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Effects of Hepatic Glycogen Content on Hepatic Insulin Action in Humans: Alteration in the Relative Contributions of Glycogenolysis and Gluconeogenesis to Endogenous Glucose Production¹

Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Robert A. Rizza, M.D., Mayo Clinic and Foundation, The Endocrine Research Unit, 200 First Street SW, 5–164 West Joseph, Rochester, Minnesota 55905. E-mail: rizza.robert{at}mayo.edu

Hepatic glycogen content varies by almost 2-fold during the day, generally increasing from a nadir before breakfast to a peak 4–5 h after supper. To determine whether differences in hepatic glycogen content of this magnitude alter hepatic insulin action, nine subjects were studied on two occasions. On one occasion saline was infused, whereas on the other occasion an infusion of glucose [16.4 µmol/kg lean body mass (-lbm)·min] was started immediately after supper and continued throughout the night so as to spare hepatic glycogen. The nocturnal glucose infusion resulted in higher (P < 0.05) plasma glucose (6.0 ± 0.1 vs. 5.1 ± 0.1 mmol/L) and insulin (127 ± 38 vs. 49 ± 9 pmol/L) concentrations, and lower (P < 0.05) plasma glucagon concentrations (74 ± 11 vs. 97 ± 20 pg/mL) than did saline infusion. As anticipated, endogenous glucose production (EGP) was substantially lower (P < 0.001) during the glucose than during the saline infusion (7.0 ± 0.9 vs. 19.4 ± 1.3 µmol/kg-lbm·min). After discontinuation of the glucose infusion, glucose and insulin concentrations fell to levels that no longer differed from those observed during the saline infusion. In contrast, EGP increased to rates that were higher (P < 0.05) than those observed over the same interval after overnight saline infusion (19.2 ± 1.2 vs. 16.5 ± 0.7 µmol/kg-lbm·min). Despite higher EGP, the rate of incorporation of ¹⁴CO₂ into glucose was lower (P < 0.001) after glucose than that after saline infusion (9.8 ± 1.2% vs. 24.4 ± 3.0%), implying a reciprocal relationship between hepatic glycogen content and gluconeogenesis. On the other hand, when differences in basal rates were taken into account, insulin-induced suppression of both EGP and incorporation of ¹⁴CO₂ into glucose did not differ on the two occasions. Thus, whereas hepatic glycogen content influences both the absolute rate of EGP and the percent contribution of gluconeogenesis to EGP, it does not alter hepatic insulin action.

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