Epinephrine-induced Insulin Resistance in Man

Deibert, David; DeFronzo, Ralph A.

doi:10.1172/jci109718

Cited by 514 publications

(281 citation statements)

References 22 publications

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“…Blockade of β 2 ‐receptors seems to have a more profound effect than blockade of β 1 ‐receptors 5, 18. In addition, sympathetic activation can decrease the secretion of leptin,17 exacerbate insulin resistance,18 and promote the release of proinflammatory cytokines,19 all of which can lead to wasting of adipose and muscle cells.…”

Section: Discussionmentioning

confidence: 99%

Effect of beta‐adrenergic blockade with carvedilol on cachexia in severe chronic heart failure: results from the COPERNICUS trial

Clark

Coats

Krum

et al. 2017

J cachexia sarcopenia muscle

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BackgroundCardiac cachexia frequently accompanies the progression of heart failure despite the use of effective therapies for left ventricular dysfunction. Activation of the sympathetic nervous system has been implicated in the pathogenesis of weight loss, but the effects of sympathetic antagonism on cachexia are not well defined.MethodsWe prospectively evaluated changes in body weight in 2289 patients with heart failure who had dyspnoea at rest or on minimal exertion and a left ventricular ejection fraction <25%. Patients were randomly assigned (double‐blind) to receive either placebo (n = 1133) or carvedilol (n = 1156) and were followed for the occurrence of major clinical events for up to 29 months (COPERNICUS trial). Patients were not enrolled if they had signs of clinically significant fluid retention due to heart failure.ResultsPatients in the carvedilol group were 33% less likely than patients in the placebo group to experience a further significant loss of weight (>6%) (95% confidence interval: 14–48%, P = 0.002) and were 37% more likely to experience a significant gain in weight (≥5%) (95% confidence interval: 12–66%, P = 0.002). Carvedilol's ability to prevent weight loss was most marked in patients with increased body mass index at baseline, whereas its ability to promote weight gain was most marked in patients with decreased body mass index at baseline. Increases in weight were not accompanied by evidence of fluid retention. Baseline values for body mass index and change in body weight were significant predictors of survival regardless of treatment.ConclusionsCarvedilol attenuated the development and promoted a partial reversal of cachexia in patients with severe chronic heart failure, supporting a role for prolonged sympathetic activation in the genesis of weight loss.

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Section: Discussionmentioning

confidence: 99%

Effect of beta‐adrenergic blockade with carvedilol on cachexia in severe chronic heart failure: results from the COPERNICUS trial

Clark

Coats

Krum

et al. 2017

J cachexia sarcopenia muscle

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“…The cause of insulin resistance is multifactorial and has been related to hormonal and metabolic abnormalities [13,[31][32][33][34][35][36][37][38][39][40][41][43][44][45][46][47][48][49][50][51]. In contrast with Type 1 diabetes, in chronic renal failure high polypeptide hormone levels, are not necessarily the result of hypersecretion, but can be due to clearance defects.…”

Section: Discussionmentioning

confidence: 99%

Reduction of insulin resistance by combined kidney-pancreas transplantation in Type 1 (insulin-dependent) diabetic patients

et al. 1990

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Summary.To evaluate the effect of combined kidney and pancreas transplantation on insulin action and glucose metabolism, 15 Type 1 (insulin-dependent) diabetic patients who were undergoing combined kidney-pancreas transplantation were studied before transplantation by means of the euglycaemic hyperinsulinaemic clamp technique combined with 3-3H-glucose infusion and indirect calorimetry. Nine of the original 15 patients were studied again after four months and six after 12 months, successful combined kidney-pancreas transplantation with the same experimental protocol. Nine volunteers formed the group of normal subjects. Combined kidney-pancreas transplantation normalised hepatic glucose production and reduced peripheral insulin resistance in Type 1 diabetic uraemic patients, despite chronic immunosuppressive therapy. To further evaluate the hypothesis that residual insulin resistance was due to chronic steroid therapy, 11 additional subjects with chronic uveitis (six of whom were treated with only prednisone, and five treated only with cyclosporin) underwent the same protocol demonstrating a normal hepatic glucose production. The insulin-stimulated peripheral glucose uptake was reduced in the prednisonetreated group, but normal in cyclosporin-treated subjects. Four additional diabetic patients with a kidney transplant were also studied. They showed a peripheral insulin sensitivity intermediate between diabetic uraemic patients and patients after combined transplant. We conclude that shortterm (one year) combined kidney-pancreas transplantation improves glucose metabolism by restoring normal rates of hepatic glucose production and reducing peripheral insulin resistance; chronic steroid therapy is the major determinant of residual reduced insulin action. Both kidney and pancreas substitution play a role in reducing peripheral insulin resistance.

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“…There is also direct evidence contrary to the hypothesis that blood flow is an independent regulator of insulin-stimulated glucose uptake in humans [17]. In view of the contradictory data, we studied the relation between muscle blood flow and metabolism during b-adrenergic stimulation, which is known to induce insulin resistance as well as peripheral vasodilation [1]. In a recent study on the human leg, the haemodynamic effects exerted by epinephrine were suggested to be an important compensating factor for the altered insulin sensitivity [18].…”

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Induction of rat muscle insulin resistance by epinephrine is accompanied by increased interstitial glucose and lactate concentrations

1998

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Epinephrine and b-adrenergic stimulation rapidly inhibit insulin-mediated glucose uptake by induction of insulin resistance mainly in the skeletal muscle [1,2]. The insulin signalling pathway may be altered by b-adrenergic stimulation both by cAMP and cAMP independent mechanisms [3]. An inhibitory action at multiple sites is suggested since the insulin signal is disturbed at the receptor level [4] as well as in the tyrosine kinase [5], the glucose transporter protein [6] and the glycolytic pathway [7]. Moreover, induction of lipolysis by b-adrenergic stimuli leads to decreased oxidation of glucose through the action of the Randle cycle [8].The glucose transporter protein is considered to be rate-limiting for insulin-stimulated glucose uptake in the muscle. Moreover, recent research has emphasized the importance of the capillary wall as a major determinant of the transendothelial delivery of glucose [9] and insulin [10] in skeletal muscle since the interstitial concentrations of glucose and insulin are lower than those in the arterial plasma [9,10]. This is further supported by the findings that the insulin-[11] and glucose-[12] stimulated increase in muscle blood flow correlates with glucose uptake in normal as well as in insulin resistant muscles [13].The importance of blood flow for the rate of delivery of glucose and insulin to the muscles is, however, Diabetologia (1998) Summary Muscle glucose uptake and lactate release during b-adrenergic stimulation by epinephrine (epi) and b-adrenergic blockade by propranolol (prop) were investigated during an euglycaemic hyperinsulinaemic (30 pmol × kg ±1 × min ±1 ) with or without added somatostatin (0.1 mg/min; pancreatic) clamp in female rats. To assess the interstitial insulin, glucose and lactate concentrations, microdialysis was done in the medial femoral muscle in both legs. The influence of muscle skeletal blood flow on interstitial insulin, glucose and lactate was examined with the microsphere technique, using 57 Co-microspheres. Epinephrine decreased glucose infusion rate by about 75 % (p < 0.0001) and increased concentrations of interstitial glucose by about 35 % (p < 0.001) and lactate by about 65 % (p < 0.01). Plasma insulin concentration increased during b-adrenergic stimulation by about 25 % (p < 0.05) whereas the interstitial insulin concentration was unchanged. Muscle blood flow in the hindlimb was considerably enhanced by about 130 %, (p < 0.001) by epinephrine. Infusion of propranolol totally abolished all the above effects induced by epinephrine. The data show that insulin resistance and vasodilation induced by b-adrenergic stimulation with epinephrine is accompanied by increased interstitial glucose as well as lactate concentrations in muscle. The increased interstitial glucose concentration is the result of a decreased cellular uptake of glucose together with an increased capillary delivery of glucose by vasodilation. It is concluded that the severe cellular resistance to insulin induced by epinephrine could not be overcome either by the increased...

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Epinephrine-induced Insulin Resistance in Man

Cited by 514 publications

References 22 publications

Effect of beta‐adrenergic blockade with carvedilol on cachexia in severe chronic heart failure: results from the COPERNICUS trial

Effect of beta‐adrenergic blockade with carvedilol on cachexia in severe chronic heart failure: results from the COPERNICUS trial

Reduction of insulin resistance by combined kidney-pancreas transplantation in Type 1 (insulin-dependent) diabetic patients

Induction of rat muscle insulin resistance by epinephrine is accompanied by increased interstitial glucose and lactate concentrations

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