Counterregulatory Hormone Responses During Graded Hyperinsulinemic Euglycemia in Conscious Rats

It has been suggested that hyperinsulinemia per se may affect the levels of some counterregulatory hormones in the absence of hypoglycemia. We studied the effect of graded hyperinsulinemia and concomitant increased glucose metabolism on the levels of counterregulatory hormones by means of the 5-step sequential hyperinsulinemic euglycemic clamp technique, combined with [3-3H]-glucose infusion, in conscious rats. Insulin infusion rates (IIR) of 0, 0.5, 1, 3, and 16 mU/min, resulted in steady-state plasma insulin levels (mean ± SEM) of 24 ± 4, 44 ± 3, 98 ± 8, 418 ± 48, and 6626 ± 361 µU/ml, peripheral glucose uptake (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, respectively. Plasma glucagon levels were half maximally suppressed between IIRs of 0.5 and 1 mU/min and maximally suppressed at 3 mU/min. The 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 levels. The adrenal hormones corticosterone and epinephrine were not influenced during the clamp. Moreover, the circadian rhythm of corticosterone seemed unaffected. Plasma norepinephrine levels were increased (±50%, p < 0.05) at IIRs of 1 mU/min and higher, suggesting an insulin-induced stimulation of the sympathetic nervous system when peripheral plasma insulin levels exceed 98 ± 8 µU/ml. In conclusion, measurement of in vivo insulin action by means of the euglycemic clamp induces dose-dependent changes in the levels ofglucagon 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 these counterregulatory hormones that determines the ultimate action of insulin on glucose metabolism in vivo.