This chapter discusses hormonal interactions in the regulation of blood glucose. The regulation of the blood glucose concentration is a well-recognized function of the endocrine system. The efficacy of the various control mechanisms is reflected by the very limited excursions in blood glucose observed in normal humans. In normal man, the bursts of glucagon secretion precipitated by feeding pure protein prevent the inhibition in glucose production and the hypoglycemia that would otherwise accompany protein-stimulated insulin secretion. In contrast, sustained hyperglucagonemia fails to cause glucose intolerance or worsening of preexisting diabetes so long as endogenous or exogenous insulin is available. In the case of insulin, the down regulation of the insulin receptor has been observed to occur in hyperinsulinemic states. The glucagon infusion fails to alter specific binding of insulin or growth hormone, indicating the specificity of the effect of hyperglucagonemia on glucagon binding. Glucagon-induced hyperglycemia can, however, be observed either in circumstances of absolute insulin deficiency or when tissue sensitivity to this hormone is increased. The synergistic nature of these hormone–hormone interactions with respect to raising circulating plasma glucose levels may constitute the mechanism for stress hyperglycemia.

The effect of glucagon and/or epinephrine on the response to physiologic insulin infusion was evaluated in dogs. Insulin alone produced a transient fall (50%) in glucose output, a threefold rise in glucose clearance, and a decline in plasma glucose, which then stabilized (40--45 mg/dl) afer 1 h. Glucagon infusion prevented the fall in glucose output, but had no effect on insulin-induced elevations in glucose clearance. The fall in plasma glucose was delayed (20 min), but late hypoglycemia was unaltered. Epinephrine infusion blocked the fall in glucose output as well as the insulin-induced rise in glucose clearance and uptake. Thus, while epinephrine and glucagon were equally effective in preventing the fall in glucose output induced by insulin, epinephrine was more effective in preventing insulin-induced hypoglycemia by virtue of its direct inhibitory action on insulin-stimulated glucose utilization. Simultaneous addition of glucagon and epinephrine increased glucose output twofold, suppressed glucose clearance, and caused a 15--30 mg/dl increase in plasma glucose despite ongoing hyperinsulinemia. Our data thus indicate that synergistic hormone interactions may play a role in the counterregulation of insulin hypoglycemia.