Small increases in insulin inhibit hepatic glucose production solely caused by an effect on glycogen metabolism

Based on our earlier work, a 2.5-fold increase in insulin secretion should completely inhibit hepatic glucose production through the hormone's direct effect on hepatic glycogen metabolism. The aim of the present study was to test the accuracy of this prediction and to confirm that gluconeogenic flux , as measured by three independent techniques, was unaffected by the increa se in insulin. A 40-min basal period was followed by a 180-min experimental period in which an increase in insulin was induced, with euglycemia mainta ined by peripheral glucose infusion. Arterial and hepatic sinusoidal insuli n levels increased from 10 +/- 2 to 19 +/- 3 and 20 +/- 4 to 45 +/- 5 muU/m l, respectively. Net hepatic glucose output decreased rapidly from 1.90 +/- 0.13 to 0.23 +/- 0.16 mg.kg(-1).min(-1). Three methods of measuring glucon eogenesis and glycogenolysis were used: 1) the hepatic arteriovenous differ ence technique (n = 8), 2) the [C-14] phosphoenolpyruvate technique (n = 4) , and 3) the (H2O)-H-2 technique (n = 4). The net hepatic glycogenolytic ra te decreased from 1.72 +/- 0.20 to -0.28 +/- 0.15 mg.kg(-1).min(-1) (P < 0. 05), whereas none of the above methods showed a significant change in hepat ic gluconeogenic flux (rate of conversion of phosphoenolpyruvate to glucose -6-phosphate). These results indicate that liver glycogenolysis is acutely sensitive to small changes in plasma insulin, whereas gluconeogenic flux is not.