Mechanisms of postprandial glucose counterregulation in man. Physiologic role of glucagon and epinephrine vis-a-vis insulin in the prevention of hypoglycemia late after glucose ingestion

The transition from exogenous glucose delivery to endogenous glucose production late after glucose ingestion is not solely attributable to dissipation of insulin and therefore, must also involve factors that actively raise the plasma glucose concentration - glucose counterregulatory factors. We have shown that the secretion of two of these, glucagon and epinephrine, is specific for glucose ingestion and temporally related to the glucose counterregulatory process. To determine the physiologic roles of glucagon and epinephrine in prostprandial glucose counterregulation, we produced pharmacologic interventions that resulted in endogenous glucagon deficiency with and without exogenous glucagon replacement, adrenergic blockade, and adrenergic blockade coupled with glucagon deficiency starting 225 min after the ingestion of 75 g of glucose in normal subjects. Also, we assessed the effect of endogenous epinephrine deficiency alone and in combination with glucagon deficiency late after glucose ingestion in bilaterally adrenalectomized subjects. Glucagon deficiency resulted in nadir plasma glucose concentrations that were ~30% lower (P < 0.01) than control values, but did not cause hypoglycemia late after glucose ingestion. This effect was prevented by glucagon replacement. Neither adrenergic blockade nor epinephrine deficiency alone impaired the glucose counterregulatory process. However, combined glucagon and epinephrine deficiencies resulted in a progressive fall in mean plasma glucose to a hypoglycemic level late after glucose ingestion; the final glucose concentration was 40% lower (P < 0.02) than the control (epinephrine deficient) value in these patients and was nearly 50% lower (P < 0.001) than the control value and ~30% lower (P < 0.05) than the glucagon-deficient value in normal subjects. We conclude (a) the transition from eexogenous glucose delivery to endogenous glucose production late after glucose ingestion is the result of the coordinated diminution of insulin secretion and the resumption of glucagon secretion. (b) Epinephrine does not normally play a critical role in this process, but enhanced epinephrine secretion compensates largely and prevents hypoglycemia when glucagon secretion is deficient.