Hypoinsulinemia is not critical to glucose recovery from hypoglycemia in humans

To test the hypothesis that glucose recovery from hypoglycemia can occur in the absence of decrements in insulin below baseline, we studied nine normal humans on six occasions. In a control study, saline was infused. In five experimental studies, insulin (0.6 mU·kg^-1·min^-1) was infused from 0 to 80 min, to produce hypoglycemia (~3.3 mM). Then, from 80 to 180 min, insulin was not infused or was infused in four different doses (0.1, 0.2, 0.4, and 0.6 mU·kg^-1·min^-1), and glucose recovery was assessed. In the recovery periods, approximately fourfold peripheral with approximately twofold portal insulin elevations prevented glucose recovery (glucose = 3.6 ± 0.1 mM, counterregulatory hormone levels elevated throughout). However, biological glucose recovery, documented by increments to 4.3 ± 0.1 mM and decrements in all counterregulatory hormones (glucagon, epinephrine, growth hormone, and cortisol) to control levels, occurred despite nearly twofold peripheral hyperinsulinemia (54 ± 4 vs. 32 ± 4 pM, P < 0.01) in the absence of portal hypoinsulinemia (58 ± 4 vs. 68 ± 8 pM). Thus we conclude that, although dissipation of insulin normally plays an important role in the correction of hypoglycemia, biological glucose recovery from hypoglycemia to glucose levels more than sufficient to disengage glucose counterregulatory systems and well above those required to produce symptoms of hypoglycemia can occur in the absence of decrements in portal insulin below baseline and despite mild peripheral hyperinsulinemia.