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Original Article

Autonomic Blockade Improves Insulin Sensitivity in Obese Subjects

Alfredo Gamboa, Luis E. Okamoto, Amy C. Arnold, Rocio A. Figueroa, André Diedrich, Satish R. Raj, Sachin Y. Paranjape, Ginnie Farley, Naji Abumrad, Italo Biaggioni
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https://doi.org/10.1161/HYPERTENSIONAHA.114.03738
Hypertension. 2014;HYPERTENSIONAHA.114.03738
Originally published July 7, 2014
Alfredo Gamboa
From the Division of Clinical Pharmacology, Departments of Medicine (A.G., L.E.O., A.C.A., R.A.F., A.D., S.R.R., S.Y.P., G.F., I.B.), Pharmacology (S.R.R., I.B.), Biomedical Engineering (A.D.), and Surgery (N.A.), Vanderbilt University, Nashville, TN.
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Luis E. Okamoto
From the Division of Clinical Pharmacology, Departments of Medicine (A.G., L.E.O., A.C.A., R.A.F., A.D., S.R.R., S.Y.P., G.F., I.B.), Pharmacology (S.R.R., I.B.), Biomedical Engineering (A.D.), and Surgery (N.A.), Vanderbilt University, Nashville, TN.
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Amy C. Arnold
From the Division of Clinical Pharmacology, Departments of Medicine (A.G., L.E.O., A.C.A., R.A.F., A.D., S.R.R., S.Y.P., G.F., I.B.), Pharmacology (S.R.R., I.B.), Biomedical Engineering (A.D.), and Surgery (N.A.), Vanderbilt University, Nashville, TN.
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Rocio A. Figueroa
From the Division of Clinical Pharmacology, Departments of Medicine (A.G., L.E.O., A.C.A., R.A.F., A.D., S.R.R., S.Y.P., G.F., I.B.), Pharmacology (S.R.R., I.B.), Biomedical Engineering (A.D.), and Surgery (N.A.), Vanderbilt University, Nashville, TN.
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André Diedrich
From the Division of Clinical Pharmacology, Departments of Medicine (A.G., L.E.O., A.C.A., R.A.F., A.D., S.R.R., S.Y.P., G.F., I.B.), Pharmacology (S.R.R., I.B.), Biomedical Engineering (A.D.), and Surgery (N.A.), Vanderbilt University, Nashville, TN.
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Satish R. Raj
From the Division of Clinical Pharmacology, Departments of Medicine (A.G., L.E.O., A.C.A., R.A.F., A.D., S.R.R., S.Y.P., G.F., I.B.), Pharmacology (S.R.R., I.B.), Biomedical Engineering (A.D.), and Surgery (N.A.), Vanderbilt University, Nashville, TN.
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Sachin Y. Paranjape
From the Division of Clinical Pharmacology, Departments of Medicine (A.G., L.E.O., A.C.A., R.A.F., A.D., S.R.R., S.Y.P., G.F., I.B.), Pharmacology (S.R.R., I.B.), Biomedical Engineering (A.D.), and Surgery (N.A.), Vanderbilt University, Nashville, TN.
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Ginnie Farley
From the Division of Clinical Pharmacology, Departments of Medicine (A.G., L.E.O., A.C.A., R.A.F., A.D., S.R.R., S.Y.P., G.F., I.B.), Pharmacology (S.R.R., I.B.), Biomedical Engineering (A.D.), and Surgery (N.A.), Vanderbilt University, Nashville, TN.
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Naji Abumrad
From the Division of Clinical Pharmacology, Departments of Medicine (A.G., L.E.O., A.C.A., R.A.F., A.D., S.R.R., S.Y.P., G.F., I.B.), Pharmacology (S.R.R., I.B.), Biomedical Engineering (A.D.), and Surgery (N.A.), Vanderbilt University, Nashville, TN.
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Italo Biaggioni
From the Division of Clinical Pharmacology, Departments of Medicine (A.G., L.E.O., A.C.A., R.A.F., A.D., S.R.R., S.Y.P., G.F., I.B.), Pharmacology (S.R.R., I.B.), Biomedical Engineering (A.D.), and Surgery (N.A.), Vanderbilt University, Nashville, TN.
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Abstract

Obesity is an important risk factor for the development of insulin resistance. Initial compensatory mechanisms include an increase in insulin levels, which are thought to induce sympathetic activation in an attempt to restore energy balance. We have previously shown, however, that sympathetic activity has no beneficial effect on resting energy expenditure in obesity. On the contrary, we hypothesize that sympathetic activation contributes to insulin resistance. To test this hypothesis, we determined insulin sensitivity using a standard hyperinsulinemic euglycemic clamp protocol in obese subjects randomly assigned in a crossover design 1 month apart to receive saline (intact day) or trimetaphan (4 mg/min IV, autonomic blocked day). Whole-body glucose uptake (MBW in mg/kg per minute) was used as index of maximal muscle glucose use. During autonomic blockade, we clamped blood pressure with a concomitant titrated intravenous infusion of the nitric oxide synthase inhibitor N-monomethyl-L-arginine. Of the 21 obese subjects (43±2 years; 35±2 kg/m2 body mass index) studied, 14 were insulin resistant; they were more obese, had higher plasma glucose and insulin, and had higher muscle sympathetic nerve activity (23.3±1.5 versus 17.2±2.1 burst/min; P=0.03) when compared with insulin-sensitive subjects. Glucose use improved during autonomic blockade in insulin-resistant subjects (MBW 3.8±0.3 blocked versus 3.1±0.3 mg/kg per minute intact; P=0.025), with no effect in the insulin-sensitive group. These findings support the concept that sympathetic activation contributes to insulin resistance in obesity and may result in a feedback loop whereby the compensatory increase in insulin levels contributes to greater sympathetic activation.

  • autonomic nervous system
  • insulin resistance
  • obesity
  • Received April 21, 2014.
  • Revision received May 1, 2014.
  • Accepted June 13, 2014.
  • © 2014 American Heart Association, Inc.
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    Autonomic Blockade Improves Insulin Sensitivity in Obese Subjects
    Alfredo Gamboa, Luis E. Okamoto, Amy C. Arnold, Rocio A. Figueroa, André Diedrich, Satish R. Raj, Sachin Y. Paranjape, Ginnie Farley, Naji Abumrad and Italo Biaggioni
    Hypertension. 2014;HYPERTENSIONAHA.114.03738, originally published July 7, 2014
    https://doi.org/10.1161/HYPERTENSIONAHA.114.03738

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    Autonomic Blockade Improves Insulin Sensitivity in Obese Subjects
    Alfredo Gamboa, Luis E. Okamoto, Amy C. Arnold, Rocio A. Figueroa, André Diedrich, Satish R. Raj, Sachin Y. Paranjape, Ginnie Farley, Naji Abumrad and Italo Biaggioni
    Hypertension. 2014;HYPERTENSIONAHA.114.03738, originally published July 7, 2014
    https://doi.org/10.1161/HYPERTENSIONAHA.114.03738
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  • Epidemiology, Lifestyle, and Prevention
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  • Basic, Translational, and Clinical Research
    • Endothelium/Vascular Type/Nitric Oxide
    • Clinical Studies
    • Autonomic Nervous System

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