The pancreatic-adrenocortical-pituitary clamp technique for study of counterregulation in humans

The present experiments were undertaken to develop an approach to analyze the contribution of individual glucose counterregulatory hormones in humans. For this purpose, 24 normal subjects were studied twice: once (control experiments) hypoglycemia was induced by subcutaneous infusion of insulin; and once [pancreatic-adrenocortical-pituitary (PAP) clamp technique] the spontaneous responses of plasma glucagon, growth hormone, and cortisol to hypoglycemia were prevented by intravenous somatostatin and oral metyrapone, respectively, and each hormone was infused at variable rates, which reproduced spontaneous changes in their circulating concentrations in the control experiments. Plasma glucose rate of decrease (0.052 +/- 0.003 vs. 0.06 +/- 0.003 mg X dl-1 X min-1), plasma glucose nadir (49.8 +/- 1.2 vs. 50 +/- 1.0 mg/dl), initial suppression of glucose production (0.22 +/- 0.01 vs. 0.23 +/- 0.01 mg X kg-1 X min-1), subsequent compensatory increase in glucose production (0.54 +/- 0.05 vs. 0.48 +/- 0.04 mg X kg-1 X min-1), and the increase in glucose utilization (0.45 +/- 0.05 vs. 0.42 +/- 0.05 mg X kg-1 X min-1) in PAP clamp and control experiments, respectively, were not significantly different and were significantly correlated. Changes in plasma alanine, lactate, free fatty acids, 3-beta-hydroxybutyrate concentrations were also virtually identical in the PAP clamp experiments and in control experiments. We conclude that the PAP clamp technique can faithfully reproduce the spontaneous hormonal and substrate responses to hypoglycemia and should be useful to assess the contribution of individual hormones during counterregulation by creating an isolated (total or partial) deficiency of a particular hormone without confounding compensatory changes in secretion of other counterregulatory hormones.