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 less than .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 less than .05) and net hepatic alanine uptake (NHAU 2.97 +/- 0.45 to 4.61 +/- 0.48 mumol . kg-1 . min-1, P less than .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 less than .05) or NHAU (3.69 +/- 0.80 to 5.10 +/- 0.69 mumol . kg-1 . min-1, P less than .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 mumol . kg-1 . min-1) but completely inhibited the increase in overall gluconeogenic conversion.(ABSTRACT TRUNCATED AT 250 WORDS)