EFFECTS OF PHYSIOLOGICAL HYPERINSULINEMIA ON COUNTERREGULATORY RESPONSE TO PROLONGED HYPOGLYCEMIA IN NORMAL HUMANS

To test the hypothesis that differing physiological insulin levels can modify the counterregulatory response to prolonged hypoglycemia, expe riments were carried out in 10 healthy male subjects. Insulin was infu sed subcutaneously for 8 h in two separate randomized protocols, so th at steady-state levels of 132 +/- 6 pM (low) and 402 +/- 18 pM (high) were obtained. The fall in plasma glucose was controlled by the glucos e-clamp technique. Plasma glucose fell slowly and similarly in both gr oups, reaching an identical steady-state (final 120 min of each study) level of 3.4 +/- 0.1 mM. Steady-state plasma epinephrine (2.5 +/- 0.4 vs. 1.5 +/- 0.2 nM) and norepinephrine (1.5 +/- 0.2 vs. 1.1 +/- 0.1 n M) were significantly (P < 0.05) greater during high- compared with lo w-dose insulin infusions. Plasma glucagon was reduced during high comp ared with low infusions (104 +/- 9 vs. 150 +/- 19 ng/l, P < 0.05). Gro wth hormone, cortisol, and pancreatic polypeptide increased significan tly but were not different during the two insulin infusions. Hepatic g lucose production (HGP) was equal during the steady-state period (8.4 +/- 1.0 mu mol.kg(-1).min(-1)) of each infusion. Blood lactate levels (1,255 +/- 73 vs. 788 +/- 69 mu mol/l, P < 0.02) were increased in hig h compared with low, but nonesterified fatty acid (205 +/- 43 vs. 579 +/- 65 mu mol/l) and 3-hydroxybutyrate (40 +/- 36 vs. 159 +/- 51 mu mo l/l) were reduced (P < 0.002) during the high-compared with low-dose i nfusions. Changes from baseline in systolic blood pressure (Delta 13 /- 2 vs. 1 +/- 1 mmHg), mean arterial pressure (Delta 2 +/- 1 vs. -5 /- 1 mmHg), and heart rate (Delta 10 +/- 2 vs. 2 +/- 2 beats/min) were increased (P < 0.05) during high- compared with low-dose infusions. W e conclude that the counterregulatory response in normal humans can be modified during prolonged equivalent hypoglycemia by a threefold-grea ter increase in physiological levels of insulin so that 1) catecholami ne secretion and cardiovascular responses are amplified, 2) glucagon s ecretion is attenuated, and 3) HGP is maintained similarly by offsetti ng changes in counterregulatory hormones.