COUNTERREGULATORY HORMONE RESPONSES DURING GRADED HYPERINSULINEMIC EUGLYCEMIA IN CONSCIOUS RATS

It has been suggested that hyperinsulinemia per se may affect the leve ls of some counterregulatory hormones in the absence of hypoglycemia. We studied the effect of graded hyperinsulinemia and concomitant incre ased glucose metabolism on the levels of counterregulatory hormones by means of the 5-step sequential hyperinsulinemic euglycemic clamp tech nique, combined with [3-H-3]-glucose infusion, in conscious rats. Insu lin infusion rates (IIR) of 0, 0.5, 1, 3, and 16 mU/min, resulted in s teady-state plasma insulin levels (mean +/- SEM) of 24 +/- 4, 44 +/- 3 , 98 +/- 8, 418 +/- 48, and 6626 +/- 361 mu U/ml, peripheral glucose u ptake (PGU) of 3.1 +/- 0.2, 3.6 +/- 0.3, 5.4 +/- 0.3, 9.2 +/- 0.4, and 12.4 +/- 0.2 mg/min and hepatic glucose production (HGP) of 3.1 +/- 0 .2, 2.4 +/- 0.4, 0.8 +/- 0.3, -0.1 +/- 0.2, and -0.5 +/- 0.3 mg/min, r espectively. Plasma glucagon levels were half maximally suppressed bet ween IIRs of 0.5 and 1 mU/min and maximally suppressed at 3 mU/min. Th e suppression exactly paralleled the inhibition of HGP (r = 0.87 +/- 0 .04, p < 0.02) but not the stimulation of PGU (r = -0.66 +/- 0.12, p = NS). This suggests that the inhibition of HGP by insulin is at least partially mediated by a simultaneous suppression of plasma glucagon le vels. The adrenal hormones corticosterone and epinephrine were not inf luenced during the clamp. Moreover, the circadian rhythm of corticoste rone seemed unaffected. Plasma norepinephrine levels were increased (/- 50%, p < 0.05) at IIRs of 1 mU/min and higher, suggesting an insuli n-induced stimulation of the sympathetic nervous system when periphera l plasma insulin levels exceed 98 +/- 8 mu U/ml. In conclusion, measur ement of in vivo insulin action by means of the euglycemic clamp induc es dose-dependent changes in the levels of glucagon and norepinephrine but not in epinephrine and corticosterone. This has to be taken into account because it is, in fact, the interaction between insulin and th ese counterregulatory hormones that determines the ultimate action of insulin on glucose metabolism in vivo.