The aim of this study was to investigate the effect of hyperinsulinemia on the first and second phase of arginine-induced insulin release in humans. Seven healthy subjects underwent three studies (lasting 360 min): a control study using saline infusion and two euglycemic clamps using a low-dose (0.33 mU · kg−1 · min−1) and a high-dose (1.20 mU · kg−1 · min−1) insulin infusion. After a 3-h equilibration period, arginine (25 g) was infused for 30 min, and insulin and C-peptide responses to arginine were followed for 180 min. At the end of the equilibration period, before arginine administration, steady-state insulin levels were (means ± SE) 60.0 ± 2.4, 165.6 ± 1.8, and 455.4 ± 7.8 pmol/l during saline, low-dose, and high-dose insulin infusions, respectively. The time course of insulin release during the arginine test was calculated from C-peptide concentrations by using C-peptide kinetic modeling and deconvolution. In particular, first-phase and second-phase insulin response was obtained by integrating the time course of the insulin release during either the first 5 min or the following 40 min of the arginine test, respectively. Whereas first-phase insulin release was independent of any effect induced by either insulin infusion, second-phase insulin release was reduced in a similar degree by both insulin infusion doses. First phase was 75.5 ± 10.1, 73.7 ± 12.8, and 73.4 ± 10.3 pmol/kg, whereas second phase was 266.1 ± 46.0, 143.1 ± 33.5, and 133.0 ± 30.2 pmol/kg for saline, low-dose, and high-dose insulin infusions, respectively. We conclude that second-phase, but not first-phase, arginine-induced insulin release is modulated by the pre-stimulus insulin levels. In addition, the inhibitory effect exerted by insulin on second-phase insulin response to arginine appears to be maximized at insulin levels only four times basal.

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