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, experiments were carried out in 10 healthy male subjects. Insulin was infused subcutaneously for 8 h in two separate randomized protocols, so that steady-state levels of 132 +/- 6 pM (low) and 402 +/- 18 pM (high) were obtained. The fall in plasma glucose was controlled by the glucose-clamp technique. Plasma glucose fell slowly and similarly in both groups, 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 nM) were significantly (P < 0.05) greater during high- compared with low-dose insulin infusions. Plasma glucagon was reduced during high compared with low infusions (104 +/- 9 vs. 150 +/- 19 ng/l, P < 0.05). Growth hormone, cortisol, and pancreatic polypeptide increased significantly but were not different during the two insulin infusions. Hepatic glucose 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 high compared with low, but nonesterified fatty acid (205 +/- 43 vs. 579 +/- 65 mu mol/l) and 3-hydroxybutyrate (40 +/- 36 vs. 159 +/- 51 mu mol/l) were reduced (P < 0.002) during the high-compared with low-dose infusions. 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. We conclude that the counterregulatory response in normal humans can be modified during prolonged equivalent hypoglycemia by a threefold-greater increase in physiological levels of insulin so that 1) catecholamine secretion and cardiovascular responses are amplified, 2) glucagon secretion is attenuated, and 3) HGP is maintained similarly by offsetting changes in counterregulatory hormones.