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 μmol · kg−1 · min−1 (P < 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 < 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 < 0.01) stimulated gluconeogenesis ([U-14C]alanine to glucose) twofold (188 ± 22% increase compared to 114 ± 6% in saline control studies, P < 0.01). However, despite increasing gluconeogenesis, overall HGO did not change (10.6 ± 0.5 vs. 10.7 ± 0.6 μmol · kg−1 · min−1) during lipid infusion. On the other hand, when the increase in glucose recirculated to the liver as a result of decreased overnight Rd was mimicked by an incremental infusion of glucose after an overnight fast, the fall in HGO observed during sleep was reproduced independent of changes in plasma glucose and insulin values. This study suggests that peripheral events such as Rd and lipolysis may regulate HGO in nondiabetic men by a dual-control mechanism independent of insulin secretion. The relative contributions of gluconeogenesis and glycogenolysis to HGO may vary according to the levels of gluconeogenic promoters (e.g., FFA) and substrates without altering overall HGO. However, HGO may be regulated quantitatively by changes in Rd, which alter the amount of glucose recirculated to the liver.

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