Mechanism by which Glucose and Insulin Inhibit Net Hepatic Glycogenolysis in Humans

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Abstract

13 C NMR spectroscopy was used to assess flux rates of hepatic glycogen synthase and phosphorylase in overnightfasted subjects under one of four hypoglucagonemic conditions:protocol I, hyperglycemic ([approximate] 10 mM) -hypoinsulinemia ([approximate] 40 pM); protocol II, euglycemic ([approximate] 5 mM) -hyperinsulinemia ([approximate] 400 pM); protocol III, hyperglycemic ([approximate] 10 mM) -hyperinsulinemia ([approximate] 400 pM); and protocol IV; euglycemic ([approximate] 5 mM) -hypoinsulinemia ([approximate] 40 pM). Inhibition of net hepatic glycogenolysis occurred in both protocols I and II compared to protocol IV but via a different mechanism. Inhibition of net hepatic glycogenolysis occurred in protocol I mostly due to decreased glycogen phosphorylase flux, whereas in protocol II inhibition of net hepatic glycogenolysis occurred exclusively through the activation of glycogen synthase flux. Phosphorylase flux was unaltered, resulting in extensive glycogen cycling. Relatively high rates of net hepatic glycogen synthesis were observed in protocol III due to combined stimulation of glycogen synthase flux and inhibition of glycogen phosphorylase flux. In conclusion, under hypoglucagonemic conditions: (a) hyperglycemia, per se, inhibits net hepatic glycogenolysis primarily through inhibition of glycogen phosphorylase flux; (b) hyperinsulinemia, per se, inhibits net hepatic glycogenolysis primarily through stimulation of glycogen synthase flux; (c) inhibition of glycogen phosphorylase and the activation of glycogen synthase are not necessarily coupled and coordinated in a reciprocal fashion; and (d) promotion of hepatic glycogen cycling may be the principal mechanism by which insulin inhibits net hepatic glycogenolysis and endogenous glucose production in humans under euglycemic conditions. (J. Clin. Invest. 1998. 101:1203-1209.)

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