We examined the mechanism of norepinephrine's ketogenic activity in normal man. The contribution of norepinephrine's lipolytic activity to the subsequent ketosis was assessed by comparing the degree of ketosis attained during hormone infusion and the degree of ketosis observed after heparin-induced free fatty acid substrate generation. In addition, we examined the effect of norepinephrine infusion on the plasma concentration of other stress hormones (glucagon, cortisol, and growth hormone) with the experimental protocol.

The results obtained during norepinephrine infusion into normal man demonstrated that norepinephrine's lipolytic activity was not the principal determinant of its ketogenic activity. In fact, less than 50% of norepinephrine's ketogenic activity could be attributed to the rise in plasma free fatty acid concentration. Furthermore, the ketosis that resulted from plasma norepinephrine elevation may have been a direct hormonal effect at the liver or may have been secondary to the norepinephrine-induced elevation of glucagon and/or suppression of insulin.

Our results emphasize the important role that endogenous insulin secretion plays on modulating the ketogenic effects of the stress hormones. Thus, norepinephrine, which suppresses plasma insulin secretion, is markedly ketogenic compared with the normal ketogenic response to glucagon, in spite of the fact that both of these stress hormones may activate ketogenesis via cyclic AMP formation. In conclusion, this study, in concert with a previous study in diabetic man, firmly established norepinephrine as a major ketogenic hormone in man.

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