Hormonal effects of norepinephrine on acute glucose disposal in humans: A minimal model analysis

Marangou, Andreas G.; Alford, F. P.; Ward, Glenn; Liskaser, Frank; Aitken, P.; Weber, Kathryn M.; Boston, Raymond C.; Best, James D.

doi:10.1016/0026-0495(88)90124-2

Cited by 80 publications

(43 citation statements)

References 39 publications

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“…Another potential confounder that deserves comment is the possible role of norepinephrine (NE), which can be elevated by Epi and glucose infusions (8). The simultaneous increase of NE could at least partly explain the decreased glucose clearance and the delayed suppression of EGP (17).…”

Section: Discussionmentioning

confidence: 99%

Epinephrine effects on insulin-glucose dynamics: the labeled IVGTT two-compartment minimal model approach

Vicini

Avogaro²,

Spilker

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

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effects on insulin-glucose dynamics: the labeled IVGTT two-compartment minimal model approach. Am J Physiol Endocrinol Metab 283: E78-E84, 2002; 10.1152/ajpendo. 00530.2001.-The hyperglycemic effects of epinephrine (Epi) are established; however, the modulation of Epi-stimulated endogenous glucose production (EGP) by glucose and insulin in vivo in humans is less clear. Our aim was to determine the effect of exogenously increased plasma Epi concentrations on insulin and glucose dynamics. In six normal control subjects, we used the labeled intravenous glucose tolerance test (IVGTT) interpreted with the two-compartment minimal model, which provides not only glucose effectiveness (S G 2* ), insulin sensitivity (S I 2* ), and plasma clearance rate (PCR) at basal state, but also the time course of EGP. Subjects were randomly studied during either saline or Epi infusion (1.5 g/min). Exogenous Epi infusion increased plasma Epi concentration to a mean value of 2,034 Ϯ 138 pmol/l. During the stable-label IVGTT, plasma glucose, tracer glucose, and insulin concentrations were significantly higher in the Epi study. The hormone caused a significant (P Ͻ 0.05) reduction in PCR in the Epi state when compared with the basal state. The administration of Epi has a striking effect on EGP profiles: the nadir of the EGP profiles occurs at 21 Ϯ 7 min in the basal state and at 55 Ϯ 13 min in the Epi state (P Ͻ 0.05). In conclusion, we have shown by use of a two-compartment minimal model of glucose kinetics that elevated plasma Epi concentrations have profound effects at both hepatic and tissue levels. In particular, at the liver site, this hormone deeply affects, in a time-dependent fashion, the inhibitory effect of insulin on glucose release. Our findings may explain how even a normal subject may have the propensity to develop glucose intolerance under the influence of small increments of Epi during physiological stress. insulin action; endogenous glucose production; glucose effectiveness THE AUTONOMIC NERVOUS SYSTEM modulates glucose and fat metabolism through both direct neural effects and hormonal effects. In humans, epinephrine (Epi) stimulates lipolysis, ketogenesis, thermogenesis, and glycolysis and raises plasma glucose concentrations by stimulating both glycogenolysis and gluconeogenesis (9). At the liver site, Epi increases hepatic glucose production either directly by stimulating glycogenolysis or indirectly by increasing gluconeogenesis, which is responsible for 60% of the overall increase in hepatic glucose production (19). These effects are exerted through both ␣-and ␤-adrenergic stimuli (20,21).Although the hyperglycemic effects of Epi on the liver are firmly established, less clear is the modulation of Epi-stimulated endogenous glucose production (EGP) by insulin in vivo in humans. In rat studies, it was shown that, when Epi is combined with insulin infusion, there is a 50% reduction in liver glycogen content with evidence for a transient activation of hepatic glucose output by Epi in the initial 60 min of its exposur...

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Section: Discussionmentioning

confidence: 99%

Epinephrine effects on insulin-glucose dynamics: the labeled IVGTT two-compartment minimal model approach

Vicini

Avogaro²,

Spilker

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

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“…The second hypothesis is suggested by the fact that circulating free fatty acids are increased in heart failure (50), possibly as a consequence of the increased norepinephrine concentrations seen in heart failure (51). Norepinephrine can increase free fatty acid (FFA) levels (52), and FFA in turn can decrease glucose utilization both in heart (5) and skeletal muscle (53) by substrate competition (54). Because norepinephrine levels would be expected to be higher in the patients with the largest reduction in ejection fraction, cardiac insulin resistance should be proportional to the ejection fraction.…”

Section: Discussionmentioning

confidence: 99%

Cardiac and skeletal muscle insulin resistance in patients with coronary heart disease. A study with positron emission tomography.

Paternostro¹,

Camici²,

Lammerstma³

et al. 1996

J. Clin. Invest.

145

106

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Patients with coronary artery disease or heart failure have been shown to be insulin resistant. Whether in these patients heart muscle participates in the insulin resistance, and whether reduced blood flow is a mechanism for such resistance is not known. We measured heart and skeletal muscle blood flow and glucose uptake during euglycemic hyperinsulinemia (insulin clamp) in 15 male patients with angiographically proven coronary artery disease and chronic regional wall motion abnormalities. Six age-and weightmatched healthy subjects served as controls. Regional glucose uptake was measured by positron emission tomography using [

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“…56 Infusion studies in volunteers support a role for increased norepinephrine levels in HF as a cause of elevated plasma FFA. 57 In turn, FFAs reciprocally augment SNS activity, at least in normal controls. 58 In human skeletal muscle, a dose-response relationship exists between plasma FFA 27,59,60,61 and defects in insulin signaling.…”

Section: Adrenergic Mechanisms That Underlie Altered Myocardial Metabmentioning

confidence: 99%

Metabolic Mechanisms in Heart Failure

Ashrafian

Frenneaux

Opie³

2007

Circulation

457

301

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Abstract-Although neurohumoral antagonism has successfully reduced heart failure morbidity and mortality, the residual disability and death rate remains unacceptably high. Though abnormalities of myocardial metabolism are associated with heart failure, recent data suggest that heart failure may itself promote metabolic changes such as insulin resistance, in part through neurohumoral activation. A detrimental self-perpetuating cycle (heart failure 3 altered metabolism 3 heart failure) that promotes the progression of heart failure may thus be postulated. Accordingly, we review the cellular mechanisms and pathophysiology of altered metabolism and insulin resistance in heart failure. It is hypothesized that the ensuing detrimental myocardial energetic perturbations result from neurohumoral activation, increased adverse free fatty acid metabolism, decreased protective glucose metabolism, and in some cases insulin resistance. The result is depletion of myocardial ATP, phosphocreatine, and creatine kinase with decreased efficiency of mechanical work. On the basis of the mechanisms outlined, appropriate therapies to mitigate aberrant metabolism include intense neurohumoral antagonism, limitation of diuretics, correction of hypokalemia, exercise, and diet. We also discuss more novel mechanistic-based therapies to ameliorate metabolism and insulin resistance in heart failure. For example, metabolic modulators may optimize myocardial substrate utilization to improve cardiac function and exercise performance beyond standard care. The ultimate success of metabolic-based therapy will be manifest by its capacity further to lessen the residual mortality in heart failure. Key Words: fatty acids Ⅲ glucose Ⅲ heart failure Ⅲ insulin resistance D espite significant therapeutic advances, heart failure (HF) remains a leading cause of morbidity and mortality in developed 1 and increasingly in developing countries, 2 with a 5-year mortality rate of Ϸ50%, which rivals or exceeds that of many cancers. 3 This unacceptably high residual mortality and morbidity has mandated a reevaluation of cardiac biology with the aim to identify novel therapeutic strategies for HF. Because the daily turnover of ATP (Ϸ6 to 35 kg) is very many times that of the myocardial ATP pool, and even the healthy heart only extracts Ϸ25% of energy derivable from substrates, 4 it is not surprising that even subtle variations in the efficiency of energy generation or utilization may have a profound cumulative impact on cellular energy levels. 5 Thus cardiac energetics in particular and metabolism in general represent promising targets for HF therapy. 6 Correspondingly, numerous studies have identified decreased cardiac energy levels and flux as a consistent feature of HF. 6,7 These observations have been reinforced by genomic studies 8 and have focused considerable attention on metabolic modulation as a therapy for HF. 6 Specifically, altered myocardial carbohydrate metabolism and the related state of myocardial insulin resistance (IR), in which given concentrations of...

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Hormonal effects of norepinephrine on acute glucose disposal in humans: A minimal model analysis

Cited by 80 publications

References 39 publications

Epinephrine effects on insulin-glucose dynamics: the labeled IVGTT two-compartment minimal model approach

Epinephrine effects on insulin-glucose dynamics: the labeled IVGTT two-compartment minimal model approach

Cardiac and skeletal muscle insulin resistance in patients with coronary heart disease. A study with positron emission tomography.

Metabolic Mechanisms in Heart Failure

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