Stimulatory effect of norepinephrine on ketogenesis in normal and insulin-deficient humans

Elevation of plasma norepinephrine concentrations to stress levels (1,800 pg/ml) resulted in normal subjects in a significant increase in ketone body production by 155% (determined by use of [14C]acetoacetate infusions), in a decrease of the metabolic clearance rate by 38%, hyperketonemia, and in increased plasma free fatty acid (FFA) levels by 57% after 75 min. Norepinephrine infusion during somatostatin-induced insulin deficiency resulted in an augmented and sustained increase in ketone body concentrations due to increased production and decreased peripheral clearance of ketone bodies. Norepinephrine's stimulatory effect on lipolysis waned with time, and its effect on ketogenesis in normal subjects was greater than its influence on plasma FFA levels, and thus presumably on hepatic FFA uptake, suggesting a direct stimulatory effect on hepatic ketogenesis. The data demonstrate that in normal humans the hyperketonemic effect of elevated plasma norepinephrine concentrations results from a combination of three factors: increased ketone body production from augmented FFA supply to the liver; accelerated hepatic ketogenesis; and modestly decreased metabolic clearance of ketone bodies. Acute insulin deficiency augments all these effects and results in progressive ketosis.