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

Abstract

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.

Beta‐adrenergic blockade restores glucose's antiketogenic activity after exercise in carbohydrate‐depleted athletes.

“…This conclusion has been supported by in vivo studies conducted by Bahnsen et al (1984), and by in vitro studies on isolated hepatocytes by Burrin, Farrer & Alberti (1982), Kosugi et al (1983) and Oberhaensli et al (1985). In keeping with our findings, the catecholamines' ketogenicity has been shown to be independent of the other major ketogenic hormones (glucagon and growth hormone), as their stimulatory action on 3-hydroxybutyrate production is augmented, rather than suppressed, by simultaneous somatostatin treatment (Beaufrere et al 1983;Bahnsen et al 1984;Keller et al 1984;Weis, Keller & Stauffacher, 1984). The plasma noradrenaline concentrations required for ketogenesis are generally, however, in the pharmacological or pathological range (> 1500 pg/ml) (Schade & Eaton, 1977Burrin et al 1982;Pernet et al 1983;Bahnsen et al 1984;Oberhaensli et al 1985), suggesting that if the catecholamines have a physiological role in ketone body homeostasis, they are acting as neurotransmitters, rather than as hormones on the liver.…”

“…Although infusions of adrenaline, noradrenaline and salbutamol in normal and insulin-dependent diabetic humans, have, in some studies (Schade & Eaton, 1977Silverberg, Shah, Haymond & Cryer, 1978;Giindogdu, Brown, Juul, Sachs & Sonksen, 1979;Clutter, Bier, Shah & Cryer, 1980;Pernet, Walker & Gill, 1983;Keller, Gerber & Stauffacher, 1984;Bahnsen, Burrin, Johnston, Pernet, Walker & Alberti, 1984;Berk, Clutter, Skor, Shah, Gingerich, Parvin & Cryer, 1985), been shown to cause moderate increases in the blood ketone body concentration, fl-adrenergic blockade has, to our knowledge, not previously been shown to have any antiketogenic effect (Rosen, Clutter, Shah, Miller, Bier & Cryer, 1983;Kosugi, Harano, Nakano, Suzuki, Kashiwagi & Shigeta, 1983;Beylot, Sautot, Dechaud, Cohen, Riou, Serusclat & Mornex, 1985;Oberhaensli, Schwendimann & Keller, 1985), except partially in somatostatin-induced hyperketonaemia (Beaufrere, Beylot, Riou, Serusclat, Cohen, Souquet & Mornex, 1983;Rosen et al 1983). This would indicate that f-adrenergic blockade will normally lower the blood ketone body concentration only in the absence of both insulin and glucagon.…”

Heart failure ketosis

“…First, neuroendocrine activation is common [1,13] and was seen in our study group as elevated concentrations of noradrenaline, cortisol and growth hormone in the circulation. All these hormones promote ketogenesis by increasing the supply of free fatty acids through a lipolytic action which is particularly prominent if the antilipolytic effect of insulin is blunted [14][15][16][17][18][19]. Noradrenaline may also have a direct ketogenic action in the liver and can reduce the clearance of ketone bodies in the periphery [15].…”

“…All these hormones promote ketogenesis by increasing the supply of free fatty acids through a lipolytic action which is particularly prominent if the antilipolytic effect of insulin is blunted [14][15][16][17][18][19]. Noradrenaline may also have a direct ketogenic action in the liver and can reduce the clearance of ketone bodies in the periphery [15]. Another factor that could favour ketogenesis in CHF is an imbalance between the supply and need of calories.…”

Management of Hyperglycemic Crises in Patients With Diabetes

“…In addition, epinephrine facilitates hepatic ketogenesis directly (82,83). Norepinephrine at concentrations that approximate those seen in the synaptic cleft stimulates lipolysis by adipocytes and enhances ketogenesis (84,85).…”