Synergistic Interactions among Antiinsulin Hormones in the Pathogenesis of Stress Hyperglycemia in Humans*

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Abstract
We infused epinephrine, glucagon, and cortisol in combination into health y overnight-fasted subjects in doses designed to simulate changes in severe stress. Whenall three hormones were infused simultaneously, glucose levels rose above 200 mg/dl in spite of a 100–200% increase in plasma insulin. In contrast, infusion of each hormone individually produced eithera mild (<120 mg/dl) or a transient elevation in the plasma glucoseconcentration. With the combined hormone infusion,the increment in plasmaglucose was 3-fold greater than the sum of the responses to the individual hormones (< 0.001). The marked hyperglycemia in this setting is a resultof ongoing glucose overproduction which is stimulated by epinephrine and glucagon and sustained by cortisol. Furthermore, epinephrine(and possibly cortisol) inhibited glucose disposal despite concomitant hyperinsulinemia. In contrast to their effects on glucoseregulation, the simultaneous infusion of epinephrine, glucagon, and cortisol failed to cause hyperketonemia. We conclude that the combined infusion of epinephrine, glucagon, and cortisol produces a greater than additive hyperglycemic response in normal humans. These data suggest that the clinical occurrence of fasting hyperglycemia in a setting of hypersecretion of multiple antiinsulin hormones (stress hyperglycemia)may result, at least in part, from synergistic interactionsamong these hormones.