) added at 0200. Glucose appearance (Ra) fell from 11.7 +/- 1.1 at 2430 to 8.9 +/- 0.8 mumol.kg-1.min-1 (P less than 0.05) at 0200. The fall in Ra was associated with decreases in FFA (0.57 +/- 0.10 to 0.48 +/- 0.07 mM) and glycerol (0.08 +/- 0.01 to 0.06 +/- 0.01 mM). Infusion of heparin significantly increased FFA and glycerol (1.09 +/- 0.21 and 0.11 +/- 0.01 mM, respectively, P less than 0.01) and resulted in a significant fall in plasma alanine, suggesting that gluconeogenesis had been increased. However, rates of glucose turnover were indistinguishable from overnight studies without heparin. In additional studies (n = 6), intralipid and heparin-induced FFA elevation (from 0.61 +/- 0.07 to 0.95 +/- 0.05 mM, P less than 0.01) stimulated gluconeogenesis ([U-14C]alanine to glucose) twofold (188 +/- 22% increase compared to 114 +/- 6% in saline control studies, P less than 0.01). However, despite increasing gluconeogenesis, overall HGO did not change (10.6 +/- 0.5 vs. 10.7 +/- 0.6 mumol.kg-1.min-1) during lipid infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
We have previously reported a 25% fall in glucose utilization (Rd) and glucose production (Ra) in normal volunteers during an overnight fast, when glycogenolysis accounts for approximately 70% of hepatic glucose output (HGO). This reduction in Ra and Rd was positively correlated with reductions in glycerol and FFA. To determine if a similar fall in HGO occurs after a prolonged fast when HGO depends solely upon gluconeogenesis, seven normal male volunteers were fasted for 72 h. Glucose kinetics were then assessed overnight using a [3-3H]glucose infusion from 2200-0800 h. Plasma glucose (3.6 +/- 0.1 mM), immunoreactive insulin (2.7 +/- 0.4 mU/L), C-peptide (0.22 +/- 0.03 nmol/l), Rd (1.30 +/- 0.03 mg/kg.min), and Ra (1.28 +/- 0.03 mg/kg.min) were suppressed, and plasma glucagon (98.8 +/- 13.2 pmol/L) was elevated compared to values obtained during the overnight fast, but none of these parameters changed overnight after the 3-day fast. Plasma lactate (0.98 +/- 0.09 mmol/L) and alanine (0.18 +/- 0.03 mmol/L) levels were also unchanged throughout the night. Plasma glycerol (0.14 +/- 0.03 mmol/L) and FFA (0.98 +/- 0.07 mmol/L) were significantly elevated compared to values during the overnight fast, but failed to fall during the study as had been observed during a 14-h fast. We conclude that the modulation of HGO observed during an overnight fast does not occur during prolonged fasting. The lack of nocturnal modulation of HGO when plasma FFA and glycerol levels are fixed at elevated concentrations supports a role of FFA and/or glycerol in the modulation of HGO during an overnight fast.
In order to examine the role of fructose 2,6-bisphosphate (Fru-2,6-P2) in non-esterified-fatty-acid-stimulated gluconeogenesis, Fru-2,6-P2 levels were measured in cultured rat hepatocytes under conditions mimicking the fasted state. After addition of either 1.5 mM-palmitate or 10 nM-glucagon, [U-14C]lactate incorporation into glucose increased 2-fold, but only glucagon suppressed Fru-2,6-P2. Prevention of palmitate oxidation with a carnitine palmitoyltransferase-I inhibitor (2-bromopalmitate) diminished glucose production and Fru-2,6-P2 levels. Addition of exogenous glucose to the media increased Fru-2,6-P2 in a dose-related manner, which was further augmented by addition of palmitate. When Fru-2,6-P2 levels were examined in cells cultured under conditions mimicking the fed state (significantly higher basal Fru-2,6-P2 levels and lower glucose production), palmitate oxidation was associated with a significant fall in Fru-2,6-P2. In conclusion, the present studies have demonstrated a dissociation between fatty-acid-stimulated gluconeogenesis and changes in Fru-2,6-P2 in cultured rat hepatocytes. Further experiments suggest that the accumulation of intracellular hexose 6-phosphate as a result of fatty-acid-stimulated gluconeogenesis masks a putative inhibitory effect of fatty acids on Fru-2,6-P2 concentrations.
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