The normal pancreatic response to an exogenous glucagon infusion is a biphasic release of insulin. In our study the ability of each component of insulin release to counter the effects of the glucagon on gluconeogenesis and alanine metabolism was assessed by mimicking first- and/or second-phase insulin release with infusions of somatostatin and intraportal insulin. When a fourfold increase in glucagon was brought about in the presence of fixed basal insulin release, there was a large increase in overall glucose production and gluconeogenesis. The increase in the conversion of [14C]alanine into [14C]glucose (169 ± 42%, P < .05) was accompanied by an increase in the fractional extraction of alanine by the liver (FEA 0.32 ± 0.06 to 0.66 ± 0.10, P < .05) and net hepatic alanine uptake (NHAU 2.97 ± 0.45 to 4.61 ± 0.48 μmol kg1 · min1 P < .05). Simulated first-phase insulin release had no effect on the ability of glucagon to increase FEA (0.32 ± 0.03 to 0.66 ± 0.03, P < .05) or NHAU (3.69 ± 0.80 to 5.10 ± 0.69 μmol · kg1 · min−1 P < .05) but did limit the increase in overall gluconeogenic conversion (114 ± 37%). Second-phase insulin release had no effect on either the glucagon-induced increase in FEA (0.35 ± 0.08 to 0.73 ± 0.04) or NHAU (3.35 ± 0.92 to 5.13 ± 0.85 μmol · kg−1 · min−1) but completely inhibited the increase in overall gluconeogenic conversion. Combined first- and second-phase insulin release was also unable to prevent the glucagon-induced increase in FEA (0.35 ± 0.09 to 0.65 ± 0.06, P < .05) and-NHAU (2.59 ± 0.56 to 3.50 ± 0.37 μmol · kg−1 · min−1) but completely inhibited the glucagon-induced rise in gluconeogenic conversion. These data show that the glucagon-induced increase in gluconeogenic conversion was remarkably sensitive to relatively small (≃8 μU/ml) changes in circulating insulin. Even a brief (5-min) pulse of insulin markedly reduced the effect of glucagon on the overall gluconeogenic process for a prolonged period. Furthermore, the inhibitory action of insulin appeared to occur within the hepatocyte rather than at the cell membrane because the increase in the fractional extraction of alanine by the liver and indeed the rise in hepatic alanine uptake caused by glucagon were unaffected by the increase in insulin.
Relative Importance of First- and Second-Phase Insulin Secretion in Glucose Homeostasis in Conscious Dog: II. Effects on Gluconeogenesis
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Kurt E Steiner, Stephanie M Mouton, Philip E Williams, William W Lacy, Alan D Cherrington; Relative Importance of First- and Second-Phase Insulin Secretion in Glucose Homeostasis in Conscious Dog: II. Effects on Gluconeogenesis. Diabetes 1 July 1986; 35 (7): 776–784. https://doi.org/10.2337/diab.35.7.776
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